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Simple Summary: Acute promyelocytic leukemia (APL) stands as a remarkable success in achieving high cure rates with chemotherapy-free treatment regimens. Despite these remarkable outcomes, hematologists managing patients with APL take into consideration the distinct side effects associated with the two dual differentiation agents, i.e., all-transretinoic acid (ATRA) and arsenic trioxide (ATO). The objective of this paper is to review relevant literature data and discuss the recommended management strategies of non-hematologic early and late complications that arosein patients diagnosed with APL who were treated with ATO and ATRA-based regimens. The hallmark of acute promyelocytic leukemia (APL) is the presence of the characteristic fusion transcript of the promyelocytic leukemia gene with the retinoic acid receptor α gene (PML::RARA). The PML::RARA fusion is a molecular target for all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). Therapies based on ATRA plus ATO have excellent outcomes in terms of complete remission rates, overall survival, and achievement of deep and durable molecular responses with a very low incidence of relapse. However, although the combination of ATRA and ATO has lower hematologic toxicity than standard chemotherapy, its use is associated with a spectrum of distinctive toxicities, such as differentiation syndrome, liver toxicity, QT interval prolongation, and neurotoxicity. Rigorous monitoring of patients' clinical evolution is indispensable for identifying and addressing each complication. The objective is to maintain an equilibrium between treatment-induced adverse events and therapeutic efficacy. This paper focused on non-hematologic complications associated with the combination of ATRA and ATO. Additionally, we discuss late-onset complications of this therapy. In summary, the majority of treatment-related adverse events are manageable, self-limiting, and reversible. More so, there seems to be a lower incidence rate of secondary neoplasms compared to standard chemotherapy. However, further research is required to assess how the ATRA plus ATO regimen affects the emergence of additional comorbidities. [ABSTRACT FROM AUTHOR]

Simple Summary: Patients with advanced non-small cell lung cancer (NSCLC) with epidermal growth factor receptor gene (EGFR) Exon 20 insertion mutations (Exon20ins) used to have poor outcomes after the failure of platinum-based therapies. Amivantamab, a drug that targets two proteins involved in NSCLC (EGFR/MET), was developed and studied in the CHRYSALIS clinical trial. This paper summarizes an analysis comparing outcomes for amivantamab from CHRYSALIS to the outcomes for a mix of treatments that were used in real-world clinical practice (real-world physician's choice [RWPC]). RWPC data were collected from hospitals across Europe in the CATERPILLAR real-world evidence (RWE) study. The outcomes of 114 patients from CHRYSALIS were compared to 55 lines of treatment (LOTs) from CATERPILLAR-RWE, accounting for differences in patient characteristics between the two populations. Overall, the results show that amivantamab was at least twice as good as RWPC for platinum pre-treated patients in terms of tumor response and survival rates. Patients with advanced non-small cell lung cancer (NSCLC) with epidermal growth factor receptor gene (EGFR) Exon 20 insertions (Exon20ins) at the second line and beyond (2L+) have an unmet need for new treatment. Amivantamab, a bispecific EGFR- and MET-targeted antibody, demonstrated efficacy in this setting in the phase 1b, open-label CHRYSALIS trial (NCT02609776). The primary objective was to compare the efficacy of amivantamab to the choices made by real-world physicians (RWPC) using an external control cohort from the real-world evidence (RWE) chart review study, CATERPILLAR-RWE. Adjustment was conducted to address differences in prognostic variables between cohorts using inverse probability weighting (IPW) and covariate adjustments based on multivariable regression. In total, 114 patients from CHRYSALIS were compared for 55 lines of therapy from CATERPILLAR-RWE. Baseline characteristics were comparable between the amivantamab and IPW-weighted RWPC cohorts. For amivantamab versus RWPC using IPW adjustment, the response rate ratio for the overall response was 2.14 (p = 0.0181), and the progression-free survival (PFS), time-to-next-treatment (TTNT) and overall survival (OS) hazard ratios (HRs) were 0.42 (p < 0.0001), 0.47 (p = 0.0063) and 0.48 (p = 0.0207), respectively. These analyses provide evidence of clinical and statistical benefits across multiple outcomes and adjustment methods, of amivantamab in platinum pre-treated patients with advanced NSCLC harboring EGFR Exon20ins. These results confirm earlier comparisons versus pooled national registry data. [ABSTRACT FROM AUTHOR]

Simple Summary: The research paper reported on a newly developed screening technique called Microtube Array Membrane Hollow Fiber Assay (MTAM-HFA) used for determining the most effective medication for breast cancer patients. The study found that the MTAM-HFA approach had a high level of accuracy in predicting the patient's response to the medication therapy, and there was a significant correlation between the screening outcome and the clinical outcome. The findings suggest that the MTAM-HFA technique has great potential for developing customized therapy for cancer care. With its ability to identify precise therapies for breast cancer patients, the MTAM-HFA screening method could transform cancer therapy, resulting in better outcomes for patients. The study provides valuable information for healthcare professionals and researchers working on breast cancer therapy research. Breast cancer is a severe public health problem, and early treatment with powerful anticancer drugs is critical for success. The researchers investigated the clinical results of a novel screening tool termed Microtube Array Membrane Hollow Fiber Assay (MTAM-HFA) in breast cancer patients in this clinical investigation. In all trial participants, the MTAM-HFA was utilized to identify active medicines for the treatment of breast cancer. The MTAM-HFA was shown to be extremely useful in predicting patient response to anticancer medication therapy in this study. Furthermore, the substantial association between the MTAM-HFA screening outcome and the clinical outcome of the respective patients emphasizes the promise of this unique screening technology in discovering effective anticancer medication combinations for the treatment of breast cancer. These findings indicate that the MTAM-HFA has clinical significance and might be a valuable tool in the development of tailored therapy for cancer care. This study provides helpful information for physicians and scientists working on breast cancer therapy research. The potential benefits of employing MTAM-HFA to find accurate therapies for breast cancer patients might lead to enhanced personalized medicine approaches to cancer care, resulting in better patient outcomes. Overall, the MTAM-HFA screening approach has the potential to revolutionize customized cancer therapy, providing hope to both patients and physicians. [ABSTRACT FROM AUTHOR]

Simple Summary: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract, mostly driven by activating mutations in KIT or PDGFRα oncogenes. The introduction of tyrosine kinase inhibitors (TKIs) has revolutionized the treatment of GIST resulting in a substantial gain in median overall survival. Nowadays, imatinib, sunitinib, regorafenib, and ripretinib are registered as first, second, third, and fourth-line therapies, and avapritinib is registered specifically for GISTs harboring a PDGFRα exon 18/D842V mutation. As a result, health-related quality of life (HRQoL) has become more relevant for this surviving population, which is increasing in number. In daily clinical practice, the side effects of TKIs and their impact on the daily lives of patients are the main reason for treatment adjustments. Currently, an overview of HRQoL issues and side effects of different TKIs registered for the treatment of GIST is lacking. Background: The introduction of tyrosine kinase inhibitors (TKIs) has revolutionized the treatment of gastrointestinal stromal tumors (GISTs), resulting in a substantial gain in median overall survival. Subsequently, health-related quality of life (HRQoL) has become more relevant. Here, we systematically review the available literature on HRQoL issues and side effects of different TKIs registered for the treatment of GIST. Methods: A search through five databases was performed. Full reports in English describing HRQoL outcomes and/or side effects in GIST patients on TKI therapy were included. Results: A total of 104 papers were included; 13 studies addressed HRQoL, and 96 studies investigated adverse events. HRQoL in patients treated with imatinib, regorafenib, and ripretinib remained stable, whereas most sunitinib-treated patients reported a decrease in HRQoL. Severe fatigue and fear of recurrence or progression were specifically assessed as HRQoL issues and had a negative impact on overall HRQoL as well as psychological and physical well-being. The majority of studies focused on physician-reported side effects. Nearly all GIST patients treated with a TKI experienced at least one adverse event, mostly mild to moderate. Conclusions: Despite the fact that almost all patients treated with a TKI experienced side effects, this did not seem to affect overall HRQoL during TKI therapy. In daily practice, it are the side effects that hamper a patient's HRQoL resulting in treatment adjustments, suggesting that the reported side effects were underestimated by physicians, or the measures used to assess HRQoL do not capture all relevant issues that determine a GIST patient's HRQoL. [ABSTRACT FROM AUTHOR]

Simple Summary: Squamous cell carcinoma of the anus or anal cancer is increasing in prevalence, and the standard treatment of mitomycin and 5-fluorouracil is too toxic for many patients. Unfortunately, there is currently no standard of care for what to do for this disease when someone is not a candidate for this aggressive treatment. Here, we demonstrate the promising preliminary toxicity profile and efficacy of the combination of weekly carboplatin and paclitaxel chemotherapy for patients with localized anal cancer. This regimen was able to complete 80% of the intended treatments with anticipated toxicities, and 89% achieved a complete clinical response. This combination is a promising regimen and is already being investigated further in a clinical trial. Background: Although squamous cell carcinoma of the anus (SCCA) is a relatively uncommon malignancy in the United States, it continues to increase in incidence. Treatment for locoregional disease includes mitomycin and 5-fluorouracil with radiation. This combination is associated with significant toxicity, limiting its use in patients who are older or have certain comorbidities. Carboplatin and paclitaxel (C/P) is an accepted treatment regimen for metastatic SCCA. We aim to evaluate the efficacy and toxicity of weekly C/P given with radiation for patients unable to receive standard chemoradiation for SCCA. Methods: From our cancer registry, adult patients who received weekly intravenous C/P concurrent with standard-dose radiation for localized SCCA were included in this study. Clinical response was determined based on the evidence of disease on imaging and/or anoscopy. Toxicities were graded according to the CTCAE v5. Results: Ten patients were included; eight were female, and the median age was 75.5 years (54–87). Six had T2 disease, and four had T3 tumors. Four had node-positive disease. The majority (70%) of patients were dosed at standard C (AUC 2) and P (50 mg/m2), with a limited subset requiring dose reduction for baseline performance status. Patients completed a mean of 78.3% (40–100%) of the intended treatments. A total of 89% of the patients achieved a complete clinical response. With a median follow-up of 25.8 months (3.4–50.4 months), 67% of the patients are alive and without recurrence. Two patients have had local recurrence, and one patient had metastatic progression. The most common toxicities of any grade included leukopenia (100%), anemia (100%), radiation dermatitis (100%), diarrhea (100%), and fatigue (100%). Grade 3 or higher toxicities included neutropenic fever (20%), neutropenia (30%), and anemia (30%). Conclusions: This study demonstrates promising tolerability and efficacy for weekly C/P chemoradiation for patients with anal cancer unable to receive mitomycin and 5-fluorouracil. This regimen merits further investigation in prospective clinical trials. [ABSTRACT FROM AUTHOR]

Simple Summary: This study aimed to evaluate the derived neutrophil to lymphocyte ratio (dNLR) in predicting the prognosis of patients with locally advanced oral squamous cell carcinoma, as well as the survival benefits from induction chemotherapy with docetaxel, cisplatin, and 5-fluorouracil (5-FU). The dNLR is an independent negative predictive factor for the disease. Patients with cTNM stage III disease and a low dNLR may benefit from induction chemotherapy. Background: This study aimed to evaluate the derived neutrophil to lymphocyte ratio (dNLR) in predicting the prognosis of patients with locally advanced oral squamous cell carcinoma (LAOSCC) and to assess the survival benefits from docetaxel, cisplatin, and 5-fluorouracil (5-FU) (TPF) induction chemotherapy (IC). Methods: Patients from a phase III trial involving TPF IC in stage III/IVA OSCC patients (NCT01542931) were enrolled. Receiver operating characteristic curves were constructed, and the area under the curve was computed to determine dNLR cutoff points. Kaplan–Meier survival estimates and Cox proportional hazards models were used for longitudinal analysis. Results: A total of 224 patients were identified (median age: 55.4 years; range: 26 to 75 years; median follow-up: 90 months; range: 3.2 to 93 months). The cutoff point for the dNLR was 1.555. Multivariate analysis showed that the dNLR was an independent negative predictive factor for survival (overall survival (OS): hazard ratio (HR) = 1.154, 95% confidence interval (CI): 1.018–1.309, p = 0.025; disease-free survival (DFS): HR = 1.123, 95% CI: 1.000–1.260, p = 0.050; local recurrence-free survival (LRFS): HR = 1.134, 95% CI: 1.002–1.283, p = 0.047; distant metastasis-free survival (DMFS): HR = 1.146, 95% CI: 1.010–1.300, p = 0.035). A low dNLR combined with cTNM stage III disease predicted benefit from TPF IC for the patients [OS (χ2 = 4.674, p = 0.031), DFS (χ2 = 7.134, p = 0.008), LRFS (χ2 = 5.937, p = 0.015), and DMFS (χ2 = 4.832, p = 0.028)]. Conclusions: The dNLR is an independent negative predictive factor in LAOSCC patients. Patients with cTNM stage III disease and a low dNLR can benefit from TPF IC. [ABSTRACT FROM AUTHOR]

