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Objective: Deep learning (DL) has shown promising results for improving mammographic breast cancer diagnosis. However, the impact of artificial intelligence (AI) on the breast cancer screening process has not yet been fully elucidated in terms of potential workload reduction. We aim to assess if AI-based triaging of breast cancer screening mammograms could reduce the radiologist's workload with non-inferior sensitivity. Methods: PubMed, EMBASE, Cochrane Central, and Web of Science databases were systematically searched for studies that evaluated AI algorithms on computer-aided triage of breast cancer screening mammograms. We extracted data from homogenous studies and performed a proportion meta-analysis with a random-effects model to examine the radiologist's workload reduction (proportion of low-risk mammograms that could be theoretically ruled out from human's assessment) and the software's sensitivity to breast cancer detection. Results: Thirteen studies were selected for full review, and three studies that used the same commercially available DL algorithm were included in the meta-analysis. In the 156,852 examinations included, the threshold of 7 was identified as optimal. With these parameters, radiologist workload decreased by 68.3% (95%CI 0.655–0.711, I ² = 98.76%, p < 0.001), while achieving a sensitivity of 93.1% (95%CI 0.882–0.979, I ² = 83.86%, p = 0.002) and a specificity of 68.7% (95% CI 0.684–0.723, I ² = 97.5%, p < 0.01). Conclusions: The deployment of DL computer-aided triage of breast cancer screening mammograms reduces the radiology workload while maintaining high sensitivity. Although the implementation of AI remains complex and heterogeneous, it is a promising tool to optimize healthcare resources. [ABSTRACT FROM AUTHOR]

Cardiac tumors are rare and encompass a variety of presentations. Clinical symptoms are usually nonspecific, but they can present as obstructive, embolic, or constitutional symptoms. Treatment options and prognosis vary highly depending on the subtype, tumor size, and location. Surgical resection is usually the first-line therapy, except for cardiac lymphomas, and provides favorable long-term prognosis in most benign tumors. Cardiac sarcomas, however, are usually diagnosed in advanced stages, and the treatment relies on a multimodal approach with chemotherapy and radiotherapy. Metastatic cardiac tumors are usually related to advanced disease and carry an overall poor prognosis. [ABSTRACT FROM AUTHOR]

The landscape of non-coding mutations in cancer progression and immune evasion is largely unexplored. Here, we identify transcrptome-wide somatic and germline 3′ untranslated region (3′-UTR) variants from 375 gastric cancer patients from The Cancer Genome Atlas. By performing gene expression quantitative trait loci (eQTL) and immune landscape QTL (ilQTL) analysis, we discover 3′-UTR variants with cis effects on expression and immune landscape phenotypes, such as immune cell infiltration and T cell receptor diversity. Using a massively parallel reporter assay, we distinguish between causal and correlative effects of 3′-UTR eQTLs in immune-related genes. Our approach identifies numerous 3′-UTR eQTLs and ilQTLs, providing a unique resource for the identification of immunotherapeutic targets and biomarkers. A prioritized ilQTL variant signature predicts response to immunotherapy better than standard-of-care PD-L1 expression in independent patient cohorts, showcasing the untapped potential of non-coding mutations in cancer. The role of non-coding mutations in cancer progression and immune evasion needs to be further explored. Here, the authors investigate the potential of common somatic and germline 3′ untranslated region variants in predicting response to immunotherapy in gastric patients. [ABSTRACT FROM AUTHOR]

Induced oncoproteins degradation provides an attractive anti-cancer modality. Activation of anaphase-promoting complex (APC/CCDH1) prevents cell-cycle entry by targeting crucial mitotic proteins for degradation. Phosphorylation of its co-activator CDH1 modulates the E3 ligase activity, but little is known about its regulation after phosphorylation and how to effectively harness APC/CCDH1 activity to treat cancer. Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1)-catalyzed phosphorylation-dependent cis-trans prolyl isomerization drives tumor malignancy. However, the mechanisms controlling its protein turnover remain elusive. Through proteomic screens and structural characterizations, we identify a reciprocal antagonism of PIN1-APC/CCDH1 mediated by domain-oriented phosphorylation-dependent dual interactions as a fundamental mechanism governing mitotic protein stability and cell-cycle entry. Remarkably, combined PIN1 and cyclin-dependent protein kinases (CDKs) inhibition creates a positive feedback loop of PIN1 inhibition and APC/CCDH1 activation to irreversibly degrade PIN1 and other crucial mitotic proteins, which force permanent cell-cycle exit and trigger anti-tumor immunity, translating into synergistic efficacy against triple-negative breast cancer. Unveiling the regulation of mitotic protein degradation is crucial for cancer therapy. Here, the authors reveal that a reciprocal inhibition of PIN1-APC/CCDH1 controls the cell cycle and mitotic protein degradation, offering a synergistic anti-tumor strategy. [ABSTRACT FROM AUTHOR]

