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Background: We report phase 1b data from patients enrolled in the JAVELIN Solid Tumor clinical trial (NCT01772004) with unresectable stage IIIC or IV melanoma that had progressed after ≥1 line of therapy for metastatic disease. Patients and methods: Patients received avelumab (10 mg/kg)--a human anti--PD-L1 antibody. Assessments included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. Results: As of December 31, 2016, 51 patients were treated and followed for a median of 24.2months (range, 16.1-31.5). Most patients had cutaneous (n =28 [54.9%]) or ocular (n = 16 [31.4%]) melanoma and had received a median of 2 prior lines of therapy (range, 0-4), including ipilimumab (n = 26 [51.0%]). The confirmed ORR was 21.6% (95% CI, 11.3-35.3; complete response, 7.8%; partial response, 13.7%). The median duration of response was not estimable (95% CI, 2.6 months-not estimable). Median PFS and OS were 3.1 months (95% CI, 1.4-6.3) and 17.2 months (95% CI, 6.6-not estimable), respectively. Subgroup analyses suggested meaningful clinical activity (ORR [95% CI]) in patients with non-ocular melanoma (31.4% [16.9--49.3]), PD-L1--positive tumors (42.1% [20.3-66.5]), or prior ipilimumab therapy (30.8% [14.3--51.8]). Thirty-nine patients (76.5%) had a treatment-related adverse event (TRAE), most commonly infusion-related reaction (29.4%), fatigue (17.6%), and chills (11.8%); 4 patients (7.8%) had a grade 3 TRAE. Five patients (9.8%) had an immune-related TRAE (all were grade 1/2). No grade 4 TRAEs or treatment-related deaths were reported. Conclusion: Avelumab showed durable responses, promising survival outcomes, and an acceptable safety profile in patients with previously treated metastatic melanoma. [ABSTRACT FROM AUTHOR]

Enthusiasm has emerged for the potential of liquid biopsies to provide easily accessible genetic biomarkers for early diagnosis and mutational cancer characterization. We here systematically investigated the suitability of circulating cell‐free DNA (cfDNA) analysis for mutation detection in colorectal cancer (CRC) patients with respect to clinicopathological disease stage. Droplet Digital PCR (ddPCR) was performed to detect common point mutations in the KRAS and BRAF oncogenes in cfDNA from 65 patients and compared to mutations in tumor tissue. Stage of disease was classified according to UICC (Union for International Cancer Control) criteria. In tumor tissue, KRAS or BRAF mutations were present in 35 of 65 cases (44% UICC stage I, 50% stage II, 47% stage III, and 62% stage IV). Although cfDNA was detected in 100% of patients, ddPCR displayed the tumor tissue mutation in only 1 of 6 (17%) stage II patients, whereas 10 of 18 (56%) reported variants were verified in cfDNA samples of the stage IV cohort. No BRAF or KRAS mutation was detected in cfDNA from patients with wild‐type tumor tissue. In one case of mutant stage II colon cancer (KRAS‐G12C), the G12D variant was detected in cfDNA instead. Further workup revealed that circulating tumor‐derived DNA and liver metastases originated from a synchronous KRAS‐mutated cancer of the pancreas. Our results demonstrate that ddPCR‐based analysis is highly specific and useful for mutation monitoring, but the sensitivity limits its usefulness for early cancer detection. [ABSTRACT FROM AUTHOR]

Cells must accurately and quickly detect DNA damage through a set of checkpoint mechanisms that enable repair and control proliferation. Heterogeneous levels of cellular stress and noisy signaling processes can lead to phenotypic variability but little is known about their role in underlying proliferation heterogeneity. Here we study two previously published single cell datasets and find that cells encode heterogeneous levels of endogenous and exogenous DNA damage to shape proliferation heterogeneity at the population level. Using a comprehensive time series analysis of short- and long-term signaling dynamics of p53 and p21, we show that DNA damage levels are quantitatively translated into p53 and p21 signal parameters in a gradual manner. Analyzing instantaneous proliferation and signaling differences among equally-radiated cells, we identify time-localized changes in the period of p53 pulses that drive cells out of a low proliferative state. Our findings suggest a novel role of the p53-p21 network in quantitatively encoding DNA damage strength and fine-tuning proliferation trajectories.The authors unveil a scaling relationship between DNA damage, p53-p21 signaling, and proliferation. The analysis reveals unexpected temporal shifts in p53 and p21 dynamics, encoding damage strength and driving proliferation changes. [ABSTRACT FROM AUTHOR]

Given the complexities of multimodality treatment for patients with head and neck cancer, the rationale for the use of multidisciplinary teams (MDTs) to define individual optimal treatment strategies on a per-patient basis is apparent. Increased use of guideline-directed approaches, reduced time to treatment and improved outcomes, which result from use of an MDT approach in head and neck cancer, have been documented. A discussion of these recent advances, as well as presentation of available country-specific guidance on the roles and responsibilities of team members, supports the creation of similar local-language recommendations for the treatment of patients with head and neck cancer. Finally, expert practical advice on the implementation of MDTs may enable the establishment of the MDT approach more universally around the world. [ABSTRACT FROM AUTHOR]

Background: Targeting the epidermal growth factor receptor (EGFR) pathway is an important approach for a variety of tumors. This study assessed the effect of cetuximab, an anti-EGFR monoclonal antibody, on three gastric cancer cell lines with different phenotypes in vitro and in a therapeutic orthotopic murine gastric cancer model. Methods: Three human gastric cancer cell lines (AGS, MKN-45, NCI-N87) were evaluated for cell surface EGFR expression, and K-ras and BRAF mutations. In vitro, the effects of cetuximab, carboplatin, irinotecan, and docetaxel were investigated. Orthotopic tumors derived from MKN-45 and NCI-N87 were established in nude mice. After 4 weeks, the animals received cetuximab (1 mg/kg, weekly i.p.) or carboplatin (20 mg/kg, weekly i.p.), or both agents. The volume of the primary tumor and local and systemic tumor spread were determined at autopsy at 14 weeks. Tumor sections were immunostained for EGFR, as well as stained for CD31 to analyze microvessel density. Results: Cell surface expression of EGFR was found only in AGS and NCI-N87 cells. AGS cells displayed a codon 12 K-ras mutation, and all three cell lines were BRAF wild-type. In vitro, cetuximab significantly reduced cell viability and proliferation only in EGFR-positive/K-ras wild-type NCI-N87 cells (−48%). In vivo, cetuximab in combination with carboplatin synergistically reduced tumor volume (−75%), dissemination (−63%), and vascularization (−47%) in NCI-N87 xenografts. Tumors derived from EGFR-negative MKN-45 cells were unaffected by cetuximab. Conclusions: Cetuximab is effective in K-ras wild-type, EGFR-expressing gastric cancer cell lines and xenografts. In vivo, the combination of cetuximab with carboplatin displayed synergistic antitumor activity. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: In a randomised study (GM301; dacarbazine with/without oblimersen), patients with advanced melanoma were stratified based on performance status, metastatic site and lactate dehydrogenase (LDH). Progression-free survival and response and durable response rates showed a highly significant difference favouring dacarbazine–oblimersen and a nearly significant survival difference. All efficacy parameters significantly favoured dacarbazine–oblimersen in patients with normal baseline LDH [⩽1.1×upper limit of normal (ULN)]. Each stratification factor was assessed for an interaction with treatment on survival and an interaction was detected only for LDH. Experimental design: Baseline LDH values in Study GM301 treatment groups were combined and analysed using cutoffs above and below 1×ULN. Baseline LDH in EORTC study 18951 (dacarbazine, cisplatin, interferon-alfa-2b with/without interleukin-2 in advanced melanoma) was independently analysed using the same approach. In Study GM301, the relation between treatment effect and LDH, treatment effect and tumour size, LDH and tumour size and LDH and disease site were determined. Results: In Study GM301 (N =760) and Study 18951 (N =325), LDH was within the upper range of normal for a large number of patients. This was not exhibited in the general population, suggesting such values may be elevated rather than normal in melanoma. A highly ordered and monotonic relationship was apparent between LDH and survival: survival worsened as LDH became more elevated, even when LDH remained within normal range. LDH and tumour size were poorly correlated; elevated LDH was not associated with any one disease site. LDH was highly predictive of oblimersen effect. Conclusion: In designing studies, LDH should be considered, regardless of tumour size or disease site. [Copyright &y& Elsevier]