Simple Summary: Roughly 430,000 new cases of renal cell carcinoma (RCC) occurred worldwide in 2022, and about one-third of RCC cases are diagnosed at an advanced stage of disease (aRCC). When patients with aRCC fail first-line treatment, they commonly receive one of the recommended second-line treatments, i.e., axitinib, cabozantinib, lenvatinib plus everolimus, pazopanib, sunitinib, or tivozanib. Axitinib is a second-generation tyrosine kinase inhibitor that inhibits vascular endothelial growth factor receptor tyrosine kinases 1, 2, and 3. It has been available since 2011 for the treatment of aRCC after the failure of prior therapy with sunitinib or cytokines. The aim of our research was to understand how axitinib compares with other treatment options considering data from clinical trials and observational studies that reflect real-world clinical practice. Therefore, we conducted a systematic literature review to summarise evidence on commonly used and recommended treatments in aRCC after the failure of prior therapy with sunitinib or cytokines. Background: We conducted a systematic literature review (SLR) to identify clinical evidence on treatments in advanced renal cell carcinoma (aRCC) after the failure of prior therapy with cytokines, tyrosine kinase inhibitors, or immune checkpoint inhibitors. Herein, we summarise the evidence for axitinib in aRCC after the failure of prior therapy with cytokines or sunitinib. Methods: This SLR was registered with PROSPERO (CRD42023492931) and followed the 2020 PRISMA statement and the Cochrane guidelines. Comprehensive searches were conducted in MEDLINE and Embase as well as for conference proceedings. Study eligibility was defined according to population, intervention, comparator, outcome, and study design. Results: Of 1252 titles/abstracts screened, 266 peer-reviewed publications were reviewed, of which 182 were included. In addition, 28 conference abstracts were eligible. Data on axitinib were reported in 55 publications, of which 16 provided efficacy and/or safety outcomes on axitinib after therapy with sunitinib or cytokines. In these patients, median progression-free and overall survival ranged between 5.5 and 8.7 months and 11.0 and 69.5 months, respectively. Conclusions: Axitinib is commonly used in clinical practice and has a well-characterised safety and efficacy profile in the treatment of patients with aRCC after the failure of prior therapy with sunitinib or cytokines. [ABSTRACT FROM AUTHOR]

Simple Summary: High-dose post-transplant cyclophosphamide is effective in preventing graft-versus-host disease (GVHD) but is associated with adverse outcomes such as delayed engraftment, infections, and cardiac issues. This pilot study evaluated the efficacy and toxicity of reduced-dose PTCY (40 mg/kg/day) in patients undergoing HLA-matched allogeneic hematopoietic stem cell transplantation (alloHSCT). Neutrophil and platelet engraftment occurred at medians of 15 and 16 days, respectively. At day 100, the incidences of grade II–IV and III–IV acute GVHD were 18.2% and 4.5%, respectively, with no cases of grade IV acute GVHD or steroid-refractory disease. One-year incidence of moderate-severe chronic GVHD was 6.4%. Both incidences, acute GVHD and chronic GVHD, are similar to our previous experience with higher doses of PTCY. Two-year overall survival and relapse-free survival were 77.1% and 58.3%. There were low incidences of infections and only one early cardiac event. These results suggest that reduced-dose PTCY provides adequate immunosuppression with a low toxicity profile. PTCY 50 mg/kg/day on days +3/+4 is an excellent strategy to prevent GVHD. However, its use is associated with adverse outcomes such as delayed engraftment, increased risk of infection, and cardiac complications. This pilot study evaluates the efficacy and toxicity of a reduced dose of PTCY (40 mg/kg/day) combined with tacrolimus in 22 peripheral blood HLA-matched alloHSCT patients. At day +100, the cumulative incidences of grade II–IV and III–IV acute GVHD were 18.2% and 4.5%, respectively. No grade IV acute GVHD or steroid-refractory disease was observed. The cumulative incidences of all-grade and moderate-severe chronic GVHD at 1-year were 11.4% and 6.4%, respectively. No patient died from transplant-related complications. Two-year OS and RFS were 77.1% and 58.3%, respectively. All patients engrafted, with neutrophil and platelet recovery occurring at a median of 15 (IQR 14–16) and 16 days (IQR 12–23), respectively. The cumulative incidences of bloodstream bacterial infections, polyomavirus BK hemorrhagic cystitis, HHV6 reactivation, CMV reactivation, and fungal infections were 13.6%, 9.1%, 9.1%, 4.6%, and 6%, respectively. Only one early cardiac event was observed. These results suggest that PTCY 40 mg/kg/day on a +3/+4 schedule provides adequate immunosuppression to allow for engraftment and prevent clinically significant GVHD with a low toxicity profile. [ABSTRACT FROM AUTHOR]

Simple Summary: Neoadjuvant chemotherapy in breast cancer facilitates breast and axillary surgery and offers significant prognostic value. We present a retrospective cohort of 482 stage II and III breast cancer patients treated with neoadjuvant chemotherapy based on anthracycline and taxans, plus antiHER2 in HER2-positive cases. The 10-year estimated disease free survival was 77.3% (95%CI 73.3–81.4%) and the Breast cancer specific survival 83.7% (95%CI 80.3–87.2%). The statistically independent factors related to patient survival were pathology subtype (lobular cancers HR, 4); molecular surrogate subtype (triple negative HR, 4); type of surgery (mastectomy HR, 2), response to chemotherapy (the risk incremented according to the residual cancer burden in 2.2, 4.4 and 8.0 times in I, II and III, respectively) and vascular invasion (HR, 2.4). BRCA carriers presented a longer survival, with an estimated 10 years DDFS of 89.6% vs. 77.2% for non-carriers, p = 0.054. Long-term outcomes after neoadjuvant chemotherapy can help patients and clinicians make well-informed decisions. Introduction: Neoadjuvant chemotherapy in breast cancer offers the possibility to facilitate breast and axillary surgery; it is a test of chemosensibility in vivo with significant prognostic value and may be used to tailor adjuvant treatment according to the response. Material and Methods: A retrospective single-institution cohort of 482 stage II and III breast cancer patients treated with neoadjuvant chemotherapy based on anthracycline and taxans, plus antiHEr2 in Her2-positive cases, was studied. Survival was calculated at 5 and 10 years. Kaplan–Meier curves with a log-rank test were calculated for differences according to age, BRCA status, menopausal status, TNM, pathological and molecular surrogate subtype, 20% TIL cut-off, surgical procedure, response to chemotherapy and the presence of vascular invasion. Results: The pCR rate was 25.3% and was greater in HER2 (51.3%) and TNBC (31.7%) and in BRCA carriers (41.9%). The factors independently related to patient survival were pathology and molecular surrogate subtype, type of surgery, response to NACT and vascular invasion. BRCA status was a protective prognostic factor without reaching statistical significance, with an HR 0.5 (95%CI 0.1–1.4). Mastectomy presented a double risk of distant recurrence compared to breast-conservative surgery (BCS), supporting BCS as a safe option after NACT. After a mean follow-up of 126 (SD 43) months, luminal tumors presented a substantial difference in survival rates calculated at 5 or 10 years (81.2% compared to 74.7%), whereas that for TNBC was 75.3 and 73.5, respectively. The greatest difference was seen according to the response in patients with pCR, who exhibited a 10 years DDFS of 95.5% vs. 72.4% for those patients without pCR, p < 0001. This difference was especially meaningful in TNBC: the 10 years DDFS according to an RCB of 0 to 3 was 100%, 80.6%, 69% and 49.2%, respectively, p < 0001. Patients with a particularly poor prognosis were those with lobular carcinomas, with a 10 years DDFS of 42.9% vs. 79.7% for ductal carcinomas, p = 0.001, and patients with vascular invasion at the surgical specimen, with a 10 years DDFS of 59.2% vs. 83.6% for those patients without vascular invasion, p < 0.001. Remarkably, BRCA carriers presented a longer survival, with an estimated 10 years DDFS of 89.6% vs. 77.2% for non-carriers, p = 0.054. Conclusions: Long-term outcomes after neoadjuvant chemotherapy can help patients and clinicians make well-informed decisions. [ABSTRACT FROM AUTHOR]

Simple Summary: Gorlin syndrome (GS) is a genetic disorder characterized by multiple basal cell carcinomas (BCCs) due to mutations in the hedgehog signaling pathway. Patients with GS may need dozens or even hundreds of surgical procedures in their lifetime, which can leave them severely scarred, deformed, and disfigured. In 16 patients with GS, we examined the effectiveness, safety, and length of response to oral hedgehog inhibitors. According to our retrospective study, sonidegib inhibited the growth of both newly diagnosed and pre-existing basal cell carcinomas more successfully and safely than vismodegib. Nevoid basal cell carcinoma syndrome (NBCCS), also known as Gorlin syndrome (GS), is a genetic disorder characterized by the development of multiple cutaneous BCCs due to mutations in the hedgehog signaling pathway. The use of hedgehog pathway inhibitors—vismodegib and sonidegib—has emerged as a promising therapeutic strategy for managing BCCs in individuals with GS. In a retrospective study conducted between March 2012 and January 2024, a cohort of 16 Gorlin syndrome patients who received treatment with either sonidegib or vismodegib were analyzed. The primary objectives of the study were to evaluate the efficacy, safety profile, and duration of response to oral hedgehog inhibitors in this patient population. The study assessed various parameters, including the number of new BCCs that developed before and after treatment initiation, the duration and sustainability of treatment responses, as well as the incidence of adverse effects associated with hedgehog inhibitor therapy. The findings of the study revealed that sustained treatment with hedgehog inhibitors could effectively suppress the progression of both new and existing BCCs. Furthermore, the results indicated that sonidegib exhibited superior efficacy and safety compared to vismodegib in the treatment of BCCs in individuals with GS. Notably, adjustments to the administration schedule of sonidegib were found to improve tolerability without compromising therapeutic efficacy, potentially leading to prolonged durations of treatment response and disease control. [ABSTRACT FROM AUTHOR]

Simple Summary: Although women 70 years of age and older represent a large percentage of newly diagnosed breast cancer cases, older individuals are drastically underrepresented in clinical trials. Most women diagnosed with breast cancer at 70 years of age and older present with hormone receptor-positive (HR+) breast cancer. Cyclin-dependent kinase (CDK) 4/6 inhibitor-based therapy has become the standard of care for metastatic HR+ breast cancer. This study reports that metastatic breast cancer patients ≥70 years of age receiving CDK4/6 inhibitor-based treatment, particularly when combined with an aromatase inhibitor, experience prolonged progression-free survival but display no such prolongation in overall survival and report more frequent adverse effects to treatment. The reported findings can aid in the development of optimized treatments based on age and help older patients weigh treatment options. The largest portion of breast cancer patients diagnosed after 70 years of age present with hormone receptor-positive (HR+) breast cancer subtypes. Cyclin-dependent kinase (CDK) 4/6 inhibitor treatment, in conjunction with endocrine therapy, has become standard-of-care for metastatic HR+ breast cancer. In total, 320 patients with metastatic breast cancer receiving CDK4/6 inhibitor combined with fulvestrant or an aromatase inhibitor were enrolled in an ongoing observational study or were included in an IRB-approved retrospective study. All patients receiving CDK4/6 inhibitor-based therapy that were ≥70 years of age (n = 111) displayed prolonged progression-free survival (27.6 months) as compared to patients <70 years of age (n = 209, 21.1 months, HR = 1.38, p < 0.05). Specifically, patients receiving a CDK4/6 inhibitor with an aromatase inhibitor who were ≥70 years of age (n = 79) displayed exceptionally prolonged progression-free survival (46.0 months) as compared to patients receiving the same treatment who were <70 years of age (n = 161, 21.8 months, HR = 1.71, p < 0.01). However, patients ≥70 years of age also experienced more frequent adverse responses to CDK4/6 inhibitor-based treatment leading to dose reduction, hold, or discontinuation than the younger cohort (69% and 53%, respectively). Treatment strategies that may decrease toxicity without affecting efficacy (such as dose titration) are worth further exploration. [ABSTRACT FROM AUTHOR]