PURPOSE: Poly ADP-ribose polymerase inhibitors (PARPi) are approved for patients with human epidermal growth factor receptor 2–negative metastatic breast cancer (mBC) and germline pathogenic/likely pathogenic variant (hereafter mutation) in the BRCA1 / 2 genes (g BRCA); however, clinical benefit has also been demonstrated in mBC with somatic BRCA1 / 2 mutations (s BRCA) or germline PALB2 mutations (g PALB2). This study aims to describe the genomic landscape of homologous recombination repair (HRR) gene alterations in mBC and assess PARPi treatment outcomes for patients with g BRCA compared with other HRR genes and by status of a novel homologous recombination deficiency signature (HRDsig). METHODS: A real-world (RW) clinico-genomic database (CGDB) of comprehensive genomic profiling (CGP) linked to deidentified, electronic health record–derived clinical data was used. CGP was analyzed for HRR genes and HRDsig. The CGDB enabled cohort characterization and outcomes analyses of 177 patients exposed to PARPi. RW progression-free survival (rwPFS) and RW overall survival (rwOS) were compared. RESULTS: Of 28,920 patients with mBC, g BRCA was detected in 3.4%, whereas the population with any BRCA alteration or g PALB2 increased to 9.5%. HRDsig+ represented 21% of patients with mBC. BRCA and g PALB2 had higher levels of biallelic loss and HRDsig+ than other HRR alterations. Outcomes on PARPi were assessed for 177 patients, and g BRCA and s BRCA / gPALB2 cohorts were similar: g BRCA versus s BRCA /g PALB2 rwPFS was 6.3 versus 5.4 months (hazard ratio [HR], 1.37 [0.77-2.43]); rwOS was 16.2 versus 21.2 months (HR, 1.45 [0.74-2.86]). Additionally, patients with HRDsig+ versus HRDsig– had longer rwPFS (6.3 v 2.8 months; HR, 0.62 [0.42-0.92]) and numerically longer rwOS (17.8 v 13.0 months; HR, 0.72 [0.46-1.14]). CONCLUSION: Patients with s BRCA and g PALB2 derive similar benefit from PARPi as those with g BRCA alterations. In combination, HRDsig+, s BRCA , and g PALB2 represent an additional 19% of mBC that can potentially benefit from PARPi. Randomized trials exploring a more inclusive biomarker such as HRDsig are warranted. This is real-world evidence supporting benefit of PARPi in sBRCA, gPALB2, and HRDsig. [ABSTRACT FROM AUTHOR]

Endocrine therapy is the main treatment for hormone receptor-positive (HR+) breast cancer. However, advanced tumors develop resistance to endocrine therapy, rendering it ineffective as the disease progresses. There are several molecular mechanisms of primary and secondary endocrine resistance. Resistance can develop due to either alteration of the estrogen receptor pathway (e.g., ESR1 mutations) or upstream growth factors signaling pathways (e.g., PI3K/Akt/mTOR pathway). Despite progress in the development of molecularly targeted anticancer therapies, the emergence of resistance remains a major limitation and an area of unmet need. In this article, we review the mechanisms of acquired endocrine resistance in HR+ advanced breast cancer and discuss current and future investigational therapeutic approaches. [ABSTRACT FROM AUTHOR]

microRNA-22 (miR-22) is an oncogenic miRNA whose up-regulation promotes epithelial-mesenchymal transition (EMT), tumor invasion, and metastasis in hormone-responsive breast cancer. Here we show that miR-22 plays a key role in triple negative breast cancer (TNBC) by promoting EMT and aggressiveness in 2D and 3D cell models and a mouse xenograft model of human TNBC, respectively. Furthermore, we report that miR-22 inhibition using an LNA-modified antimiR-22 compound is effective in reducing EMT both in vitro and in vivo. Importantly, pharmacologic inhibition of miR-22 suppressed metastatic spread and markedly prolonged survival in mouse xenograft models of metastatic TNBC highlighting the potential of miR-22 silencing as a new therapeutic strategy for the treatment of TNBC. [ABSTRACT FROM AUTHOR]