T-cell trafficking is determined by expression patterns of chemokine receptors. The chemokine receptor CXCR3 is expressed on a subpopulation of type 1 T cells and plays an important role for migration of T cells into inflamed and tumor tissues. Here, we studied the chemokine receptor expression on specific T cells generated against the neoantigen keyhole limpet hemocyanin (KLH) in patients who had been immunized in the context of a tumor peptide vaccination trial with or without the adjuvant granulocyte-macrophage colony-stimulating factor (GM-CSF). In patients immunized in the presence of GM-CSF the fraction of CXCR3+ KLH-specific T cells was significantly higher than in patients immunized in the absence of GM-CSF (median 45 vs. 20%, P = 0.001). In contrast, the chemokine receptor CCR4, associated with migration to the skin was found in both cohorts on less than 10% of KLH-specific T cells. These results show that CXCR3 expression on vaccine-induced T cells can be modulated by modifying the local vaccine milieu. [ABSTRACT FROM AUTHOR]

It is well known that malignant cells circulate in the bloodstream of patients with solid tumors. However, the biological significance of circulating tumor cells (CTCs) and the clinical relevance of their detection are still debated. Besides technical issues regarding CTC-detection methods, discontinuous shedding of CTCs from established cancer deposits, genomic instability and metastatic inefficiency might underlie the conflicting results currently available. Nevertheless, technological advances and recent clinical findings are prompting researchers to dissect CTC biology further. Here, we review these recent findings, and discuss the prospects for the identification and molecular characterization of the CTC subset that is responsible for metastasis development. This would provide a formidable tool for prognosis evaluation, anticancer-drug development and, ultimately, cancer-therapy personalization. [Copyright &y& Elsevier]

This trial was performed to define the maximum tolerated dose (MTD) of treosulfan administered in combination with a fixed dose of gemcitabine in uveal melanoma patients. Preclinical studies suggested synergistic activity against uveal melanoma. Gemcitabine (1 g/m2) and treosulfan (2.5–4 g/m2) were administered on days 1 and 8, and cycles were repeated on day 29 for a maximum of six cycles. For treosulfan, dose escalation cohorts of 2–4 patients were enrolled. An additional 25 patients were entered at treosulfan dose levels II (3 g/m2) and III (3.5 g/m2). Thirty three patients with uveal melanoma and six patients with other histologies were accrued. Side-effects were predominantly haematological. The MTD was 3.5 g/m2 of treosulfan together with 1 g/m2 of gemcitabine. In the uveal melanoma patients, one partial response (PR) and 15 stablisations of disease (SD) were recorded and whether this translates into a survival gain should be explored further. [Copyright &y& Elsevier]

In general, metastases to the small intestine are rare, and mostly occur in melanoma. CCR9 has been shown to be the principal chemokine receptor for the thymus expressed chemokine (TECK), a chemokine selectively expressed in the small intestine and thymus. Here we show that CCR9 is highly expressed on melanoma cells and all melanoma cell lines isolated from small intestinal metastases, and on a proportion of cell lines from other sites. Only melanoma cells and cell lines from small intestinal metastases, however, were responsive to the CCR9 ligand TECK, as assessed by receptor downregulation and by actin polymerization. CCR9 expression was also found on the adenocarcinoma cell line CaCo-2 expressing characteristics of enterocytic differentiation, but not on any other cell line isolated from colorectal, breast, and lung cancer. Our data provide evidence that the aberrant functional cell surface expression of an organ-specific chemokine receptor is associated with metastasis to this site. The regulation of receptor function seems to be a critical step in the metastatic process. [ABSTRACT FROM AUTHOR]

Cytokine-based treatment regimens have been evaluated for advanced melanoma in a number of phase I and phase II trials within the last decade. Treatment with interleukin-2 (IL-2) as a single agent has resulted in response rates of approximately 15%, if a high dose of IL-2 is administered. Combination of interferon-α (IFNα) and high dose IL-2 yields response rates ranging from 10 to 41%. Response rates exceeding 50% have been reported with chemoimmunotherapy, if the treatment regimens included at least the three agents IL-2, IFNα and cisplatin. Recent randomized trials have evaluated the impact of these drugs on the survival of patients with advanced melanoma. The current ‘state of the art’ is discussed in this review.Copyright © 2000 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The introduction of adjuvant systemic treatment for patients with high-risk melanomas necessitates accurate staging of disease. However, inconsistencies in outcomes exist between disease stages as defined by the American Joint Committee on Cancer (8th edition). We aimed to develop a tool to predict patient-specific outcomes in people with melanoma rather than grouping patients according to disease stage. Patients older than 13 years with confirmed primary melanoma who underwent sentinel lymph node biopsy (SLNB) between Oct 29, 1997, and Nov 11, 2013, at four European melanoma centres (based in Berlin, Germany; Amsterdam and Rotterdam, the Netherlands; and Warsaw, Poland) were included in the development cohort. Potential predictors of recurrence-free and melanoma-specific survival assessed were sex, age, presence of ulceration, primary tumour location, histological subtype, Breslow thickness, sentinel node status, number of sentinel nodes removed, maximum diameter of the largest sentinel node metastasis, and Dewar classification. A prognostic model and nomogram were developed to predict 5-year recurrence-free survival on a continuous scale in patients with stage pT1b or higher melanomas. This model was also calibrated to predict melanoma-specific survival. Model performance was assessed by discrimination (area under the time-dependent receiver operating characteristics curve [AUC]) and calibration. External validation was done in a cohort of patients with primary melanomas who underwent SLNB between Jan 30, 1997, and Dec 12, 2013, at the Melanoma Institute Australia (Sydney, NSW, Australia). The development cohort consisted of 4071 patients, of whom 2075 (51%) were female and 1996 (49%) were male. 889 (22%) had sentinel node-positive disease and 3182 (78%) had sentinel node-negative disease. The validation cohort comprised 4822 patients, of whom 1965 (41%) were female and 2857 (59%) were male. 891 (18%) had sentinel node-positive disease and 3931 (82%) had sentinel node-negative disease. Median follow-up was 4·8 years (IQR 2·3–7·8) in the development cohort and 5·0 years (2·2–8·9) in the validation cohort. In the development cohort, 5-year recurrence-free survival was 73·5% (95% CI 72·0–75·1) and 5-year melanoma-specific survival was 86·5% (85·3–87·8). In the validation cohort, the corresponding estimates were 66·1% (64·6–67·7) and 83·3% (82·0–84·6), respectively. The final model contained six prognostic factors: sentinel node status, Breslow thickness, presence of ulceration, age at SLNB, primary tumour location, and maximum diameter of the largest sentinel node metastasis. In the development cohort, for the model's prediction of recurrence-free survival, the AUC was 0·80 (95% CI 0·78–0·81); for prediction of melanoma-specific survival, the AUC was 0·81 (0·79–0·84). External validation showed good calibration for both outcomes, with AUCs of 0·73 (0·71–0·75) and 0·76 (0·74–0·78), respectively. Our prediction model and nomogram accurately predicted patient-specific risk probabilities for 5-year recurrence-free and melanoma-specific survival. These tools could have important implications for clinical decision making when considering adjuvant treatments in patients with high-risk melanomas. Erasmus Medical Centre Cancer Institute. [ABSTRACT FROM AUTHOR]