Simple Summary: The combination of atezolizumab and bevacizumab is a standard treatment for unresectable hepatocellular carcinoma. This study investigated the relationship between the gut microbiome and treatment efficacy. Fecal samples from 37 patients with hepatocellular carcinoma treated with this combination were analyzed. Patients were divided into responders (n = 28) and non-responders (n = 9). While overall microbiome diversity was similar, certain bacteria, such as Bacteroides stercoris and Parabacteroides merdae were more abundant in responders. Patients lacking these bacteria had worse prognoses. This suggests that differences in gut microbiota play a role in the effectiveness of atezolizumab and bevacizumab therapy. The combination of atezolizumab and bevacizumab has become the first-line treatment for patients with unresectable hepatocellular carcinoma (HCC). However, no studies have reported on specific intestinal microbiota associated with the efficacy of atezolizumab and bevacizumab. In this study, we analyzed fecal samples collected before treatment to investigate the relationship between the intestinal microbiome and the efficacy of atezolizumab and bevacizumab. A total of 37 patients with advanced HCC who were treated with atezolizumab and bevacizumab were enrolled. Fecal samples were collected from the patients, and they were divided into responder (n = 28) and non-responder (n = 9) groups. We compared the intestinal microbiota of the two groups and analyzed the intestinal bacteria associated with prognosis using QIIME2. The alpha and beta diversities were not significantly different between both groups, and the proportion of microbiota was similar. The relative abundance of Bacteroides stercoris and Parabacteroides merdae was higher in the responder group than in the non-responder group. When the prognosis was analyzed by the presence or absence of those bacteria, patients without both had a significantly poorer prognosis. Differences in intestinal microbiome are involved in the therapeutic effect of atezolizumab and bevacizumab. [ABSTRACT FROM AUTHOR]

Simple Summary: Nabpaclitaxel plus gemcitabine is the standard of care treatment for advanced pancreatic ductal adenocarcinoma (PDAC), the third leading cause of cancer-related deaths worldwide. This therapy reported improved overall survival in metastatic PDAC. Despite the efficacy of available treatments, the poor outcome for patients with PDAC necessitates the need for novel therapies. In a preclinical study, a neutralizing monoclonal antibody specific to human platelet-derived growth factor receptor alpha (PDGFRα) has proven its efficacy in advanced PDAC. Further, a PDGFRα monoclonal antibody, olaratumab, in combination with chemotherapy demonstrated clinical benefit in patients with soft tissue sarcoma. In light of the above findings, the current trial evaluates the efficacy and safety of olaratumab and nabpaclitaxel plus gemcitabine combination therapy in treatment-naïve patients with metastatic PDAC. However, the combination therapy failed to improve survival outcomes compared with chemotherapy alone. Nevertheless, the safety profile of olaratumab was consistent with the previous studies. The efficacy and safety of olaratumab plus nabpaclitaxel and gemcitabine in treatment-naïve participants with metastatic pancreatic ductal adenocarcinoma was evaluated. An initial phase 1b dose-escalation trial was conducted to determine the olaratumab dose for the phase 2 trial, a randomized, double-blind, placebo-controlled trial to compare overall survival (OS) in the olaratumab arm vs. placebo arms. In phase 1b, 22 participants received olaratumab at doses of 15 and 20 mg/kg with a fixed dose of nabpaclitaxel and gemcitabine. In phase 2, 159 participants were randomized to receive olaratumab 20 mg/kg in cycle 1 followed by 15 mg/kg in the subsequent cycles (n = 81) or the placebo (n = 78) on days 1, 8, and 15 of a 28-day cycle, plus nabpaclitaxel and gemcitabine. The primary objective of the trial was not met, with a median OS of 9.1 vs. 10.8 months (hazard ratio [HR] = 1.05; 95% confidence interval [CI]: 0.728, 1.527; p = 0.79) and the median progression-free survival (PFS) was 5.5 vs. 6.4 months (HR = 1.19; 95% CI: 0.806, 1.764; p = 0.38), in the olaratumab vs. placebo arms, respectively. The most common treatment-emergent adverse event of any grade across both arms was fatigue. Olaratumab plus chemotherapy failed to improve the OS or PFS in participants with metastatic PDAC. There were no new safety signals. [ABSTRACT FROM AUTHOR]

Simple Summary: The majority of patients with advanced non-small-cell lung cancer (NSCLC) who initially respond to treatment with immune checkpoint inhibitors (ICIs), will ultimately develop resistance within four years. ICI rechallenge is considered in real-world practice, but its effectiveness following disease progression is not well-established. The aim of this review was to evaluate the clinical efficacy of rechallenge ICI therapy following disease progression, based on the critical assessment of the published data. The evidence shows limited efficacy of rechallenge immunotherapy in unselected patient populations who progressed during initial immunotherapy, yet promising efficacy in those who relapsed after treatment completion. Immune checkpoint inhibitors (ICIs) are at the forefront of advanced non-small-cell lung cancer (NSCLC) treatment. Still, only 27–46% of patients respond to initial therapy with ICIs, and of those, up to 65% develop resistance within four years. After disease progression (PD), treatment options are limited, with 10% Objective Response Rate (ORR) to second or third-line chemotherapy. In this context, ICI rechallenge is an appealing option for NSCLC. Most data on the efficacy of ICI rechallenge are based on retrospective real-world studies of small, heavily pretreated, and heterogeneous patient groups. Despite these limitations, these studies suggest that ICI monotherapy rechallenge in unselected NSCLC patient populations who discontinued initial ICI due to PD is generally ineffective, with a median Progression-Free Survival (PFS) of 1.6–3.1 months and a Disease Control Rate (DCR) of 21.4–41.6%. However, there is a subpopulation that benefits from this strategy, and further characterization of this subgroup is essential. Furthermore, immunotherapy rechallenge in patients who discontinued initial immunotherapy following treatment protocol completion and progressed after an immunotherapy-free interval showed promising efficacy, with a DCR of 75–81%, according to post hoc analyses of several clinical trials. Future research on ICI rechallenge for NSCLC should focus on better patient stratification to reflect the underlying biology of immunotherapy resistance more accurately. In this review, we summarize evidence regarding rechallenge immunotherapy efficacy following NSCLC disease progression or relapse, as well as ongoing trials on immunotherapy rechallenge. [ABSTRACT FROM AUTHOR]

Simple Summary: The efficacy of abiraterone plus prednisolone (ABI) against nonmetastatic castration-resistant prostate cancer (CRPC) remains unclear. To evaluate enzalutamide and ABI as the first-line treatment for CRPC, we conducted the randomized controlled trial including both metastatic and nonmetastatic CRPC. As a sub-analysis, we focused on nonmetastatic CRPC in this study. ABI and enzalutamide had similar efficacy and safety profiles in patients with nonmetastatic CRPC. Enzalutamide (ENZ) and abiraterone plus prednisolone (ABI) can improve the survival of patients with castration-resistant prostate cancer (CRPC). However, the agent that is more effective against nonmetastatic CRPC remains unclear. To evaluate the agent that can be used as the first-line treatment for CRPC, an investigator-initiated, multicenter, randomized controlled trial (ENABLE Study for PCa) including both metastatic and nonmetastatic CRPC was conducted in Japan. The prostate-specific antigen (PSA) response rate, overall survival, some essential survival endpoints, and safety of patients with nonmetastatic CRPC were also analyzed. In this subanalysis, 15 and 26 patients in the ENZ and ABI arms, respectively, presented with nonmetastatic CRPC. There was no significant difference in terms of the PSA response rate between the ENZ and ABI arms (80% and 64%, respectively; p = 0.3048). The overall survival did not significantly differ between the two arms (HR: 0.68; 95% CI: 0.22–2.14, p = 0.5260). No significant differences were observed in terms of radiographic progression-free survival and cancer-specific survival between the ENZ and ABI arms (HR: 0.81; 95% CI: 0.35–1.84; p = 0.6056 and HR: 0.72; 95% CI: 0.19–2.73; p = 0.6443, respectively). Only four and six patients in the ENZ and ABI arms, respectively, had ≥grade 3 adverse events. ABI and ENZ had similar efficacy and safety profiles in patients with nonmetastatic CRPC. [ABSTRACT FROM AUTHOR]

Simple Summary: Pazopanib is an oral drug for metastatic pretreated uterine leiomyosarcoma that received approval in 2012, but poor data have been reported on its activity in real life since the disease is very rare. Uterine leiomyosarcoma has a poor objective response rate to other agents. We assessed the effectiveness and safety of pazopanib in everyday clinical practice, showing its activity and tolerability in patients. Background: Uterine leiomyosarcoma (uLMS) is characterized by aggressive behavior associated with a high risk of relapse and mortality. Several therapeutic agents have been employed in the treatment of metastatic disease, with a poor objective response rate. Pazopanib, approved in 2012, is a multi-targeted, orally active small molecule that exerts its effects by inhibiting several tyrosine kinases. To date, poor research on real-life data has been conducted. We aimed to assess the effectiveness and safety of the drug in everyday clinical practice. Methods: We present results of multicenter retrospective data on 38 patients with heavily pretreated metastatic uLMS who underwent oral pazopanib during their therapeutic journey. Results: At a median follow-up of 8.6 months, the disease control rate was 55.2%, with 17% partial responses and 15 patients (39.5%) with stable disease. At a median follow-up of 8.6 months, median progression-free survival was 4 months, and median overall survival was 19.8 months. The most common grade 3 adverse events (AEs) drug-related were hepatic toxicities, diarrhea, hypertension, nausea, and vomiting (all of them with an incidence of 5% considering the whole study cohort). No grade 4 AEs occurred. Conclusions: Pazopanib in everyday clinical practice is safe and shows a good disease control rate with prolonged survival. [ABSTRACT FROM AUTHOR]

Simple Summary: On rare occasions, a handful of innovative cancer drugs may successfully go through clinical trials and manage to obtain simultaneous regulatory approvals to treat a specific disease, providing hope for improved treatment outcomes. In the past few years, physicians in North America, Europe, and other countries with stronger economies have been able to use several of the recently approved drugs to treat a blood cancer called multiple myeloma, once older therapies have failed. This study looked at the treatment outcomes associated with the wave of newer drugs in patients diagnosed with multiple myeloma in Greece. The results showed that approximately three-quarters of patients who received one of the newer drugs after having progressed on front-line therapies remained in remission a year after initiating treatment. This finding was comparable to the results from previous studies in Greek patients who were diagnosed with relapsed or refractory multiple myeloma and had previously used other therapies. Newer methodologies are needed to assess the real-world comparative effectiveness of a "generation" of pharmaceutical innovation versus the prior standard of care. This chart review study aimed to first evaluate the cumulative clinical benefits of pharmaceutical innovation in everyday relapse/refractory multiple myeloma before analyzing findings in the context of respective real-world outcomes from the bortezomib/lenalidomide era. Study endpoints included the 52-week PFS rate in second and third line of therapy (LOT), mPFS-2 across the first and second LOT, the ORR, reasons for discontinuation, and the treatment duration per therapeutic algorithm. Data from 107 patients were collected. The median follow-up was 2.0 years. Of the subjects who met the selection criteria for the second LOT, 72.2% maintained the PFS at 52 weeks. In the third-line setting, the PFS rate at 52 weeks was 63.5%. The mPFS across the first and second, the second, and the third LOTs were 26, 17, and 15 months, respectively. The ORR was 76.1% in the second and 69.7% in the third LOT. After non-response or progression, the main reason for drug discontinuation was treatment intolerability. The second-line ORR and the 52-week PFS rate were similar to previous real-world findings from the bortezomib/lenalidomide era. The cumulative mPFS across the second and third LOTs was higher than the respective mPFS across the first and second LOTs. Despite its limitations, the methodology and findings from this study may be used in future clinical and economic evaluations across all hematological malignancies. [ABSTRACT FROM AUTHOR]