Simple Summary: Poly-adenosine diphosphate ribose polymerase (PARP) inhibitors (PARPi) are effective against tumors with mutations in DNA repair genes, most commonly in the BRCA1 and BRCA2 genes. Because these tumors are unable to repair their DNA, PARPi have been used to target DNA repair pathways and are useful in the treatment of breast cancers with some of these alterations. There are two FDA-approved PARPi for patients with breast cancer—olaparib and talazoparib. The data on olaparib and talazoparib in the treatment of breast cancer are summarized in this review, and we also explore potential future applications of PARPi beyond inherited BRCA mutations. Poly-adenosine diphosphate ribose polymerase (PARP) inhibitors (PARPi) are approved for BRCA1/2 carriers with HER2-negative breast cancer in the adjuvant setting with a high risk of recurrence as well as the metastatic setting. However, the indications for PARPi are broader for patients with other cancer types (e.g., prostate and ovarian cancer), involving additional biomarkers (e.g., ATM, PALB2, and CHEK) and genomic instability scores. Herein, we summarize the data on PARPi and breast cancer and discuss their use beyond BRCA carriers. [ABSTRACT FROM AUTHOR]

Approximately 5% to 10% of women diagnosed with breast cancer will have a pathogenic variant (PV) in a hereditary cancer susceptibility gene, and this has significant implications for the management of these patients and their relatives. Despite the benefits of genetic testing, many eligible patients with breast cancer never undergo testing because of various barriers, including complicated testing criteria such as those from the National Comprehensive Cancer Network (NCCN). In 2019, the American Society of Breast Surgeons (ASBrS) proposed germline genetic testing for all patients with breast cancer to increase the identification of PV carriers. In 2020, a Mayo Clinic study highlighted the limitations of these 2 genetic testing guidelines (NCCN and ASBrS) and proposed a hybrid approach of testing all women diagnosed with breast cancer by the age of 65 years and using NCCN criteria for older patients. This commentary presents an updated analysis of the Mayo Clinic data and discusses the rationale for using the age of 60 years rather than 65 years as the cutoff for this hybrid approach. Using an age at diagnosis of ≤60 or ≤65 years for the universal testing of patients with breast cancer detected more PVs (11.9% [16 of 134] and 15.7% [21 of 134], respectively) in comparison with using the NCCN criteria. Lowering the age for universal testing from 65 to 60 years maintained the sensitivity of detecting a PV at >90% while sparing testing for an additional 10% of women. Compared with the testing of all patients, the hybrid approach would allow 31% of all women with breast cancer to forgo testing and result in fewer variants of uncertain significance identified and, therefore, would decrease the chance of harm from misinterpretation of these variants. The identification of pathogenic variants in high‐risk breast cancer genes has a significant impact on the management of patients with breast cancer and their relatives, yet many women do not receive genetic testing because of various barriers, with one of the major reasons being complex genetic testing criteria. Testing every single patient with breast cancer is not cost‐effective and has the potential for harm through the mismanagement of benign or ambiguous genetic testing results. This commentary argues that a hybrid approach of testing all patients below a certain age threshold while restricting testing on the basis of guidelines for an older population is a better approach. [ABSTRACT FROM AUTHOR]

Activating mutations of I PIK3CA i are found in 25%-40% of estrogen receptor-positive (ER+), HER2-negative (HER2-) breast cancers (BC), and in 8% of ER-negative (ER-) BC.[1] [5] Two recent studies support the benefit of PI3K inhibition in combination with endocrine therapy. Brain MRI 6 weeks later demonstrated a 14% reduction in the sum of longest distances of measurable brain metastases (24% reduction in bidimensional areas) and regressions of nonmeasurable brain metastases. A recent study showed that I PIK3CA i -mutant BC not only has a higher probability to metastasize to the brain than nonmutant BC (31% I v i 17%) but also has shorter median overall survival after the diagnosis of CNS metastasis (0.5 I v i 1.1 year).[9] The high frequency of brain metastases and their poor prognosis raise the question whether PI3K inhibitors can be beneficial for patients with active brain metastases. Breast Cancer Res; 13: R125, 2011 9 Fitzgerald DM, Muzikansky A, Pinto C, et al: Association between PIK3CA mutation status and development of brain metastases in HR+/HER2- metastatic breast cancer. [Extracted from the article]