Motivation In precision oncology (PO), clinicians aim to find the best treatment for any patient based on their molecular characterization. A major bottleneck is the manual annotation and evaluation of individual variants, for which usually a range of knowledge bases are screened. To incorporate and integrate the vast information of different databases, fast and accurate methods for harmonizing databases with different types of information are necessary. An essential step for harmonization in PO includes the normalization of tumor entities as well as therapy options for patients. Summary preon is a fast and accurate library for the normalization of drug names and cancer types in large-scale data integration. Availability and implementation preon is implemented in Python and freely available via the PyPI repository. Source code and the data underlying this article are available in GitHub at https://github.com/ermshaua/preon/. [ABSTRACT FROM AUTHOR]

Background: Anaplastic thyroid cancer (ATC) is a rare and aggressive neoplasm. We still lack effective treatment options, so survival rates remain very low. Here, we aimed to evaluate the activity of the combination of lenvatinib and pembrolizumab as systemic first-line therapy in ATC. Methods: In a retrospective analysis, we investigated the activity and tolerability of combined lenvatinib (starting dose 14 to 24 mg daily) and pembrolizumab (200 mg every three weeks) as first-line therapy in an institutional cohort of ATC patients. Results: Five patients with metastatic ATC received lenvatinib and pembrolizumab as systemic first-line therapy. The median progression-free survival was 4.7 (range 0.8–5.9) months, and the median overall survival was 6.3 (range 0.8-not reached) months. At the first follow-up, one patient had partial response, three patients had stable disease, and one patient was formally not evaluable due to interference of assessment by concomitant acute infectious thyroiditis. This patient was then stable for more than one year and was still on therapy at the data cutoff without disease progression. Further analyses revealed deficient DNA mismatch repair, high CD8+ lymphocyte infiltration, and low macrophage infiltration in this patient. Of the other patients, two had progressive disease after adverse drug reactions and therapy de-escalation, and two died after the first staging. For all patients, the PD-L1 combined positive score ranged from 12 to 100%. Conclusions: The combination of lenvatinib and pembrolizumab was effective and moderately tolerated in treatment-naïve ATC patients with occasional long-lasting response. However, we could not confirm the exceptional responses for this combination therapy reported before in pretreated patients. [ABSTRACT FROM AUTHOR]

Upfront KRAS and NRAS gene testing (' RAS ') is the standard of care for metastatic colorectal cancer (mCRC), to guide first-line treatment. The presence of RAS mutation (MT) is a negative predictor for the efficacy of anti-EGFR antibodies and the use of cetuximab and panitumumab is restricted to RAS wild-type (WT) mCRC. Conversion from RAS WT to RAS MT mCRC after treatment with anti-EGFR antibodies is a known and well-described acquired resistance mechanism. The by far less frequent 'Neo RAS wild-type' phenomenon (reversion from RAS MT to RAS WT) has recently drawn attention. The proposed effect of chemotherapy on RAS status in mCRC patients is not fully understood. Because of the intriguing biological consequence of a RAS MT to RAS WT reversion, subsequent treatment of Neo RAS WT patients with anti-EGFR antibodies is increasingly being discussed. Here, we report three clinical cases of Neo RAS WT mCRC patients, which received standard-of-care regimens for RAS MT mCRC. Anti-EGFR antibodies were used in two out of three patients after progression of the disease. One of the patients had a long-term response. In line with our observations, Neo RAS WT phenomenon occurs in clinical practice. Retesting of RAS status during treatment should be discussed in patients with unusual long-term clinical courses of RAS MT mCRC to optimise treatment strategy and to evaluate the use of anti-EGFR antibodies. • RAS gene status could be changed before and after the chemotherapy. • mCRC patients with Neo RAS wild-type could gain the benefit from EGFR inhibitor. • Retesting of RAS genes contributes to optimise treatment strategy of EGFR inhibitor. [ABSTRACT FROM AUTHOR]

Patients with malignant melanoma and distant metastases generally have an unfavorable prognosis, with a median survival of about 6 months. The mechanisms of hematogenous spread and implantation of melanoma cells are, however, poorly understood, because the standard diagnostic methods are not sensitive enough to detect oligocellular micrometastases. Recently a method using reverse transcription and polymerase chain reaction to determine tyrosinase mRNA in peripheral blood, which indicates the presence of circulating melanoma cells, has been developed. We utilized this assay to examine blood samples of 56 patients with malignant melanoma in different stages of disease. In one of 10 patients in stage I (localized disease) and in six of 17 patients with regional lymph nodes metastases (stage II) tyrosinase mRNA was detected. Tyrosinase transcripts were found in all 29 patients with distant metastases (stage III). Interestingly, tyrosinase mRNA was also detected in six patients with metastatic amelanotic malignant melanoma. In contrast, tyrosinase mRNA was not detectable in any of 39 healthy subjects or 17 patients with other malignancies. These findings may be helpful to define a patient group at high risk for systemic spread of disease. [ABSTRACT FROM AUTHOR]