Simple Summary: Third-line or further treatments are rarely given to patients with refractory mCRC. In this regard, two noteworthy innovative therapy options, with varying toxicity profiles and statistically significant improvements in overall survival (OS), progression-free survival (PFS), and disease control, are regorafenib (R) and trifluridine/tipiracil (T). This study is a subset analysis of a larger retrospective study that we have already published, with the aim of evaluating patient outcomes when R and T were administered in that order. The purpose of this analysis was to evaluate the relationship between survival outcomes and the first drug treatment duration (<3 months, 3 to <6 months, and ≥6 months) in patients who had received the regorafenib-to-trifluridine/tipiracil sequence or vice versa. Our substudy found that administering R three to six months prior to T can prolong both OS and PFS in comparison to the opposite sequence. Background: Patients with refractory metastatic colorectal cancer (mCRC) rarely receive third-line or further treatment. In this context, regorafenib (R) and trifluridine/tipiracil (T) are two important novel therapeutic choices with statistically significant increases in overall survival (OS), progression-free survival (PFS), and disease control, with different toxicity profiles. This study is a subgroup analysis of our larger retrospective study, already published, whose objective was to assess the outcomes of patients when R and T were given sequentially. Patients and Methods: The study involved thirteen Italian cancer centers on a 10-year retrospective observation (2012–2022). In this subgroup analysis, we focused our attention on the correlation between the first drug treatment duration (<3 months, 3 to <6 months and ≥6 months) and survival outcomes in patients who had received the sequence regorafenib-to-trifluridine/tipiracil, or vice versa. Results: The initial study included 866 patients with mCRC who received sequential T/R, or R/T, or T or R alone. This analysis is focused on evaluating the impact of the duration of the first treatment in the sequence on clinical outcomes (OS, PFS) and includes 146 and 116 patients of the T/R and R/T sequences, respectively. Based on the duration of the first drug treatment, subgroups for the T/R sequence included 27 patients (18.4%) who received T for <3 months, 86 (58.9%) treated for 3 to <6 months, and 33 (22.6%) treated for ≥6 months; in the reverse sequence (R as the first drug), subgroups included 18 patients (15.5%) who received their first treatment for <3 months, 62 (53.4%) treated for 3 to <6 months, and 35 (31.0%) treated for ≥6 months. In patients who received their first drug treatment for a period of 3 to <6 months, the R/T sequence had a significantly longer median OS (13.7 vs. 10.8 months, p = 0.0069) and a longer median PFS (10.8 vs. 8.5 months, p = 0.0003) than the T/R group. There were no statistically significant differences between groups with first drug treatment durations of <3 months and ≥6 months. Conclusions: Our analysis seems to suggest that the administration of R for a period of 3 to <6 months before that of T can prolong both OS and PFS, as compared to the opposite sequence. [ABSTRACT FROM AUTHOR]

Simple Summary: This study evaluates the impact of treatment sequencing on the outcomes of patients with chronic lymphocytic leukemia. By analyzing data from patients treated at the Fondazione Policlinico Universitario Agostino Gemelli IRCCS in Rome, we showed how the sequence of therapies has evolved over the years in first-line and relapsed/refractory patients and how this change in the treatment paradigm has affected survival. In addition, the poor outcome of patients exposed to cBTKi and BCL2i raises the question of what the best approach might be for treating high-risk patients. Background: This monocentric retrospective study describes the treatment patterns and outcomes of chronic lymphocytic leukemia (CLL) patients. Methods: Adult CLL patients treated between 1992 and 2022 were included. The time to next treatment (TTNT) was defined as the time from the treatment's start to the start of a subsequent therapy or death. The time to next treatment failure or death (TTNTF) was defined as the time from treatment discontinuation to the discontinuation of a subsequent therapy or death. Results: Of 637 registered patients, 318 (49.9%) received treatment. We evaluated 157 cBTKi-exposed, 34 BCL2i-exposed cBTKi-naïve, and 26 double-exposed patients. The five-year TTNT values in the cBTKi-exposed patients were 80% (median NR), 40% (median 40 months), and 21% (median 24 months) months in the first line (1L), second line (2L), and beyond the second line (>2L), respectively (p < 0.0001). The five-year TTNT values in the BCL2i-exposed patients were 83% (median NR), 72% (median NR), 12% (median 28 months) in the 1L, 2L, and >2L, respectively (p = 0.185). The median TTNTF was 9 months (range 1–87) after cBTKi and 17 months (range 8–49) after both a cBTKi and BCL2i. Conclusions: This study suggests that, in CLL patients, the earlier we used targeted therapies, the better was the outcome obtained. Nonetheless, the poor outcomes in the advanced lines of therapy highlight the need for more effective treatments. [ABSTRACT FROM AUTHOR]

Simple Summary: Targeted therapy for malignant esophageal squamous cell carcinoma (ESCC) remains a big challenge for our clinicians. In an effort to search for the vulnerability of ESCC, we applied a high-throughput drug-screening strategy and found that CuET, a copper chelation product of disulfiram, had a strong synergy effect with the JMJD3/UTX inhibitor GSK J4 in treating ESCC in vitro and in vivo. Interestingly, JMJD3/UTX's diagnostic and prognostic value, as well as the underlying mechanisms associated with endoplasmic reticulum stress were revealed. Targeting JMJD3 and UTX in combination with disulfiram has the potential to provide a new safe, effective, and available therapy for ESCC. The alcohol-averse drug disulfiram has been reported to have anti-tumor effects and is well suited for drug combinations. In order to identify potential drug combinations in esophageal squamous cell carcinoma (ESCC), we screened a bioactive compound library with the disulfiram copper chelation product CuET. The Jumonji domain-containing protein 3 (JMJD3) and the ubiquitously transcribed tetratricopeptide repeat protein X-linked (UTX) inhibitor GSK J4 were identified. To further understand the molecular mechanism underlying the efficient drug combination, we applied quantitative mass spectrometry to analyze the signaling pathway perturbation after drug treatment. The data revealed that the synergistic effect of GSK J4 and CuET was due to the interaction among JMJD3 and UTX, which may play important roles in maintaining endoplasmic reticulum (ER) homeostasis in tumor cells. Interestingly, our clinical data analysis showed that high expression of JMJD3 and UTX was associated with T stage and worse prognosis of ESCC patients, further supporting the importance of the above findings. In conclusion, our findings suggest that the combination of CuET and targeting JMJD3/UTX may be a safe, effective, and available treatment for ESCC. [ABSTRACT FROM AUTHOR]

Simple Summary: This study focused on understanding the potential use of Aloe secundiflora (AS) extracts in managing colorectal cancer (CRC). As colon tumors present complex challenges, the research aimed to assess how the AS methanolic extracts impacted the expression of specific genes related to CRC, namely CASPS9, 5-LOX, Bcl2, Bcl-xL, and COX-2. The results demonstrated that the AS extracts, when applied to CRC cell lines, effectively upregulated CASPS9 expression, promoting apoptosis in a dose-dependent manner. Simultaneously, the extracts downregulated the expressions of 5-LOX, Bcl2, and Bcl-xL, crucial in curbing cancer progression. The study suggests that using AS extracts and methanol as an extraction solvent could be beneficial in managing CRC. Furthermore, the researchers recommend exploring the specific metabolites in AS involved in these pathways to better understand how they impede the development and spread of CRC. This research provides promising insights into potential natural treatments for colorectal cancer, offering hope for improved therapies in the future. Colon tumors have a very complicated and poorly understood pathogenesis. Plant-based organic compounds might provide a novel source for cancer treatment with a sufficient novel mode of action. The objective of this study was to analyze and evaluate the efficacy of Aloe secundiflora's (AS) methanolic extracts on the expression of CASPS9, 5-LOX, Bcl2, Bcl-xL, and COX-2 in colorectal cancer (CRC) management. Caco-2 cell lines were used in the experimental study. In the serial exhaustive extraction (SEE) method, methanol was utilized as the extraction solvent. Upon treatment of CASPS9 with the methanolic extracts, the expression of the genes was progressively upregulated, thus, dose-dependently increasing the rate of apoptosis. On the other hand, the expressions of 5-LOX, Bcl2, and Bcl-xL were variably downregulated in a dose-dependent manner. This is a unique novel study that evaluated the effects of AS methanolic extracts in vitro on CRC cell lines using different dosage concentrations. We, therefore, recommend the utilization of AS and the application of methanol as the extraction solvent of choice for maximum modulatory benefits in CRC management. In addition, we suggest research on the specific metabolites in AS involved in the modulatory pathways that suppress the development of CRC and potential metastases. [ABSTRACT FROM AUTHOR]

Simple Summary: This review based on a literature search aims at showing the impact of Texture Analysis in the prediction of response to neoadjuvant radiotherapy and/or chemoradiotherapy. The manuscript explores radiomics approaches in different fields of neoadjuvant radiotherapy, including esophageal cancer, lung cancer, sarcoma and rectal cancer in order to shed a light in the setting of neoadjuvant radiotherapy that can be used to tailor the best subsequent therapeutical strategy. Introduction: Neoadjuvant radiotherapy is currently used mainly in locally advanced rectal cancer and sarcoma and in a subset of non-small cell lung cancer and esophageal cancer, whereas in other diseases it is under investigation. The evaluation of the efficacy of the induction strategy is made possible by performing imaging investigations before and after the neoadjuvant therapy and is usually challenging. In the last decade, texture analysis (TA) has been developed to help the radiologist to quantify and identify the parameters related to tumor heterogeneity, which cannot be appreciated by the naked eye. The aim of this narrative is to review the impact of TA on the prediction of response to neoadjuvant radiotherapy and or chemoradiotherapy. Materials and Methods: Key references were derived from a PubMed query. Hand searching and ClinicalTrials.gov were also used. Results: This paper contains a narrative report and a critical discussion of radiomics approaches in different fields of neoadjuvant radiotherapy, including esophageal cancer, lung cancer, sarcoma, and rectal cancer. Conclusions: Radiomics can shed a light on the setting of neoadjuvant therapies that can be used to tailor subsequent approaches or even to avoid surgery in the future. At the same, these results need to be validated in prospective and multicenter trials. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancers of the biliary tract are rare but severe with high mortality rates. Randomised controlled trials suggest that chemotherapies such as gemcitabine and oxaliplatin (GemOx) may relieve symptoms and prolong life, but less is known on the efficacy and safety of such regimens in real life. The current paper assessed the real-world outcome of GemOx in all patients with advanced biliary tract cancer treated at any cancer centre in the South East Region of Sweden over a period of nine years. The median overall survival was nine months and time to disease progression five months. Prognostic factors such as performance status and gall bladder (rather than bile duct) localisation of the primary tumour were identified. Most patients received a lower dose of oxaliplatin than proposed by previous studies, which seemed feasible as few patients had severe adverse events. This study supports further use of GemOx as standard of care. Background: Gemcitabine and oxaliplatin (GemOx) is a standard combination regimen in advanced biliary tract cancer (BTC). There is limited evidence on its efficacy and safety in real life. Methods: A retrospective multicentre cohort study in the South East Region of Sweden, covering nine years (2011–2020) and three hospitals where GemOx was treatment of choice, was designed. Clinicopathological prognostic parameters were explored. Results: One hundred and twenty-one patients with advanced BTC were identified. Median overall and progression-free survival (OS and PFS) were 8.9 (95% CI = 7.2–10.6) and 5.3 (95% CI = 3.8–6.7) months. Performance status according to Eastern Cooperative Oncology Group (PS according to ECOG) 1–2 and primary gallbladder carcinoma were independent predictors for poor OS. PS and derived neutrophil/lymphocyte ratio were predictive for PFS. The most common severe type of myelosuppresion was grade 3 neutropenia that was recorded in 8%. Fifty-three (43.8%) experienced at least one episode of unplanned hospitalisation. One hundred and seventeen (97%) received oxaliplatin with lower dosage than was utilized in previous phase III trials (80–85 vs. 100 mg/m2) and a majority received further dose reductions of oxaliplatin and/or gemcitabine. Conclusion: The outcome of GemOx in advanced BTC appears comparable in controlled trials and real-world contexts. A lower dose of oxaliplatin seems more tolerable without compromising the outcome. [ABSTRACT FROM AUTHOR]