Multigene panels are frequently used to determine the presence of a germline pathogenic variant (PV). 5 Prochazkova K, Pavlikova K, Minarik M, et al: Somatic TP53 mutation mosaicism in a patient with Li-Fraumeni syndrome. 23 Villani A, Tabori U, Schiffman J, et al: Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: A prospective observational study. [Extracted from the article]

We present a case of an unusual presentation of acute promyelocytic leukaemia (APML), which presented with Fournier gangrene (FG). A 38-year-old man presented with malaise, groin swelling, anal bleeding, fever and was found to have FG. Initial workup revealed pancytopaenia, borderline low fibrinogen, prolonged international normalized ratio (INR), which raised the suspicion for leukaemia. The peripheral blood differential revealed leucopaenia with absolute neutropaenia and a 5% abnormal promyelocytes but no blasts, suspicious for APML. Bone marrow biopsy was performed and fluorescence in situ hydridization (FISH), karyotype and PCR confirmed a t(15;17) translocation, establishing a diagnosis of APML. After 1 month of therapy for intermediate risk APML with All-trans retinoic acid (ATRA ) and arsenic trioxide (ATO ), repeat chromosomal analysis and repeat bone marrow biopsy revealed no evidence of residual APML. After the consolidation phase was started with ATRA and ATO regimen, the wound healed after 2 months and the patient achieved complete remission. [ABSTRACT FROM AUTHOR]

We report the first case of double-hit (MYC and BCL6) monomorphic post-transplant lymphoproliferative disorder in a patient status post liver transplantation. Our patient is a 71-year-old man with a past medical history of Budd–Chiari syndrome complicated by cirrhosis and hepatocellular carcinoma. He underwent a deceased donor liver transplantation 2 years prior to presentation and was maintained on tacrolimus and mycophenolate mofetil for immunosuppression. He presented with a 3-week history of classical B-symptoms. Initial workup was notable for elevated lactate dehydrogenase. Abdomen ultrasound revealed multiple hypoechoic lesions, raising suspicion for a post-transplant lymphoproliferative disorder. Biopsy showed pleomorphic large neoplastic cells throughout, consistent with a diagnosis of diffuse large B-cell lymphoma. Cytogenetics then revealed rearrangements in both MYC and BCL-6, consistent with double-hit lymphoma. His immunosuppressive regimen was subsequently tapered and he was started on DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab) regimen. [ABSTRACT FROM AUTHOR]

We present a case of a 47-year-old man with severe thrombocytopenia. The differential diagnosis for thrombocytopenia is wide. The assessment includes an evaluation for falsely low platelet counts (pseudothrombocytopenia), immune-mediated platelet destruction, bone marrow dysfunction, or increased consumption and sequestration. After extensive and systematic workup, we found a relationship of his thrombocytopenia with haemodialysis. Although not widely recognised by clinicians, partly due to an incomplete understanding of its pathophysiology, haemodialysis is also a potential cause of thrombocytopenia. His platelet counts completely normalised after the substitution of his haemodialysis membrane. We concluded that our patient had haemodialysis-induced thrombocytopenia, most likely secondary to electron-beam sterilisation. [ABSTRACT FROM AUTHOR]

Glioblastoma multiforme is an astrocyte-derived tumour representing the most aggressive primary brain malignancy. The median overall survival is 10–12 months, but it drops to 3–8.5 months for the cohort with more than 65 years old, which account to half of all patients. Initial management in this patient population aims to balance overall patient survival and quality of life with the inherent risks of treatment intervention, which include maximal safe tumour resection, radiation and temozolomide (TMZ) chemotherapy. This is accomplished through risk stratification as a function of patient age, functional status, comorbidities, tumour location and methylguanine methyltransferase promoter methylation status. We describe the care of a patient with prolonged febrile neutropaenia, with a rare but fatal complication from TMZ-induced idiosyncratic reaction, leading to aplastic anaemia and a provoking diagnosis of low-grade B-cell non-Hodgkin’s lymphoma. [ABSTRACT FROM AUTHOR]