Background: We report phase 1b data from patients enrolled in the JAVELIN Solid Tumor clinical trial (NCT01772004) with unresectable stage IIIC or IV melanoma that had progressed after ≥1 line of therapy for metastatic disease. Patients and methods: Patients received avelumab (10 mg/kg)—a human anti–PD-L1 antibody. Assessments included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. Results: As of December 31, 2016, 51 patients were treated and followed for a median of 24.2 months (range, 16.1–31.5). Most patients had cutaneous (n = 28 [54.9%]) or ocular (n = 16 [31.4%]) melanoma and had received a median of 2 prior lines of therapy (range, 0–4), including ipilimumab (n = 26 [51.0%]). The confirmed ORR was 21.6% (95% CI, 11.3–35.3; complete response, 7.8%; partial response, 13.7%). The median duration of response was not estimable (95% CI, 2.6 months-not estimable). Median PFS and OS were 3.1 months (95% CI, 1.4–6.3) and 17.2 months (95% CI, 6.6-not estimable), respectively. Subgroup analyses suggested meaningful clinical activity (ORR [95% CI]) in patients with non-ocular melanoma (31.4% [16.9–49.3]), PD-L1–positive tumors (42.1% [20.3–66.5]), or prior ipilimumab therapy (30.8% [14.3–51.8]). Thirty-nine patients (76.5%) had a treatment-related adverse event (TRAE), most commonly infusion-related reaction (29.4%), fatigue (17.6%), and chills (11.8%); 4 patients (7.8%) had a grade 3 TRAE. Five patients (9.8%) had an immune-related TRAE (all were grade 1/2). No grade 4 TRAEs or treatment-related deaths were reported. Conclusion: Avelumab showed durable responses, promising survival outcomes, and an acceptable safety profile in patients with previously treated metastatic melanoma. Trial registration: ClinicalTrials.gov identifier: NCT01772004. [ABSTRACT FROM AUTHOR]

Background: Risk-reducing salpingo-oophorectomy (RRSO) is recommended to women with a pathogenic BRCA variant, but as a main side effect, RRSO could lead to an early onset of menopause. Aim: To evaluate the impact of RRSO and preoperative menopausal status on menopausal symptoms, sexual functioning, and quality of life (QOL). Methods: The study was conducted between November 2019 and April 2020. Women were included who tested positive for a pathogenic BRCA1/2 variant between 2015 and 2018. Depression levels, QOL, and global health status were measured and compared with those of women who opted against RRSO. Furthermore, women who underwent RRSO treatment were asked to report menopausal complaints that they experienced at 1 month postsurgery and any current complaints. Outcomes: RRSO had no significant impact on QOL, but women who were premenopausal at the time of surgery reported more sexual complaints than postmenopausal women. Results: In total, 134 carriers of a BRCA mutation were included: 90 (67%) underwent RRSO and 44 (33%) did not. At the time of the survey, neither the control nor experimental group experienced significant changes in QOL (b = –0.18, P = .59). Women who underwent RRSO reported a significantly lower global health status (b = –0.66, P = .05). Women who were premenopausal at the time of surgery were bothered more by sexual symptoms (b = 0.91, P = .19) but experienced fewer vasomotor complaints (b = –1.09, P = .13) than women who were postmenopausal at the time of RRSO. Clinical Implications: The decrease of sexual functioning after RRSO should be an integral part of preoperative counseling because it is important for BRCA carriers, especially for premenopausal women. Strengths and Limitations: Some strengths of the present study were the long follow-up, a high response rate, and the existence of a control group, whereas defining menopausal status by last menstrual bleeding and self-report of data (eg, breast cancer history) increased the risk of errors. Conclusion: Our study indicated that women who underwent RRSO experienced no difference in QOL when compared with women without RRSO and that patients with premenopausal status seemed to be at higher risk to experience sexual complaints after surgery. [ABSTRACT FROM AUTHOR]

Objectives: Patients with head and neck squamous cell carcinoma (HNSCC) can experience severe symptom burden and/or difficulty swallowing, leading to problems with treatment adherence/administration. In LUX-Head and Neck 1 (LH&N1; NCT01345682), second-line afatinib improved progression-free survival (PFS) versus methotrexate in patients with recurrent/metastatic HNSCC. We report adherence and safety across pre-specified and additional subgroups potentially linked to afatinib PFS benefit in LH&N1 (p16 status, smoking history), and afatinib adherence, safety and efficacy by administration (oral versus feeding tube; post-hoc analysis).Methods: Patients were randomized (2:1) to afatinib (40 mg/day) or intravenous methotrexate (40 mg/m2/week).Results: Among 320 afatinib-treated and 160 methotrexate-treated patients, 83-92% and 76-92% (of patients with data available) across all subgroups took ≥80% of treatment. Across p16 status and smoking history subgroups, the most common treatment-related adverse events (AEs) were diarrhea (70-91%), rash/acne (72-84%), stomatitis (34-73%) with afatinib; and included stomatitis (39-100%), fatigue (22-50%), nausea (19-36%) with methotrexate. Dose reduction decreased AE incidence/severity. Baseline characteristics were generally similar between oral/feeding tube (n = 276/n = 46) groups. 89%/89% (of patients with data available) took ≥80% of assigned afatinib. Median PFS was 2.6 versus 2.7 months (hazard ratio: 0.997; 95% confidence interval: 0.72-1.38). The most common afatinib-related AEs were: rash/acne (74% versus 74%), diarrhea (73% versus 65%), stomatitis (40% versus 30%).Conclusion: Subgroup analyses of LH&N1 demonstrate that afatinib has predictable and manageable safety across patient subgroups, with high treatment adherence, and is effective via oral and feeding tube administration. [ABSTRACT FROM AUTHOR]

The author reflects on a clinical case which addresses the issue of spontaneous regression of colorectal cancer. He cites several uncertainties that confront the issue including the potential of incorrect diagnosis and the lack of clear data concerning the frequency of regression. He also mentions the implications of cytokine treatments on the occurrence spontaneous regression in cancer.

In addition to being risk factors for pancreatic cancer, parameters such as smoking, diabetes, or obesity might also act as potential prognostic factors for the survival of patients initially diagnosed with pancreatic cancer. By implementing one of the largest retrospective study cohorts of 2323 pancreatic adenocarcinoma (PDAC) patients treated at a single high-volume center, potential prognostic factors for survival were evaluated on the basis of 863 cases. Since parameters such as smoking, obesity, diabetes, and hypertension can cause severe chronic kidney dysfunction, the glomerular filtration rate was also considered. In the univariate analyses, albumin (p < 0.001), active smoking (p = 0.024), BMI (p = 0.018), and GFR (p = 0.002) were identified as metabolic prognostic markers for overall survival. In multivariate analyses, albumin (p < 0.001) and chronic kidney disease stage 2 (GFR < 90 mL/min/1.37 m2; p = 0.042) were identified as independent metabolic prognostic markers for survival. Smoking presented a nearly statistically significant independent prognostic factor for survival with a p-value of 0.052. In summary, low BMI, status of active smoking, and reduced kidney function at the time of diagnosis were associated with lower overall survival. No prognostic association could be observed for presence of diabetes or hypertension. [ABSTRACT FROM AUTHOR]