Simple Summary: Non-covalent Bruton's tyrosine kinase inhibitors (ncBTKi) are being investigated for the treatment of B-cell malignancies, including chronic lymphocytic leukemia (CLL). These agents hold promise for the treatment of CLL, especially CLL requiring treatment after prior discontinuation of covalent Bruton's tyrosine kinase inhibitors such as ibrutinib, acalabrutinib and zanubrutinib for either intolerance or progression of disease. This review outlines current preclinical and clinical data for the use of ncBTKi in CLL. Recently reported data has shown durable responses for the ncBTKi pirtobrutinib in CLL patients previously treated with a covalent BTKi with a median PFS of 19.6 months. We also discuss recently discovered mechanisms of resistance to ncBTKis, including acquired mutations in the BTK protein not in the C481 position. In addition, we highlight ongoing clinical trials that are incorporating ncBTKis in CLL as monotherapy or in combination therapies with other agents. The results of these trials as well as ongoing research regarding mechanisms of resistance to ncBTKi and covalent Bruton's Tyrosine Kinase inhibitors will be important to determine where ncBTKi may fit into the treatment of CLL. Covalent Bruton's tyrosine kinase inhibitors (cBTKi) have led to a paradigm shift in the treatment of chronic lymphocytic leukemia (CLL). These targeted oral therapies are administered as standard treatments in both the front-line and relapsed and/or refractory settings. Given their administration as a continuous therapy with a "treat-to-progression" strategy, limitations of their use include discontinuation due to toxicity or from progression of the disease. Non-covalent Bruton's tyrosine kinase inhibitors (ncBTKi) distinguish themselves by binding reversibly to the BTK target, which may address the limitations of toxicity and acquired resistance seen with cBTKi. Several ncBTKis have been studied preclinically and in clinical trials, including pirtobrutinib and nemtabrutinib. Pirtobrutinib, which is now FDA approved for relapsed and/or refractory mantle cell lymphoma (MCL), has shown outstanding safety and preliminary efficacy in CLL in phase 1 and 2 clinical trials, with phase 3 trials underway. This agent may fill an unmet medical need for CLL patients requiring treatment after a cBTKi. Pirtobrutinib is particularly promising for the treatment of "double exposed" CLL, defined as CLL requiring treatment after both a cBTKi and venetoclax. Some patients have now developedacquired resistance to pirtobrutinib, and resistance mechanisms (including novel acquired mutations in BTK outside of the C481 position) have been recently described. Further study regarding the mechanisms of resistance to pirtobrutinib in patients without prior cBTKi exposure, as well as the potential for cross-resistance between cBTKi and ncBTKis, may be important to help inform where ncBTKis will ultimately fit in the treatment sequencing paradigm for CLL. An emerging clinical challenge is the treatment of CLL after ncBTKi discontinuation. Novel therapeutic strategies are being investigated to address the treatment of patients following disease progression on ncBTKis. Such strategies include novel agents (BTK degraders, bispecific antibody therapy, CAR T-cell therapy, PKC-beta inhibitors) as well as combination approaches incorporating a ncBTKi (e.g., pirtobrutinib and venetoclax) that may help overcome this acquired resistance. [ABSTRACT FROM AUTHOR]

Simple Summary: The available chemotherapeutic regimens for metastatic pancreatic ductal adenocarcinoma (mPDAC) in Romania include FOLFIRINOX (FFX), gemcitabine-based regimens (GB), and gemcitabine monotherapy (Gem). The purpose of our study was to compare the efficacy of FFX, GB, and Gem in patients with mPDAC in real-world scenarios. Our research revealed that the overall survival (OS) of patients receiving FFX or GB was comparable, twice as long as that of patients receiving Gem, and the progression-free survival (PFS) was highest for patients receiving FFX as first-line chemotherapy (L1). Male gender, Eastern Cooperative Oncology Group Performance (ECOG-PS) 0/1, the FFX regimen, and neutrophil-to-lymphocyte ratio (NLR) > 4.15 were all independently linked to a longer OS. L1 with FFX improved both OS and PFS for second-line chemotherapy (L2). Purpose: To assess the efficacy of FOLFIRINOX(FFX), gemcitabine-based regimens (GB), and gemcitabine monotherapy (Gem) in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC). Methods: This is a retrospective study that included 83 patients with mPDAC treated with first-line chemotherapy (L1) with either FFX, GB or Gem between 2015 and 2017. Progression-free survival (PFS) for L1 and second-line chemotherapy (L2) (PFS-L1 and PFS-L2) and overall survival (OS) were estimated using the Kaplan–Meier method. Results: Median PFS-L1 for FFX, GB and Gem groups was 9 months (95% (Confidence Interval) CI 2.76–15.24), 5 months (95%CI 3.44–6.56), and 5 months (95%CI 3.76–6.24), respectively (p = 0.04). OS was 14 months (95%CI 11.16–16.85), 12 months (95%CI: 9.44–11.56), and 7 months (95%CI: 5.7–8.3) for patients treated with FFX, GB, and Gem, respectively (p = 0.0001). ECOG-PS (0/1) (Hazard Ratio (HR) 6.74, p = 0.002), age > 70 years (HR 0.25, p = 0.04), body tumors (HR 2.8, p = 0.048), CA19–9 > 39 U/mL (HR 0.26, p = 0.02), and neutrophil-to-lymphocyte ratio (NLR) > 4.15 (HR 6.76, p = 0.001) were independent prognostic factors for PFS-L1. Male gender (HR 3.02, p = 0.026), ECOG-PS (0/1) (HR 4.21, p = 0.003), L1 with FFX (HR 0.255, p = 0.007), and NLR > 4.15 (HR 2.65, p = 0.04) were independent prognostic factors of OS. PFS-L2 (HR 6.91, p = 0.013) and OS-L2 (HR 6.95, p = 0.037) were significantly higher in patients first treated with FFX. Conclusions: The OS of patients who receive FFX or GB is comparable. The best PFS-L1 belongs to the FFX group. Male gender, ECOG-PS 0/1, the FFX regimen, and NLR > 4.15 were independent predictors of OS. PFS-L2 and OS-L2 were favorably impacted by L1 with FFX. [ABSTRACT FROM AUTHOR]

Simple Summary: ALK-rearranged non-small cell lung cancer treatment has radically changed in the last few years thanks to the development of ALK inhibitors, which clearly improved survival. To our knowledge, even though many studies correlate body mass index (BMI) with lung cancer immunotherapy, conflicting results have emerged in non-smoker patients treated with other drugs. Indeed, it is unclear whether body size variables and metabolism could affect ALK-inhibitor efficacy. The aim of this retrospective study is to correlate BMI status with survival outcomes in patients treated with commonly used ALK inhibitors in different lines of treatment. We observed that BMI status could impact survival outcomes, particularly in patients treated with Alectinib as the first line. Further prospective studies should examine this interesting phenomenon. No evidence exists as to whether body mass index (BMI) impairs clinical outcomes from ALK inhibitors (ALKi) in patients with ALK-rearranged non-small cell lung cancer (NSCLC). Retrospective data of patients affected by metastatic ALK-rearranged NSCLC treated with ALKi were collected. We divided patients into "low- BMI" (≤25 kg/m2) and "high- BMI" (>25 kg/m2) categories and correlated them with overall survival (OS) and progression-free survival (PFS). We included 40 patients treated with ALKi. We observed a 3-year OS of 81.5% in high-BMI vs. 49.6% in low-BMI categories (p = 0.049); the 3-year first-line PFS was superior in high-BMI vs. low-BMI patients (47% vs. 19%, p = 0.019). As expected, patients treated with Alectinib had a 55.6% 3-year PFS vs. 7.1% for others treated with ALKi (p = 0.025). High-BMI was associated with a 100% 3-year PFS rate vs. 25.4% in low-BMI Alectinib patients (p = 0.03). BMI was independently correlated with first-line PFS and OS at multivariate analysis with PS (HR 0.39, CI 95% 0.16–0.96, p = 0.042; HR 0.18, CI 95% 0.05–0.61, p = 0.006). High-BMI was associated with higher efficacy in ALK-rearranged patients. These results are particularly exciting for Alectinib and could be correlated to mechanisms that should be investigated in subsequent prospective studies. [ABSTRACT FROM AUTHOR]

Simple Summary: In situ vaccination (ISV) envisages the intratumoral injection of immunostimulatory molecules, which inflame the tumor and induce anti-tumor immune responses. Since bacterial outer membrane vesicles (OMVs) are naturally decorated with components which stimulate innate immunity, we tested whether OMVs can be used in ISV. Using three different tumor mouse models, we demonstrated the effectiveness of OMVs in inhibiting tumor development and in curing a large fraction of treated mice. We also show that if combined with tumor-specific neoantigens, the anti-tumor activity of OMVs is further enhanced. These latter results are particularly relevant since they support the use of a general strategy to optimize any in situ vaccination protocol. Considering their potency and the ease with which are produced, OMV-based ISV has the potential to become a standard of care for most solid tumors, particularly as a neoadjuvant therapy to be performed before surgery. In situ vaccination (ISV) is a promising cancer immunotherapy strategy that consists of the intratumoral administration of immunostimulatory molecules (adjuvants). The rationale is that tumor antigens are abundant at the tumor site, and therefore, to elicit an effective anti-tumor immune response, all that is needed is an adjuvant, which can turn the immunosuppressive environment into an immunologically active one. Bacterial outer membrane vesicles (OMVs) are potent adjuvants since they contain several microbe-associated molecular patterns (MAMPs) naturally present in the outer membrane and in the periplasmic space of Gram-negative bacteria. Therefore, they appear particularly indicted for ISV. In this work, we first show that the OMVs from E. coli BL21(DE3)Δ60 strain promote a strong anti-tumor activity when intratumorally injected into the tumors of three different mouse models. Tumor inhibition correlates with a rapid infiltration of DCs and NK cells. We also show that the addition of neo-epitopes to OMVs synergizes with the vesicle adjuvanticity, as judged by a two-tumor mouse model. Overall, our data support the use of the OMVs in ISV and indicate that ISV efficacy can benefit from the addition of properly selected tumor-specific neo-antigens. [ABSTRACT FROM AUTHOR]

Simple Summary: Mitotane (MTT) is the treatment of choice for adrenocortical carcinoma. Male hypogonadism is often diagnosed in male patients treated with this drug. This research aims to consider possible side effects induced by MTT in the testis and a hypothetical detrimental effect deriving from androgenic deficiency. Furthermore, considering the increased potentiality of treatment for adrenocortical carcinoma, we want to provide male patients of childbearing age, as in other oncological diseases, the opportunity to consider a sperm cryopreservation program. Background: Clinical evidence has shown frequent hypogonadism following mitotane (MTT) treatment in male patients with adrenocortical carcinoma. This study aimed to evaluate the impact of MTT on male gonadal function. Methods: Morphological analysis of testes and testosterone assays were performed on adult CD1 MTT-treated and untreated mice. The expression of key genes involved in interstitial and tubular compartments was studied by real-time PCR. Moreover, quantitative and qualitative analysis of spermatozoa was performed. Results: Several degrees of damage to the testes and a significant testosterone reduction in MTT-treated mice were observed. A significant decline in 3βHsd1 and Insl3 mRNA expression in the interstitial compartment confirmed an impairment of androgen production. Fsh-R mRNA expression was unaffected by MTT, proving that Sertoli cells are not the drug's primary target. Sperm concentrations were significantly lower in MTT-treated animals. Moreover, the drug caused a significant increase in the percentage of spermatozoa with abnormal chromatin structures. Conclusion: MTT negatively affects the male reproductive system, including changes in the morphology of testicular tissue and reductions in sperm concentration and quality. [ABSTRACT FROM AUTHOR]