Poly(ADP)ribosylation inhibitors (PARP i s) are toxic to cancer cells with homologous recombination (HR) deficiency but not to HR-proficient cells in the tumor microenvironment (TME), including tumor-associated macrophages (TAMs). As TAMs can promote or inhibit tumor growth, we set out to examine the effects of PARP inhibition on TAMs in BRCA1-related breast cancer (BC). The PARP i olaparib causes reprogramming of TAMs toward higher cytotoxicity and phagocytosis. A PARP i -related surge in NAD+ increases glycolysis, blunts oxidative phosphorylation, and induces reverse mitochondrial electron transport (RET) with an increase in reactive oxygen species (ROS) and transcriptional reprogramming. This reprogramming occurs in the absence or presence of PARP1 or PARP2 and is partially recapitulated by addition of NAD derivative methyl-nicotinamide (MNA). In vivo and ex vivo , the effect of olaparib on TAMs contributes to the anti-tumor efficacy of the PARP i. In vivo blockade of the "don't-eat-me signal" with CD47 antibodies in combination with olaparib improves outcomes in a BRCA1-related BC model. [Display omitted] • PARP inhibition reprograms metabolism and transcription in macrophages • Accumulation of NAD increases reactive oxygen species via reverse electron transport • High ROS production and phagocytic capacity result in anti-tumor function • The combination of olaparib with CD47 antibodies improves outcomes in a mouse model Wang et al. demonstrate that a PARP inhibitor used to treat breast tumors with homologous recombination (HR) deficiency reprograms the HR-proficient macrophages in the tumor microenvironment toward an anti-tumor phenotype. Blocking the "don't-eat-me" signal on tumor cells with anti-CD47 antibodies enhances the therapeutic efficacy of olaparib in a mouse model. [ABSTRACT FROM AUTHOR]

A 76-year-old man with situs inversus totalis underwent a successful off-pump three-vessel coronary artery bypass surgery. The postoperative course was uneventful, and the patient was discharged 8 days later. At 9-month follow-up a coronary computed tomography angiography confirmed the viability of all of the grafts, and one year after the operation the patient remained asymptomatic. It comprises the fifth Brazilian case of a coronary surgery in a patient with situs inversus totalis and the first one of the country of a coronary artery bypass surgery without the use of the cardiopulmonary bypass in this condition. [ABSTRACT FROM AUTHOR]

As open access resource, the role of Internet has been increasing in our professional life. There are several emergent new tools that can facilitate and make it more efficient to get accurate and reliable information. In this article, we discuss how we can manage to get the most from these new instruments, like blogs, Facebook, Twitter, and LinkedIn, in order to improve clinical practice. With good sense and some caution, these can turn to be of valuable help in our careers. [ABSTRACT FROM AUTHOR]

The introduction of next-generation sequencing has resulted in testing multiple genes simultaneously to identify inherited pathogenic variants (PVs) in cancer susceptibility genes. PVs with low minor allele frequencies (MAFs) (< 25-35%) are highlighted on germline genetic test reports. In this review, we focus on the challenges of interpreting PVs with low MAF in breast cancer patients undergoing germline testing and the implications for management.The clinical implications of a germline PV are substantial. For PV carriers in high-penetrance genes like BRCA1, BRCA2, and TP53, prophylactic mastectomy is often recommended and radiation therapy avoided when possible for those with Li-Fraumeni syndrome (LFS). For germline PV carriers in more moderate-risk genes such as PALB2, ATM, and CHEK2, annual breast MRI is recommended and prophylactic mastectomies considered for those with significant family histories. Detection of PVs in cancer susceptibility genes can also lead to recommendations for other prophylactic surgeries (e.g., salpingo-oophorectomy) and increased surveillance for other cancers. Therefore, recognizing when a PV is somatic rather than germline and distinguishing somatic mosaicism from clonal hematopoiesis (CH) is essential. Mutational events that occur at a post-zygotic stage are somatic and will only be present in tissues derived from the mutated cell, characterizing classic mosaicism. Clonal hematopoiesis is a form of mosaicism restricted to the hematopoietic compartment.Among the genes in multi-gene panels used for germline testing of breast cancer patients, the detection of a PV with low MAF occurs most often in TP53, though has been reported in other breast cancer susceptibility genes. Distinguishing a germline TP53 PV (LFS) from a somatic PV (TP53 mosaicism or CH) has enormous implications for breast cancer patients and their relatives.We review how to evaluate a PV with low MAF. The identification of the PV in another tissue confirms mosaicism. Older age, exposure to chemotherapy, radiation, and tobacco are known risk factors for CH, as is the absence of a LFS-related cancer in the setting of a TP53 PV with low MAF. The ability to recognize and understand the implications of somatic PVs, including somatic mosaicism and CH, enables optimal personalized care of breast cancer patients. [ABSTRACT FROM AUTHOR]