Aim: Chemoresistance is a major cause of treatment failure in colorectal cancer (CRC) therapy. In this study, the impact of the IGF2BP family of RNA-binding proteins on CRC chemoresistance was investigated using in silico, in vitro, and in vivo approaches. Methods: Gene expression data from a well-characterized cohort and publicly available cross-linking immunoprecipitation sequencing (CLIP-Seq) data were collected. Resistance to chemotherapeutics was assessed in patient-derived xenografts (PDXs) and patient-derived organoids (PDOs). Functional studies were performed in 2D and 3D cell culture models, including proliferation, spheroid growth, and mitochondrial respiration analyses. Results: We identified IGF2BP2 as the most abundant IGF2BP in primary and metastastatic CRC, correlating with tumor stage in patient samples and tumor growth in PDXs. IGF2BP2 expression in primary tumor tissue was significantly associated with resistance to selumetinib, gefitinib, and regorafenib in PDOs and to 5-fluorouracil and oxaliplatin in PDX in vivo. IGF2BP2 knockout (KO) HCT116 cells were more susceptible to regorafenib in 2D and to oxaliplatin, selumitinib, and nintedanib in 3D cell culture. Further, a bioinformatic analysis using CLIP data suggested stabilization of target transcripts in primary and metastatic tumors. Measurement of oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) revealed a decreased basal OCR and an increase in glycolytic ATP production rate in IGF2BP2 KO. In addition, real-time reverse transcriptase polymerase chain reaction (qPCR) analysis confirmed decreased expression of genes of the respiratory chain complex I, complex IV, and the outer mitochondrial membrane in IGF2BP2 KO cells. Conclusions: IGF2BP2 correlates with CRC tumor growth in vivo and promotes chemoresistance by altering mitochondrial respiratory chain metabolism. As a druggable target, IGF2BP2 could be used in future CRC therapy to overcome CRC chemoresistance. [ABSTRACT FROM AUTHOR]

Describes the rapid regression of chemotherapy refractory lymphocyte predominant Hodgkin's disease after administration of Rituximab and interleukin-2. Mechanism of action of Rituximab; Medical history of a lymphocyte predominant Hodgkin's disease patient treated with Rituximab; Dose administration.

Simple Summary: Inflammation markers such as the neutrophil to lymphocyte ratio (NRL), the platelet to lymphocyte ratio (PLR), the lymphocyte to monocyte ratio (LMR) and the CRP to albumin ratio (CAR) have recently gained attention due to their potential as prognostic scores for overall survival (OS) in pancreatic cancer. So far, these parameters have not been validated in a larger cohort to predict OS in terms of potential recurrence after curative intended resection or in terms of patient response to chemotherapy. In the largest single-center analysis of 1294 patients, inflammation markers were compared and a new highly significant combined score, termed the inflammatory benchmark index (IBI), comprising five inflammatory markers was developed. In multivariate analyses NLR (p = 0.001), LMR (p = 0.038), CAR (p < 0.001) and IBI (p < 0.001) were identified as independent prognostic markers for overall survival. Inflammatory properties are known to promote tumor progression leading to an impaired median overall survival (mOS). Various small studies have focused on a wide range of inflammation-based prognostic indicators. By using sufficient data from 1294 out of 2323 patients diagnosed with pancreatic cancer between 2009 and 2021 at our cancer center, inflammatory markers such as the neutrophil to lymphocyte ratio (NRL), the platelet to lymphocyte ratio (PLR), the lymphocyte to monocyte ratio (LMR) and the CRP to albumin ratio (CAR) were evaluated. We identified a new combined score, termed the inflammatory benchmark index (IBI). We performed univariate and multivariate overall survival analyses and identified optimal prognostic cut-off values for each parameter. In univariate analyses, advanced age (p < 0.001), gender (p < 0.001), tumor stage (p < 0.001), CA19-9 (p = 0.001), NLR (p = 0.001), LMR (p = 0.004), PLR (p = 0.004), CAR (p = 0.001) and IBI (p = 0.001) were identified as prognostic markers. In multivariate analyses advanced age (p < 0.001), gender (p = 0.001), tumor stage (p < 0.001), CA19-9 (p < 0.001), NLR (p = 0.001), LMR (p = 0.038), CAR (p < 0.001) and IBI (p < 0.001) were independent prognostic markers. These findings emphasize the impact of inflammation in pancreatic cancer, provide easily accessible prognostic values for the clinician, and may be useful as stratification parameters for trials aimed at patient inflammation or immune response. [ABSTRACT FROM AUTHOR]

Purpose: An increasing number of international studies demonstrate serious negative effects of the COVID-19 pandemic on the timely diagnosis of cancer and on cancer treatment. Our study aimed to quantitatively and qualitatively evaluate the capacities of German Comprehensive Cancer Centers (CCCs) in different areas of complex oncology care during the first 2 years of the COVID-19 pandemic. Methods: Prospective panel survey over 23 rounds among 18 CCCs in Germany between March 2020 and June 2022. Results: The COVID-19 pandemic substantially affected the oncological care system in Germany during the first 2 years. Persistent limitations of care in CCCs primarily affected follow-up (− 21%) and psycho-oncologic care (− 12%), but also tumor surgery (− 9%). Substantial limitations were also reported for all other areas of multidisciplinary oncological care. Conclusions: This study documents the limitations of oncological care during the COVID-19 pandemic and highlights the need to develop strategies to avoid similar limitations in the future. [ABSTRACT FROM AUTHOR]

Head and neck squamous cell carcinoma (HNSCC) is one of the most common solid cancers worldwide. It is mainly caused by exposure to tobacco smoke and alcohol as well as infection with the human papilloma virus (HPV). The prognosis is poor, especially once it recurs or metastasizes. Current therapeutic options include surgery, radio- and chemotherapy. Epidermal growth factor receptor (EGFR) inhibitors are so far the only targeted agents that have been approved in head and neck cancer. Primary or secondary resistance is frequent or will eventually develop. Several driver mutations and other genomic aberrations have been described in HNSCC including EGFR overexpression and amplification. Yet, no predictive biomarkers for the application of EGFR inhibitors have been identified. Further targeted agents are in development for HNSCC, of which inhibitors of the PI3K pathway are the closest to clinical application. In recent years, the incidence of HPV-driven HNSCC has risen in Western countries. HPV-positive and -negative HNSCC are distinct molecular tumor entities, and consequences for targeted therapies have been discussed. This review looks at approved and investigational targeted treatment strategies as well as potential predictive biomarkers such as the HPV status to guide treatment. [ABSTRACT FROM AUTHOR]

Background: Structured and harmonized implementation of molecular tumor boards (MTB) for the clinical interpretation of molecular data presents a current challenge for precision oncology. Heterogeneity in the interpretation of molecular data was shown for patients even with a limited number of molecular alterations. Integration of high-dimensional molecular data, including RNA- (RNA-Seq) and whole-exome sequencing (WES), is expected to further complicate clinical application. To analyze challenges for MTB harmonization based on complex molecular datasets, we retrospectively compared clinical interpretation of WES and RNA-Seq data by two independent molecular tumor boards.Methods: High-dimensional molecular cancer profiling including WES and RNA-Seq was performed for patients with advanced solid tumors, no available standard therapy, ECOG performance status of 0-1, and available fresh-frozen tissue within the DKTK-MASTER Program from 2016 to 2018. Identical molecular profiling data of 40 patients were independently discussed by two molecular tumor boards (MTB) after prior annotation by specialized physicians, following independent, but similar workflows. Identified biomarkers and resulting treatment options were compared between the MTBs and patients were followed up clinically.Results: A median of 309 molecular aberrations from WES and RNA-Seq (n = 38) and 82 molecular aberrations from WES only (n = 3) were considered for clinical interpretation for 40 patients (one patient sequenced twice). A median of 3 and 2 targeted treatment options were identified per patient, respectively. Most treatment options were identified for receptor tyrosine kinase, PARP, and mTOR inhibitors, as well as immunotherapy. The mean overlap coefficient between both MTB was 66%. Highest agreement rates were observed with the interpretation of single nucleotide variants, clinical evidence levels 1 and 2, and monotherapy whereas the interpretation of gene expression changes, preclinical evidence levels 3 and 4, and combination therapy yielded lower agreement rates. Patients receiving treatment following concordant MTB recommendations had significantly longer overall survival than patients receiving treatment following discrepant recommendations or physician's choice.Conclusions: Reproducible clinical interpretation of high-dimensional molecular data is feasible and agreement rates are encouraging, when compared to previous reports. The interpretation of molecular aberrations beyond single nucleotide variants and preclinically validated biomarkers as well as combination therapies were identified as additional difficulties for ongoing harmonization efforts. [ABSTRACT FROM AUTHOR]