Simple Summary: Taking into consideration the high risk of patients with cancer for severe COVID-19 infection, prioritization has been given to primary prevention with both primary and booster vaccination. However, robust evidence for vaccination efficacy remains limited, due to the lack of available clinical trials including patients with active cancer. The rates of both humoral and cellular immune response remain rather vague, and they are mainly based on data deriving from retrospective studies of limited internal and external validity. We aimed to gather and analyze the current available literature on the efficacy of COVID-19 vaccination among patients with different types of malignancies receiving different treatments. Our results highlight that patients with cancer present suboptimal immune responses after COVID-19 vaccination, which is more prominent among patients with hematological malignancies. The exclusion of patients with cancer in clinical trials evaluating COVID-19 vaccine efficacy and safety, in combination with the high rate of severe infections, highlights the need for optimizing vaccination strategies. The aim of this study was to perform a systematic review and meta-analysis of the published available data from prospective and retrospective cohort studies that included patients with either solid or hematological malignancies according to the PRISMA Guidelines. A literature search was performed in the following databases: Medline (Pubmed), Scopus, Clinicaltrials.gov, EMBASE, CENTRAL and Google Scholar. Overall, 70 studies were included for the first and second vaccine dose and 60 studies for the third dose. The Effect Size (ES) of the seroconversion rate after the first dose was 0.41 (95%CI: 0.33–0.50) for hematological malignancies and 0.56 (95%CI: 0.47–0.64) for solid tumors. The seroconversion rates after the second dose were 0.62 (95%CI: 0.57–0.67) for hematological malignancies and 0.88 (95%CI: 0.82–0.93) for solid tumors. After the third dose, the ES for seroconversion was estimated at 0.63 (95%CI: 0.54–0.72) for hematological cancer and 0.88 (95%CI: 0.75–0.97) for solid tumors. A subgroup analysis was performed to evaluate potential factors affecting immune response. Production of anti-SARS-CoV-2 antibodies was found to be more affected in patients with hematological malignancies, which was attributed to the type of malignancy and treatment with monoclonal antibodies according to the subgroup analyses. Overall, this study highlights that patients with cancer present suboptimal humoral responses after COVID-19 vaccination. Several factors including timing of vaccination in relevance with active therapy, type of therapy, and type of cancer should be considered throughout the immunization process. [ABSTRACT FROM AUTHOR]

Simple Summary: The approval of combination treatments such as chemoimmunotherapy was a breakthrough in managing chronic lymphocytic leukemia and small lymphocytic lymphoma (CLL/SLL) patients. However, benefits remain suboptimal. A Bruton tyrosine kinase inhibitor (BTKi) is an effective treatment for these patients. This meta-analysis reviewed published studies to compare the efficacy and safety of BTKis versus combination therapy in CLL/SLL. One thousand five hundred ten patients from four trials were analyzed. BTKi monotherapy was associated with significantly longer progression-free survival (PFS) and an improved overall response rate without excess toxicity. We observed similar benefits for PFS among patients with high-risk diseases. In addition, patients receiving second-generation BTKis (acalabrutinib or zanubrutinib) had fewer grade ≥ 3 adverse events than those receiving the combination treatment. Further studies are essential to enhance these results and determine the optimal therapy for managing CLL/SLL patients. This study may help hematologists plan the treatment of CLL/SLL. The effectiveness and safety of combination treatments such as chemoimmunotherapies in chronic lymphocytic leukemia and small lymphocytic lymphoma (CLL/SLL) remain controversial. Bruton tyrosine kinase inhibitors (BTKis) are an effective therapy for CLL/SLL patients. This meta-analysis aimed to compare the efficacy and safety of BTKis versus combination therapy in CLL/SLL patients. We searched the PubMed, Cochrane, Medline, and Embase databases through February 2023 for relevant randomized controlled trials (RCTs). Four RCTs (including 1510 patients) were found and met the inclusion criteria. Progression-free survival (PFS) was significantly improved with BTKis when compared to the combination therapy (hazard ratio (HR), 0.30; 95% confidence interval (CI), 0.22–0.40), while a pooled analysis of overall survival did not favor single-agent BTKis over the combination therapy (HR, 0.87; 95% CI, 0.67–1.15). We observed consistent benefits for PFS among patients with high-risk disease characteristics. Although there was no difference in complete response between the two arms (risk ratio (RR), 0.54; 95% CI, 0.20–1.46), BTKi use was related to a better overall response rate (RR, 1.10; 95% CI, 1.04–1.16). The risk of grade ≥3 adverse events (AEs) was comparable between the two arms (RR, 0.82; 95% CI, 0.55–1.23). However, the risk of grade ≥3 AEs was significantly lower in the second-generation BTKi group than in the combination therapy group (RR, 0.73; 95% CI, 0.54–0.98). Overall, BTKis have superior efficacy compared to the combination regimens in patients with untreated or treated CLL/SLL without excess toxicity. Further studies are needed to confirm these results and determine the optimal therapy for managing patients with CLL/SLL. [ABSTRACT FROM AUTHOR]

Simple Summary: Recent practice-changing trials have highlighted the importance of polyadenosine diphosphate-ribose polymerase inhibitors (PARPi) in metastatic castrate resistant prostate cancer (mCRPC). PARP plays a quintessential role in repairing deoxyribonucleic acid (DNA) single-strand breaks by signaling and recruiting the necessary repair machinery to damaged areas. In mCRPC, where mutations are more likely to impair important repair pathways such as the homologous recombinational repair (HRR), remaining PARP repair pathways become critical to cell survival and can be exploited with targeted therapies. The purpose of our review was to compare and contrast recent pivotal trials in this setting and explore future avenues of research. Poly-adenosine diphosphate-ribose polymerase plays an essential role in cell function by regulating apoptosis, genomic stability and DNA repair. PARPi is a promising drug class that has gained significant traction in the last decade with good outcomes in different cancers. Several trials have sought to test its effectiveness in metastatic castration resistant prostate cancer (mCRPC). We conducted a comprehensive literature review to evaluate the current role of PARPi in this setting. To this effect, we conducted queries in the PubMed, Embase and Cochrane databases. We reviewed and compared all major contemporary publications on the topic. In particular, recent phase II and III studies have also demonstrated the benefits of olaparib, rucaparib, niraparib, talazoparib in CRPC. Drug effectiveness has been assessed through radiological progression or overall response. Given the notion of synthetic lethality and potential synergy with other oncological therapies, several trials are looking to integrate PARPi in combined therapies. There remains ongoing controversy on the need for genetic screening prior to treatment initiation as well as the optimal patient population, which would benefit most from PARPi. PARPi is an important asset in the oncological arsenal for mCRPC. New combinations with PARPi may improve outcomes in earlier phases of prostate cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: The clinical development of new cancer drugs is based on clinical trials that compare the new drug with the one representing the standard of care. However, it takes some time for the new drug to become available for patient use. In the meantime, the standard of care may have been updated and therefore the efficacy of the new drug needs to be tested against the new standard of care. This objective is usually pursued by performing indirect comparisons: since no "real" trial is available comparing the new drug with the new standard of care, this comparison is carried out by means of a simulated trial wherein patients of real trials are reconstructed individually, pooled together according to an original design of comparison, and finally subjected to standard statistics. Previously published trials are used to perform this comparison. We describe a new method to perform these indirect comparisons, called the IPDfromKM-Shiny method, that lies midway between simple interpolation and advanced statistics. More than 10 investigations have already been conducted in which this method has been used to perform indirect comparisons, especially in the area of haemato-oncology. In the light of these preliminary experiences, the IPDfromKM-Shiny method is proving to be a valid advancement for conducting comparative research in the area of evidence-based medicine. In the area of evidence-based medicine, the IPDfromKM-Shiny method is an innovative method of survival analysis, midway between artificial intelligence and advanced statistics. Its main characteristic is that an original software investigates the Kaplan-Meier graphs of trials so that individual-patient data are reconstructed. These reconstructed patients represent a new form of original clinical material. The typical objective of investigations based on this method is to analyze the available evidence, especially in oncology, to perform indirect comparisons, and determine the place in therapy of individual agents. This review examined the most recent applications of the IPDfromKM-Shiny method, in which a new web-based software—published in 2021—was used. Reported here are 14 analyses, mostly focused on oncological treatments. Indirect comparisons were based on overall survival or progression free survival. Each of these analyses provided original information to compare treatments with one another and select the most appropriate depending on patient characteristics. These analyses can also be useful to assess equivalence from a regulatory viewpoint. All investigations stressed the importance of heterogeneity to better interpret the evidence generated by IPDfromKM-Shiny investigations. In conclusion, these investigations showed that the reconstruction of individual patient data through this online tool is a promising new method for analyzing trials based on survival endpoints. This new approach deserves further investigation, particularly in the area of indirect comparisons. [ABSTRACT FROM AUTHOR]

Simple Summary: Patients with triple-negative breast cancer have a poor outcome owing to the clinically aggressive behavior of the disease and the lack of hormonal or targeted therapies. Identification of new actionable targets to guide the development of effective treatments remains a critical clinical need. It has been recently suggested that the protein kinase ERK4 has oncogenic signaling activity in triple-negative breast cancer cells and represents a promising novel therapeutic target. However, we raise questions about the experimental approaches used to validate the oncogenic function of ERK4 in breast cancer. ERK3 and ERK4 define a distinct and understudied subfamily of mitogen-activated protein kinases (MAPKs). Little is known about the physiological roles of these atypical MAPKs and their association with human diseases. Interestingly, accumulating evidence points towards a role for ERK3 and ERK4 signaling in the initiation and progression of various types of cancer. Notably, a recent study reported that ERK4 is expressed in a subset of triple-negative breast cancer (TNBC) cell lines and that this expression is critical for AKT activation and for sustaining TNBC cell proliferation in vitro and tumor growth in mice. The authors also showed that depletion of ERK4 sensitizes TNBC cells to phosphatidylinositol-3-kinase (PI3K) inhibitors. They concluded that ERK4 is a promising therapeutic target for TNBC and has potential for combination therapy with PI3K inhibitors. Here, we raise concerns about the cellular models and experimental approaches used in this study, which compromise the conclusions on the oncogenic role of ERK4 in TNBC. [ABSTRACT FROM AUTHOR]

Simple Summary: Clinical trials have demonstrated the effectiveness of pazopanib as a primary treatment for metastatic renal cell carcinoma (mRCC). The approval of tyrosine kinase inhibitors and checkpoint-inhibitors represented further progress in the mRCC treatment landscape. Yet, with the recent changes in treatment options, there are scarce real-world data on these substances, including pazopanib. The PAZOREAL study investigated the effectiveness and safety of pazopanib (first-line), nivolumab (second-line), and everolimus (second- and third-line) in a real-life setting. This study included 376 mRCC patients who received first-line treatment with pazopanib and assessed the treatment's effectiveness, safety, and resultant quality of life. The median time on the drug for the study population was 10.0 months; for primary treatment with pazopanib, it was 6.3 months. The median overall survival (mOS) for the entire study population was 35.9 months. No new safety signals were detected. PAZOREAL provides valuable real-world data for the primary treatment of mRCC with pazopanib. The approval of tyrosine kinase inhibitors and checkpoint inhibitors represented a remarkable progression in the therapeutic landscape for the treatment of metastatic renal cell carcinoma (mRCC). Yet, in the ever-evolving landscape of mRCC treatment, real-world data on these agents, including pazopanib, are scarce. The non-interventional PAZOREAL study investigated the effectiveness and safety of pazopanib (first-line), nivolumab (second-line), and everolimus (second- and third-line) in a real-life setting. The multicentric study included 376 mRCC patients who received first-line treatment with pazopanib and assessed time on the drug (primary endpoint), overall survival, best responses, disease control rates, as well as safety signals and health-related quality of life. The median overall time on the drug was 10.0 months, with first-line pazopanib having a median time on drug of 6.3 months. The median overall survival was 35.9 months. The disease control rate for first-line pazopanib was 56.9%. No new safety signals were detected. PAZOREAL provides valuable real-world data for first-line treatment with pazopanib. [ABSTRACT FROM AUTHOR]