In patients with advanced squamous cell carcinoma of the head and neck (SCCHN), aggressive treatment is effective, but can significantly impact their health-related quality of life (HRQoL), particularly if there is damage to the structures involved in swallowing, breathing, speech or physical appearance. Long-term psychosocial support may be required for patients whose basic functioning and social interactions are affected. In randomised clinical trials in SCCHN, HRQoL has not been routinely reported and, with a number of different HRQoL tools available, data for many of the parameters that patients consider important in their day-to-day lives are not widely available to clinicians. In addition, the assessment of HRQoL outside of the clinical trial setting is even scarcer. In an era of personalised medicine, an individualised approach to assessing QoL (iQoL) is of paramount importance when treating and monitoring patients with SCCHN; by responding to QoL concerns, appropriate treatment regimens that result in meaningful improvements in clinical outcomes and quality of survival (QoS) for patients can be adopted. In this review we describe the tools available for assessing HRQoL in cancer patients and provide an overview of the HRQoL data currently available in head and neck cancer. How this information can be used to individualise treatment to optimise clinical outcomes, maximise the patient's day-to-day living and minimise healthcare spending in SCCHN is discussed. [ABSTRACT FROM AUTHOR]

Squamous cell cancer of the head and neck (SCCHN) is a frequent aggressive malignancy with limited therapeutic options. Increasing evidence suggests that mammalian target of rapamycin (mTOR)-inhibitors might be effective in advanced SCCHN. However, non-invasive biomarkers for early prediction of treatment efficacy are not established in SCCHN. Highly proliferating tumours are characterised by enhanced cell turnover which is associated with enhanced apoptosis. During apoptosis of epithelial cells caspases cleave cytokeratin (CK)-18 can be detected in the blood. In this study we analysed sera from patients with relapsed or metastatic SCCHN patients who have been treated with temsirolimus for caspase-cleaved and total (caspase-cleaved and uncleaved) CK-18 by enzyme-linked immunosorbent assays (ELISAs). In addition, caspase-3 activity was detected by luminometric substrate assay. SCCHN patients revealed higher serum levels of those biomarkers compared to healthy controls. Importantly, patients with short progression-free survival (PFS) showed higher serum levels of caspase-3 activity compared to patients with longer PFS (⩾2 months). Caspase-3 activity is inversely correlated with PFS. A cut-off value for caspase-3 activity was determined that correctly predicted PFS <2 months with a sensitivity of 86% and a specificity of 67%. These data demonstrate that detection of serum caspase-3 activity might be a useful non-invasive biomarker for early identification of SCCHN patients not responding to treatment with novel targeted therapies such as mTOR-inhibitors. [ABSTRACT FROM AUTHOR]

Targeted therapies for metastatic uveal melanoma have shown limited benefit in biomarker-unselected populations. The Treat20 Plus study prospectively evaluated the feasibility of a precision oncology strategy in routine clinical practice. Fresh biopsies were analyzed by high-throughput genomics (whole-genome, whole-exome, and RNA sequencing). A multidisciplinary molecular and immunologic tumor board (MiTB) made individualized treatment recommendations based on identified molecular aberrations, patient situation, drug, and clinical trial availability. Therapy selection was at the discretion of the treating physician. The primary endpoint was the feasibility of the precision oncology clinical program. Molecular analyses were available for 39/45 patients (87%). The MiTB provided treatment recommendations for 40/45 patients (89%), of whom 27/45 (60%) received ≥1 matched therapy. First-line matched therapies included MEK inhibitors (n = 15), MET inhibitors (n = 10), sorafenib (n = 1), and nivolumab (n = 1). The best response to first-line matched therapy was partial response in one patient (nivolumab based on tumor mutational burden), mixed response in two patients, and stable disease in 12 patients for a clinical benefit of 56%. The matched therapy population had a median progression-free survival and overall survival of 3.3 and 13.9 months, respectively. The growth modulation index with matched therapy was >1.33 in 6/17 patients (35%) with prior systemic therapy, suggesting clinical benefit. A precision oncology approach was feasible for patients with metastatic uveal melanoma, with 60% receiving a therapy matched to identify molecular aberrations. The clinical benefit after checkpoint inhibitors highlights the value of tumor mutational burden testing. • Demonstration of the feasibility of precision oncology for advanced uveal melanoma. • Complete whole-genome and RNA sequencing data were generated for 87% of patients. • Following treatment recommendations, 60% of patients received ≥1 matched therapy. • First-line therapies included inhibitors of MEK, MET, sorafenib, and nivolumab. • Clinical benefit rate in 56% of patients with one partial response under nivolumab. [ABSTRACT FROM AUTHOR]

Background: Cytogenetic testing (CGT) in uveal melanoma patients reveals prognostic information about the individual risk of developing distant metastasis with dismal prognosis. There is currently no medical intervention strategy with proven effect on the prognosis, rendering the result of the cytogenetic testing purely informative. We explored patients' socio-demographic backgrounds, psychological preconditions, coping strategies, external influences, and concerns about "knowing their fate" to study their possible interactions with decision-making for CGT.Methods: Uveal melanoma patients were asked to complete questionnaires on their interest in undergoing CGT for prognostication and the factors influencing their decision. Data were collected on socio-demographics, baseline anxiety (GAD-7), depression (PHQ-9), coping strategies (Brief COPE), and assumed future concerns regarding the CGT result. Data were analyzed by using multiple ordinal logistic regression and exploring estimated marginal effects.Results: Questionnaires were returned by 121 of 131 (92.4%) patients. Fifty-two patients (43%) had no interest in CGT, 34 (28.1%) were undecided, and 35 (28.9%) were interested. We observed no significant differences regarding age, sex, partnership, education, occupation, baseline anxiety, or depression. Decision-making favoring CGT was influenced by the treating physicians, internet resources, and level of baseline anxiety. Patients were likely to reject CGT when they worried that "knowing the result will have an unintended influence" on their life.Conclusion: Decision-making about CGT for prognostication in uveal melanoma is burdensome to many patients and in general not guided by medical advice regarding further treatment and screening procedures. The psychological impact of the decision is therefore unique and requires careful support by psycho-oncologists considering the patient's fears and expectations. [ABSTRACT FROM AUTHOR]

Introduction: CeFCiD was a multicenter phase II study comparing the efficacy of cetuximab (C), 5-flourouracil, and cisplatin with the same regimen adding docetaxel (D) in recurrent/metastatic head and neck cancer. The primary analysis trial did not demonstrate survival benefit from therapy intensification in first-line recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN). The current analysis of the trial assessed the impact of treatment on quality of life (QoL). Methods: The European Organization for Research and Treatment of Cancer Quality of life Questionnaire QLQ-C30 and the tumor-specific module for head and neck cancer (QLQ-H&N35) were used to assess QoL at baseline (visit 1), after 2 (visit 3), 4 (visit 5), and 6 (visit 7) cycles of chemotherapy. Results: Of 180 patients included in this study, 86 patients (47.8%) completed the questionnaires at baseline. Considering selected scores over treatment time, there was no difference in global QoL, dyspnea, swallowing, and speech between the treatment arms in the course. For fatigue, a significant increase from baseline to visit 3 (p = 0.02), visit 5 (p = 0.002), and to visit 7 (p = 0.003) was observed for patients receiving D, cisplatin or carboplatin (P), 5-fluorouracil (F), and C. At the end of chemotherapy, the manifestation of fatigue was similar compared in the 2 treatment arms. Discussion/Conclusion: Therapy intensification not adversely affects selected scores of QoL of patients with recurrent and/or metastatic SCCHN. Nevertheless, fatigue seems to be pronounced in patients treated with D. [ABSTRACT FROM AUTHOR]

• Analysis of recurrent/metastatic head and neck cancer. • Feasibility of a 231-gene NanoString panel in determining the molecular subtypes. • Tumor budding prognostically significant in recurrent/metastatic state. We aimed to evaluate the applicability of a customized NanoString panel for molecular subtyping of recurrent or metastatic head and neck squamous cell carcinoma (R/M−HNSCC). Additionally, histological analyses were conducted, correlated with the molecular subtypes and tested for their prognostic value. We conducted molecular subtyping of R/M−HNSCC according to the molecular subtypes defined by Keck et al. For molecular analyses a 231 gene customized NanoString panel (the most accurately subtype defining genes, based on previous analyses) was applied to tumor samples from R/M−HNSCC patients that were treated in the CeFCiD trial (AIO/IAG-KHT trial 1108). A total of 130 samples from 95 patients were available for sequencing, of which 80 samples from 67 patients passed quality controls and were included in histological analyses. H&E stained slides were evaluated regarding distinct morphological patterns (e.g. tumor budding, nuclear size, stroma content). Determination of molecular subtypes led to classification of tumor samples as basal (n = 46, 45 %), inflamed/mesenchymal (n = 31, 30 %) and classical (n = 26, 25 %). Expression levels of Amphiregulin (AREG) were significantly higher for the basal and classical subtypes compared to the mesenchymal subtype. While molecular subtypes did not have an impact on survival, high levels of tumor budding were associated with poor outcomes. No correlation was found between molecular subtypes and histological characteristics. Utilizing the 231-gene NanoString panel we were able to determine the molecular subtype of R/M−HNSCC samples by the use of FFPE material. The value to stratify for different treatment options remains to be explored in the future. The prognostic value of tumor budding was underscored in this clinically well annotated cohort. [ABSTRACT FROM AUTHOR]

Safety and cellular immunogenicity of rising doses and varying regimens of a poly-epitope vaccine were evaluated in advanced metastatic melanoma. The vaccine comprised plasmid DNA and recombinant modified vaccinia virus Ankara (MVA) both expressing a string (Mel3) of seven HLA.A2/A1 epitopes from five melanoma antigens. Forty-one HLA-A2 positive patients with stage III/IV melanoma were enrolled. Patient groups received one or two doses of DNA.Mel3 followed by escalating doses of MVA.Mel3. Immunisations then continued eight weekly in the absence of disease progression. Epitope-specific CD8+ T cell responses were evaluated using ex-vivo tetramer and IFN-γ ELISPOT assays. Safety and clinical responses were monitored. Prime-boost DNA/MVA induced Melan-A-specific CD8+ T cell responses in 22/31 (71%) patients detected by tetramer assay. ELISPOT detected a response to at least one epitope in 10/31 (32%) patients. T cell responder rates were <50% with low-dose DNA/MVA, or MVA alone, rising to 91% with high-dose DNA/MVA. Among eight patients showing evidence of clinical benefit—one PR (24 months+), five SD (5 months+) and two mixed responses—seven had associated immune responses. Melan-A-tetramer+ immunity was associated with a median 8-week increase in time-to-progression ( P = 0.037) and 71 week increase in survival ( P = 0.0002) compared to non-immunity. High-dose vaccine was well tolerated. The only significant toxicities were flu-like symptoms and injection-site reactions. DNA.Mel3 and MVA.Mel3 in a prime-boost protocol generated high rates of immune response to melanoma antigen epitopes. The treatment was well tolerated and the correlation of immune responses with patient outcomes encourages further investigation. [ABSTRACT FROM AUTHOR]

2 Multi-omics characterization of pmCRC metastases, PDX tumors and PD3D models confirms similarity of matched pmCRC models and can be used for predictive biomarker analysis. Growth and treatment response of pmCRC PD3D models and high correlation of molecular characteristics indicate high similarity of each generated pair of matched pmCRC PDX and PD3D cell culture models. A) Transcriptomic single sample enrichment analysis of signatures predicting treatment response to selected anti-cancer drugs of pmCRC metastases, PDX tumors and PD3D culture cell models. For identification of novel predictive biomarkers in pmCRC for SoC and targeted drug treatments we molecularly characterized the original patient pmCRC and corresponding PDX/PD3D models by RNAseq and patient-derived pmCRC models also by mass-spectrometry proteomics and phosphoproteomics. [Extracted from the article]

For identification of novel predictive biomarkers in pmCRC for SoC and targeted drug treatments we molecularly characterized the original patient pmCRC and corresponding PDX/PD3D models by RNAseq and patient-derived pmCRC models also by mass-spectrometry proteomics and phosphoproteomics. Growth and treatment response of pmCRC PD3D models and high correlation of molecular characteristics indicate high similarity of each generated pair of matched pmCRC PDX and PD3D cell culture models. A) Transcriptomic single sample enrichment analysis of signatures predicting treatment response to selected anti-cancer drugs of pmCRC metastases, PDX tumors and PD3D culture cell models. 2 Multi-omics characterization of pmCRC metastases, PDX tumors and PD3D models confirms similarity of matched pmCRC models and can be used for predictive biomarker analysis. [Extracted from the article]

Objectives: Several patient factors have been described to influence access to optimal cancer care like socioeconomic factors or place of residence. In this study, we investigate whether data routinely collected in a clinical cancer registry can be used to identify populations of lung cancer patients with increased risk of not receiving optimal cancer care. Methods: We analysed data of 837 lung cancer patients extracted from the clinical cancer registry of a German university hospital. We compared patient populations by two indicators of optimal care, namely implementation of tumour board meeting recommendations as well as the timeliness of care. Results: There was a high rate of implementation of tumour board meeting recommendations of 94.4%. Reasons for non‐implementation were mainly a patient's own wish or a worsening of the health situation. Of all patient parameters, only tumour stage was associated with the two optimal care indicators. Conclusion: Using routine data from a clinical cancer registry, we were not able to identify patient populations at risk of not getting optimal care and the implementation of guideline‐conform care appeared to be very high in this setting. However, limitations were the ambiguity of optimal care indicators and availability of parameters predictive for patients' vulnerability. [ABSTRACT FROM AUTHOR]