Simple Summary: When evaluating new cancer therapies in clinical trials, it may take a long time to estimate their effectiveness on overall survival, an outcome typically of main interest to regulatory decision-makers. To expedite access to new therapies for patients, regulatory agencies often make their decisions based on treatment effectiveness measured on surrogate outcomes; for example looking at the impact of treatment on delaying cancer recurrence, which can be measured earlier. For such decisions to be robust, a surrogate endpoint needs to be a valid predictor of overall survival. The validation can be complex and previous research in advanced colorectal cancer has suggested that the validity of a surrogate endpoint may depend on treatment class. We have investigated this and our results indicated that the validity of surrogate endpoints is stronger within some treatment classes compared to when ignoring the treatment class. Surrogate's validity needs careful consideration to ensure appropriate regulatory decisions. Background and Aim: Findings from the literature suggest that the validity of surrogate endpoints in metastatic colorectal cancer (mCRC) may depend on a treatments' mechanism of action. We explore this and the impact of Kirsten rat sarcoma (KRAS) status on surrogacy patterns in mCRC. Methods: A systematic review was undertaken to identify randomized controlled trials (RCTs) for pharmacological therapies in mCRC. Bayesian meta-analytic methods for surrogate endpoint evaluation were used to evaluate surrogate relationships across all RCTs, by KRAS status and treatment class. Surrogate endpoints explored were progression free survival (PFS) as a surrogate endpoint for overall survival (OS), and tumour response (TR) as a surrogate for PFS and OS. Results: 66 RCTs were identified from the systematic review. PFS showed a strong surrogate relationship with OS across all data and in subgroups by KRAS status. The relationship appeared stronger within individual treatment classes compared to the overall analysis. The TR-PFS and TR-OS relationships were found to be weak overall but stronger within the Epidermal Growth Factor Receptor + Chemotherapy (EGFR + Chemo) treatment class; both overall and in the wild type (WT) patients for TR-PFS, but not in patients with the mutant (MT) KRAS status where data were limited. Conclusions: PFS appeared to be a good surrogate endpoint for OS. TR showed a moderate surrogate relationship with PFS and OS for the EGFR + Chemo treatment class. There was some evidence of impact of the mechanism of action on the strength of the surrogacy patterns in mCRC, but little evidence of the impact of KRAS status on the validity of surrogate endpoints. [ABSTRACT FROM AUTHOR]

Simple Summary: Given the low prevalence and the heterogeneity of childhood cancers, information about the safety of anti-angiogenic drugs in pediatric patients is only partially assessed. We aimed to evaluate the safety of these drugs in children with solid tumors. This systematic review and meta-analysis reported that one out of two pediatric patients using anti-angiogenic drugs in monotherapy experienced a serious adverse event despite proportions varying per single drug. Cancer is a clinical condition that can benefit from anti-angiogenic drugs (AADs). Given the low prevalence and the heterogeneity of childhood cancers, information about the safety of these drugs in pediatric patients is partially assessed. The aim of this study was to evaluate the safety of AADs in pediatric patients with solid tumors. Clinical trials and observational studies were searched in PubMed, ISI Web of Science, and ClinicalTrials database For each included study, adverse events (AEs) were extracted. A meta-analysis was conducted by pooling proportions of AEs using a random intercept logistic regression model. Seventy studies were retrieved. Most part were clinical trials (55 out of 70), and only fifteen observational studies were found. Overall, proportion of serious and non-serious AEs of AADs used as monotherapy was 46% and 89%, respectively. Proportions of serious AEs varied among drugs: sunitinib, 79%; lenvatinib, 64%; sorafenib, 48%; ramucirumab, 41%; pazopanib, 30%; and vandetanib, 27%. A higher proportion of non-serious hematological AEs was found in the patients receiving pazopanib with respect to sunitinib and lenvatinib. The safety profile of AADs has been extensively investigated for mostly drugs in phase I and II trials and is limited to acute toxicities. Overall, one out of two patients using AAD drugs in monotherapy experienced a serious AE despite proportions varied per single drugs. When AADs were combined with standard chemotherapy, the proportion of AEs varied in relation to the single combinations. [ABSTRACT FROM AUTHOR]

Simple Summary: Neoadjuvant chemotherapy (NACT) is offered to breast cancer (BC) patients to downstage the disease. However, some patients may not respond to NACT, being resistant. We used the serum metabolic profile by Nuclear Magnetic Resonance (NMR) combined with disease characteristics to differentiate between sensitive and resistant BC patients. We obtained accuracy above 80% for the response prediction and showcased how NMR can substantially enhance the prediction of response to NACT. Neoadjuvant chemotherapy (NACT) is offered to patients with operable or inoperable breast cancer (BC) to downstage the disease. Clinical responses to NACT may vary depending on a few known clinical and biological features, but the diversity of responses to NACT is not fully understood. In this study, 80 women had their metabolite profiles of pre-treatment sera analyzed for potential NACT response biomarker candidates in combination with immunohistochemical parameters using Nuclear Magnetic Resonance (NMR). Sixty-four percent of the patients were resistant to chemotherapy. NMR, hormonal receptors (HR), human epidermal growth factor receptor 2 (HER2), and the nuclear protein Ki67 were combined through machine learning (ML) to predict the response to NACT. Metabolites such as leucine, formate, valine, and proline, along with hormone receptor status, were discriminants of response to NACT. The glyoxylate and dicarboxylate metabolism was found to be involved in the resistance to NACT. We obtained an accuracy in excess of 80% for the prediction of response to NACT combining metabolomic and tumor profile data. Our results suggest that NMR data can substantially enhance the prediction of response to NACT when used in combination with already known response prediction factors. [ABSTRACT FROM AUTHOR]

Simple Summary: Treatment outcomes for non-small cell lung cancer (NSCLC) patients have significantly improved since the introduction of targeted therapy using tyrosine kinase inhibitors (TKI). Despite the initial promising results, most patients develop resistance due to on- or off-target mechanisms. On-target mutations prevent the effective binding of TKIs. In this study, we determined whether the most common on-target resistance mutation for treatment with EGFR-TKI mutation, i.e., the EGFR T790M mutation, can be detected in pre-treatment tissue samples and can predict treatment outcome. We included 33 patients who progressed with a T790M positive relapse upon treatment with EGFR-TKI between 2013 to 2019. Progression-free survival (PFS) time of the single T790M positive patient was 9 months, while the T790M negative patients had a median PFS of 10 months (range 2–27). Our results show that the presence of EGFR T790M mutations in pre-TKI samples is rare, even in patients who subsequently progressed with an EGFR T790M mutation. EGFR-mutated non-small cell lung cancer (NSCLC) patients can be effectively treated with tyrosine kinase inhibitors (TKI) but frequently present with an EGFR T790M resistance mutation at relapse. We aimed to screen for T790M in pre-treatment formalin-fixed and paraffin-embedded (FFPE) tissue samples of patients with a confirmed T790M mutation at progression. We analyzed 33 pre-treatment DNA samples of NSCLC patients who progressed upon TKI between 2013 to 2019. To establish storage-time dependent formalin fixation-induced background levels for C>T mutations, we analyzed DNA isolated from archival (stored >1 year, n = 22) and recently generated (stored <1 month, n = 11) FFPE samples and included DNA isolated from white blood cells (WBC) (n = 24) as controls. DNA samples were analyzed by droplet digital (dd)PCR, and positivity was defined by outlier detection according to Grubb's criterion. The T790M background allele frequency levels were 0.160% in DNA isolated from archival-FFPE, 0.100% in fresh FFPE, and 0.035% in WBC. Progression-free survival (PFS) time of the single T790M positive patient was 9 months, while T790M negative patients had a median PFS of 10 months (range 2–27). Proper storage time matched FFPE control samples are essential for reliable detection of T790M mutation at low VAF. The presence of EGFR T790M mutations in pre-TKI samples is rare, even in patients who progressed with EGFR T790M mutations. [ABSTRACT FROM AUTHOR]

Simple Summary: In pancreatic ductal adenocarcinoma, FOLFIRINOX and nab-paclitaxel are recommended as first-line chemotherapy regimens. However, there are limited data to predict the efficacy of the FOLFIRINOX regimen in patient outcomes. Platinum-based chemotherapy is tolerable and responsible in patients with DNA damage repair gene mutations. However, data are still limited, and no Asian data are available yet. Here, we sought to investigate the proportion of germline BRCA 1/2 mutations in patients with germline blood tests. Finally, we investigated the treatment response of FOLFIRINOX in patients with BRCA 1/2 mutations. We found that the presence of germline BRCA 1/2 mutations was associated with an improved overall response rate in pancreatic ductal adenocarcinoma patients treated with FOLFIRINOX. The high response rate in this analysis supports the preferential use of FOLFIRINOX therapy for patients harboring a BRCA germline mutation, and supports the need for early germline testing in order to select the best therapy. We evaluated the proportion of BRCA 1/2 germline mutations in Korean patients with sporadic pancreatic ductal adenocarcinoma (PDAC) and its effect on the chemotherapeutic response of FOLFIRINOX. This retrospective study included patients who were treated at two tertiary hospitals between 2012 and 2020, were pathologically confirmed to have PDAC, and had undergone targeted next-generation sequencing-based germline genetic testing. Sixty-six patients were included in the study (24 men; median age 57.5 years). In the germline test, BRCA 1/2 pathogenic mutations were found in nine patients (9/66, 13%, BRCA 1, n = 3; BRCA 2, n = 5; and BRCA 1/2, n = 1). There was no significant difference in the baseline characteristics according to BRCA mutation positivity. Among patients who underwent FOLFIRINOX chemotherapy, patients with a BRCA 1/2 mutation showed a higher overall response rate than those without a BRCA 1/2 mutation (71.4% vs. 13.9%, p = 0.004). Patients with a germline BRCA 1/2 mutation showed longer progression-free survival than those without a BRCA 1/2 mutation, without a significant time difference (18 months vs. 10 months, p = 0.297). Patients with a BRCA 1/2 mutation in the germline blood test had a higher response rate to FOLFIRINOX chemotherapy in PDAC. The high proportion of BRCA 1/2 germline mutations and response rate supports the need for germline testing in order to predict better treatment response. [ABSTRACT FROM AUTHOR]

Simple Summary: Molecular biomarkers are utilised for the development of targeted therapy and diagnostic or prognostic tools and in strategising therapeutic approaches as they may have an effect in drug response. In lower-grade glioma (LGG), there are currently no established biomarkers that are associated with chemosensitivity. Here, we identified tumour protein 53 (TP53) hotspot mutations in TP53 codon 273 in 33% (17/51) of astrocytoma tissues and retrospectively found that these tumours were associated with significantly improved clinical outcomes when treated with chemotherapy. We used publicly available datasets to successfully confirm these findings. A potential mechanism of this chemosensitivity was explored in this study. TP53 codon 273 mutations can, thus, potentially be an indicator of chemotherapeutic efficacy in astrocytoma, and it may be useful in making astrocytoma treatment decisions. Background: Identification of prognostic biomarkers in cancers is a crucial step to improve overall survival (OS). Although mutations in tumour protein 53 (TP53) is prevalent in astrocytoma, the prognostic effects of TP53 mutation are unclear. Methods: In this retrospective study, we sequenced TP53 exons 1 to 10 in a cohort of 102 lower-grade glioma (LGG) subtypes and determined the prognostic effects of TP53 mutation in astrocytoma and oligodendroglioma. Publicly available datasets were analysed to confirm the findings. Results: In astrocytoma, mutations in TP53 codon 273 were associated with a significantly increased OS compared to the TP53 wild-type (HR (95% CI): 0.169 (0.036–0.766), p = 0.021). Public datasets confirmed these findings. TP53 codon 273 mutant astrocytomas were significantly more chemosensitive than TP53 wild-type astrocytomas (HR (95% CI): 0.344 (0.13–0.88), p = 0.0148). Post-chemotherapy, a significant correlation between TP53 and YAP1 mRNA was found (p = 0.01). In O (6)-methylguanine methyltransferase (MGMT) unmethylated chemotherapy-treated astrocytoma, both TP53 codon 273 and YAP1 mRNA were significant prognostic markers. In oligodendroglioma, TP53 mutations were associated with significantly decreased OS. Conclusions: Based on these findings, we propose that certain TP53 mutant astrocytomas are chemosensitive through the involvement of YAP1, and we outline a potential mechanism. Thus, TP53 mutations may be key drivers of astrocytoma therapeutic efficacy and influence survival outcomes. [ABSTRACT FROM AUTHOR]

Simple Summary: In earlier times, for patients with breast cancer who have metastases in distant organs, e.g., the lung, the mainstay of treatment was confined to chemotherapy. In recent years, additional therapeutic options have evolved as high-throughput commercial testing can identify alterations in genes, which are associated with cancer. Some of the identified genetic changes in each patient might be matched to a targeted therapy if the respective therapeutic agent is available. In this study, the implementation of this approach into routine clinical practice was investigated. All 95 patients with metastatic breast cancer had cancer-related genetic alterations, and, in 63 of them, these could be, in theory, matched to a genomically directed therapy. Out of 30 patients who were assigned to this therapy, 13 (43.3%) experienced an improved relapse-free period and 19 patients were still alive one year after molecular testing, in contrast to 15 out of 65 patients who received the standard therapy. Next-generation sequencing (NGS) followed by matched therapy has opened up new therapeutic options to patients with metastatic breast cancer (mBC). Here we report our experience with this approach in everyday clinical practice. This retrospective study included 95 patients with mBC who were genotyped with the FoundationOne® (CDx) assay in a commercial molecular pathology laboratory. Genetic alterations were identified in all tumor specimens, and 83 patients (87.4%) had a median of 2 (range, 1–6) potentially actionable alterations. A multidisciplinary tumor board recommended genomically guided therapy to 63 patients, 30 of whom received such treatment. Everolimus (n = 15) and anti-human epidermal growth factor receptor 2 (HER2) therapy (n = 6) were most frequently administered. The ratio of progression-free survival (PFS) under NGS-based therapy to PFS under the last line of standard therapy prior to NGS was >1.3 in 13 (43.3%) patients, indicative of a clinical benefit to NGS-directed therapy. One-year overall survival rates were 22.7% (95% CI, 6.5–44.4) in 65 patients allocated to the standard therapy versus 62.9% (95% CI, 41.6–78.2) in 30 patients receiving the matched therapy. In conclusion, NGS-matched treatment improved the clinical outcomes in a subgroup of mBC patients. [ABSTRACT FROM AUTHOR]

Simple Summary: We retrospectively analyzed the results of the five consecutive treatment protocols for pediatric acute myeloid leukemia (AML) used in Poland from 1983 to 2019 (excluding promyelocytic, secondary, biphenotypic, and Down syndrome AML). The study included 899 children. The probability of three-year overall, event-free, and relapse-free survival increased from 0.34 ± 0.03 to 0.75 ± 0.05, 0.31 ± 0.03 to 0.67 ± 0.05, and 0.52 ± 0.03 to 0.78 ± 0.05, respectively. A systematic reduction of early deaths and deaths in remission was achieved, while the percentage of relapses decreased only in the last therapeutic period. Surprisingly good results were obtained in the group of patients with unfavorable genetic abnormalities like KMT2A-MLLT10/t(10;11)(p12;q23) and DEK-NUP214/t(6;9)(p23;q24) who were treated in the AML-BFM 2012 Registry, while an unsatisfactory outcome was found in patients with FLT3-ITD. The use of standardized therapeutic protocols with the successive consideration of genetic prognostic factors and advances in supportive care led to a significant improvement in AML treatment outcomes over the last 40 years. Background: From 1983, standardized therapeutic protocols for pediatric acute myeloid leukemia (AML) based on the BFM group experience were introduced in Poland. We retrospectively analyzed the results of pediatric AML treatment in Poland from 1983 to 2019 (excluding promyelocytic, therapy-related, biphenotypic, and Down syndrome AML). Methods: The study included 899 children suffering from AML treated with the following: AML-PPPLBC 83 (1983–1993, n = 187), AML-PPGLBC 94 (1994–1997, n = 74), AML-PPGLBC 98 (1998–2004, n = 151), AML-BFM 2004 Interim (2004–2015, n = 356), and AML-BFM 2012 (2015–2019, n = 131). Results: The probability of three-year overall survival was 0.34 ± 0.03, 0.37 ± 0.05, 0.54 ± 0.04, 0.67 ± 0.03, and 0.75 ± 0.05; event-free survival was 0.31 ± 0.03, 0.34 ± 0.05, 0.44 ± 0.04, 0.53 ± 0.03, and 0.67 ± 0.05; and relapse-free survival was 0.52 ± 0.03, 0.65 ± 0.05, 0.58 ± 0.04, 0.66 ± 0.03, and 0.78 ± 0.05, respectively, in the subsequent periods. A systematic reduction of early deaths and deaths in remission was achieved, while the percentage of relapses decreased only in the last therapeutic period. Surprisingly good results were obtained in the group of patients treated with AML-BFM 2012 with unfavorable genetic abnormalities like KMT2A-MLLT10/t(10;11)(p12;q23) and DEK-NUP214/t(6;9)(p23;q24), while unsatisfactory outcomes were found in the patients with FLT3-ITD. Conclusions: The use of standardized, systematically modified therapeutic protocols, with the successive consideration of genetic prognostic factors, and advances in supportive care led to a significant improvement in AML treatment outcomes over the last 40 years. [ABSTRACT FROM AUTHOR]

Simple Summary: Trifluridine/tipiracil is an oral combination therapy currently approved as a salvage-line treatment in patients with metastatic colorectal cancer refractory to, or not, candidates for available therapies. However, there is no consensus on the specific factors that should be considered to select patients who benefit the most from trifluridine/tipiracil in clinical practice. The aim of our retrospective cohort study was to assess the early clinical experience with trifluridine/tipiracil in Spain and identify potential survival markers. Our findings endorse the real-life efficacy and safety of trifluridine/tipiracil for refractory metastatic colorectal cancer, as well as revealing the presence of ≤2 metastatic sites, absence of liver metastasis, alkaline phosphatase levels < 300 IU, trifluridine/tipiracil dose reductions, and neutrophil/lymphocyte ratio < 5 as survival markers. Combinations of these markers may help physicians to identify subsets of patients with refractory metastatic colorectal cancer that may benefit the most from trifluridine/tipiracil in their daily practice. Trifluridine/tipiracil is currently approved for metastatic colorectal cancer (mCRC) refractory to available therapies. However, there is no consensus on factors that predict treatment outcomes in daily practice. We assessed the early clinical experience with trifluridine/tipiracil in Spain and potential survival markers. This was a retrospective cohort study of mCRC patients who participated in the trifluridine/tipiracil early clinical experience programme in Spain. The primary outcome was overall survival (OS). Associations between OS and patient characteristics were assessed using multivariate Cox regression analyses. A total of 379 patients were included in the study. Trifluridine/tipiracil was administered for a median of 3.0 cycles and discontinued mainly due to disease progression (79.2%). The median OS was 7.9 months, with a 12-month OS rate of 30.5%. Cox analyses revealed that the following variables independently enhanced OS: ≤2 metastatic sites, no liver metastasis, alkaline phosphatase < 300 IU, trifluridine/tipiracil dose reductions, and neutrophil/lymphocyte ratio < 5. Grade ≥ 3 toxicities were reported in 141 (37.2%) patients, including mainly afebrile neutropaenia (23.2%), anaemia (12.1%), and thrombocytopaenia (5.3%). This study supports the real-life efficacy and safety of trifluridine/tipiracil for refractory mCRC and identifies tumour burden, liver metastasis, alkaline phosphatase, dose reductions, and neutrophil/lymphocyte ratio as survival markers. [ABSTRACT FROM AUTHOR]

Simple Summary: The aims of this study were to investigate aminopeptidase expression in multiple myeloma and to identify the aminopeptidases responsible for the activation of the peptide–drug conjugate melflufen in multiple myeloma. We observed a differential expression of aminopeptidases between relapsed/refractory and newly diagnosed multiple myeloma patients. A higher expression of the aminopeptidase genes XPNPEP1, RNPEP, DPP3, and BLMH in multiple myeloma plasma cells was associated with shorter patient overall survival. The peptide–drug conjugate melflufen was particularly active towards plasma cells from relapsed/refractory multiple myeloma patients. Melflufen could be hydrolyzed to its active form by the aminopeptidases LAP3, LTA4H, RNPEP, and ANPEP, all of which are expressed in multiple myeloma. These results indicate critical roles for aminopeptidases in disease progression and the activity of melflufen in multiple myeloma. Multiple myeloma (MM) is characterized by extensive immunoglobulin production leading to an excessive load on protein homeostasis in tumor cells. Aminopeptidases contribute to proteolysis by catalyzing the hydrolysis of amino acids from proteins or peptides and function downstream of the ubiquitin–proteasome pathway. Notably, aminopeptidases can be utilized in the delivery of antibody and peptide-conjugated drugs, such as melflufen, currently in clinical trials. We analyzed the expression of 39 aminopeptidase genes in MM samples from 122 patients treated at Finnish cancer centers and 892 patients from the CoMMpass database. Based on ranked abundance, LAP3, ERAP2, METAP2, TTP2, and DPP7 were highly expressed in MM. ERAP2, XPNPEP1, DPP3, RNPEP, and CTSV were differentially expressed between relapsed/refractory and newly diagnosed MM samples (p < 0.05). Sensitivity to melflufen was detected ex vivo in 11/15 MM patient samples, and high sensitivity was observed, especially in relapsed/refractory samples. Survival analysis revealed that high expression of XPNPEP1, RNPEP, DPP3, and BLMH (p < 0.05) was associated with shorter overall survival. Hydrolysis analysis demonstrated that melflufen is a substrate for aminopeptidases LAP3, LTA4H, RNPEP, and ANPEP. The sensitivity of MM cell lines to melflufen was reduced by aminopeptidase inhibitors. These results indicate critical roles of aminopeptidases in disease progression and the activity of melflufen in MM. [ABSTRACT FROM AUTHOR]

Simple Summary: Patients with extensive-stage small cell lung cancer (ED-SCLC) have a very short survival time even if they receive standard chemotherapy. Currently, the combination of chemotherapy plus immune checkpoint inhibitors (ICIs) as the first line treatment had superior survival than chemotherapy alone in randomized control trials. However, there is a lack of head-to-head comparisons for these combination regimens. We conducted a systematic review and network meta-analysis to provide a treatment ranking of ICIs for ED-SCLC. In summary, the probability of nivolumab was associated with the best ranking for overall survival, followed by atezolizumab, durvalumab, pembrolizumab, and ipilimumab. The ranking of progression free survival from the best to the worst was as follows: nivolumab, pembrolizumab, atezolizumab, durvalumab, and ipilimumab. However, nivolumab had the highest probability of grade 3–4 adverse events in our study. Further head-to head large-scale phase III randomized controlled studies are needed to verify our conclusions. Patients with extensive-stage small cell lung cancer (ED-SCLC) have a very short survival time even if they receive standard cytotoxic chemotherapy with etoposide and platinum (EP). Several randomized controlled trials have shown that patients with ED-SCLC who received a combination of EP plus immune checkpoint inhibitors (ICIs) had superior survival compared with those who received EP alone. We conducted a systematic review and network meta-analysis to provide a ranking of ICIs for our primary endpoints in terms of overall survival (OS), progression free survival (PFS), and objective response rate (ORR), as well as our secondary endpoint in terms of adverse events. The fractional polynomial model was used to evaluate the adjusted hazard ratios for the survival indicators (OS and PFS). Treatment rank was estimated using the surface under the cumulative ranking curve (SUCRA), as well as the probability of being best (Prbest) reference. EP plus nivolumab, atezolizumab or durvalumab had significant benefits compared with EP alone in terms of OS (Hazard Ratio HR = 0.67, 95% Confidence Interval CI = 0.46–0.98 for nivolumab, HR = 0.70, 95% CI = 0.54–0.91 for atezolizumab, HR = 0.73, 95% CI = 0.59–0.90 for durvalumab) but no significant differences were observed for pembrolizumab or ipilimumab. The probability of nivolumab being ranked first among all treatment arms was highest (SCURA = 78.7%, Prbest = 46.7%). All EP plus ICI combinations had a longer PFS compared with EP alone (HR = 0.65, 95% CI = 0.46–0.92 for nivolumab, HR = 0.77, 95% CI = 0.61–0.96 for atezolizumab, HR = 0.78, 95% CI = 0.65–0.94 for durvalumab, HR = 0.75, 95% CI = 0.61–0.92 for pembrolizumab), and nivolumab was ranked first in terms of PFS (SCURA = 85.0%, Prbest = 66.8%). In addition, nivolumab had the highest probability of grade 3–4 adverse events (SUCRA = 84.8%) in our study. We found that nivolumab had the best PFS and OS in all combinations of ICIs and EP, but nivolumab also had the highest probability of grade 3–4 adverse events in our network meta-analysis. Further head-to head large-scale phase III randomized controlled studies are needed to verify our conclusions. [ABSTRACT FROM AUTHOR]