Purpose: Despite promising achievements in precision cancer medicine (PCM), participating patients are still faced with manifold uncertainties, especially regarding a potential treatment benefit of molecular diagnostics (MD). Hence, MD poses considerable challenges for patient information and communication. To meet these challenges, healthcare professionals need to gain deeper insight into patients' subjective experiences. Therefore, this qualitative study examined information aspects of MD programs in cancer patients. Methods: In two German Comprehensive Cancer Centers, 30 cancer patients undergoing MD participated in semi-structured interviews on information transfer and information needs regarding MD. Additionally, patients provided sociodemographic and medical data and indicated their subjective level of information (visual analogue scale, VAS, 0–10). Results: On average patients had high levels of information (mean = 7, median = 8); nevertheless 20% (n = 6) showed an information level below 5 points. Qualitative analysis revealed that patients show limited understanding of the complex background of MD and have uncertainties regarding their personal benefit. Further, patients described unmet information needs. Existential threat in awaiting the results was experienced as burdensome. To withstand the strains of their situation, patients emphasized the importance of trusting their physician. Conclusion: The challenges in PCM consist in providing unambiguous information, especially concerning treatment benefit, and providing guidance and support. Therefore, psycho-oncology needs to develop guidelines for adequate patient communication in order to help healthcare providers and cancer patients to handle these challenges in the developing field of PCM. [ABSTRACT FROM AUTHOR]

Thyroid transcription factor 1 (TTF-1) is a well-established independent prognostic factor in lung adenocarcinoma (LUAD), irrespective of stage. This study aims to determine if TTF-1′s prognostic impact is solely based on histomorphological differentiation (tumor grading) or if it independently relates to a biologically more aggressive phenotype. We analyzed a large bi-centric LUAD cohort to accurately assess TTF-1′s prognostic value in relation to tumor grade. We studied 447 patients with resected LUAD from major German lung cancer centers (Berlin and Cologne), correlating TTF-1 status and grading with clinical, pathologic, and molecular data, alongside patient outcomes. TTF-1′s impact was evaluated through univariate and multivariate Cox regression. Causal graph analysis was used to identify and account for potential confounders, improving the statistical estimation of TTF-1′s predictive power for clinical outcomes. Univariate analysis revealed TTF-1 positivity associated with significantly longer disease-free survival (DFS) (median log HR −0.83; p = 0.018). Higher tumor grade showed a non-significant association with shorter DFS (median log HR 0.30; p = 0,62 for G1 to G2 and 0.68; p = 0,34 for G2 to G3). In multivariate analysis, TTF-1 positivity resulted in a significantly longer DFS (median log HR −0.65; p = 0.05) independent of all other parameters, including grading. Adjusting for potential confounders as indicated by the causal graph confirmed the superiority of TTF-1 over tumor grading in prognostics power. TTF-1 status predicts relapse and survival in LUAD independently of tumor grading. The prognostic power of tumor grading is limited to TTF-1-positive patients, and the effect size of TTF-1 surpasses that of tumor grading. We recommend including TTF1 status as a prognostic factor in the diagnostic guidelines of LUAD. • The prognostic power of tumor grading is limited to TTF-1-positive patients. • The prognostic value of TTF-1-status in LUAD is independent of tumor grade. • The prognostic effect size of TTF-1 surpasses that of tumor grading. [ABSTRACT FROM AUTHOR]

Precision cancer medicine (PCM) holds great promises to offer more effective therapies to patients based on molecular profiling of their individual tumours. Although the PCM approach seems intuitive, multiple conceptional and structural challenges interfere with the broad implementation of PCM into clinical practice. Accordingly, concerted national and international efforts are needed to guide the further development and broad adoption of PCM in Germany. With support of the 'German Cancer Aid' (Deutsche Krebshilfe [DKH]) a task force ' Molecular Diagnostics and Therapy' was implemented. In two workshops supported by the DKH, delegates from the fourteen comprehensive cancer centresidentified key topics essential to implement quality-guided, harmonized and adaptable PCM. Based on an online questionnaire and using a modified Delphi approach, nine statements were drafted and evaluated within the group. These statements could serve as a basis to define a collaborative strategy for PCM in the future with the aim to sustain and further improve its quality. • This consenus statement originated from collaborative efforts of all fourteen Comprehensive Cancer Centres in the German Cancer Aid network. • The consensus statement is based on all centres' consent due to implementation of a modified Delphi process. • This consensus statement will serve as a framework to establish sustainable structures for precision cancer medicine in Germany. [ABSTRACT FROM AUTHOR]

Leukemic meningitis is a rare manifestation of chronic lymphocytic leukemia (CLL) and typically occurs in advanced stages. We report the case of a 71-year-old male in whom Binet A, Rai 1 stage CLL was diagnosed in June 2002. The stage called for a “watch and wait” strategy. Six months later the patient presented with paraparesis. Magnetic resonance imaging of the lumbar spine revealed no abnormalities. Lumbar puncture disclosed xanthochromic cerebrospinal fluid (CSF) with 1003 cells/µl, 95% atypical lymphocytes. Flow cytometry confirmed typical features of CLL. Intrathecal injections of methotrexate, cytosine arabinoside and corticosteroids did not substantially reduce the CSF cell count and failed to improve the neurological symptoms. Two weeks later the patient developed a pulmonary embolism complicated by fatal secondary pneumonia. Leukemic meningitis is a rare manifestation of CLL, especially in early stages. Selective spinal paraparesis as the first symptom of meningitis in CLL is even rarer and has been reported only once. [ABSTRACT FROM AUTHOR]

Based on recent advances in the management of patients with sentinel node (SN)–positive melanoma, we aimed to develop prediction models for recurrence, distant metastasis (DM) and overall mortality (OM). The derivation cohort consisted of 1080 patients with SN-positive melanoma from nine European Organization for Research and Treatment of Cancer (EORTC) centres. Prognostic factors for recurrence, DM and OM were studied with Cox regression analysis. Significant factors were incorporated in the models. Performance was assessed by discrimination (c-index) and calibration in cross-validation across centres. The models were externally validated using a prospective cohort consisting of 705 German patients with SN-positive: 473 trial participants of the German Dermatologic Cooperative Oncology Group study (DeCOG-SLT) and 232 screened patients. A nomogram was developed for graphical presentation. The final model for recurrence and the calibrated models for DM and OM included ulceration, age, SN tumour burden and Breslow thickness. The models showed reasonable calibration. The c-index for the recurrence, DM and OM model was 0.68, 0.70 and 0.70, respectively, and 0.70, 0.72 and 0.74, respectively, in external validation. The EORTC-DeCOG model identified a robust low-risk group, with all identified low-risk patients (approximately 4% of the entire population) having a 5-year recurrence probability of <25% and an overall 5-year recurrence rate of 13%. A model including information on completion lymph node dissection (CLND) showed only marginal improvement in model performance. The EORTC-DeCOG nomogram provides an adequate prognostic tool for patients with SN-positive melanoma, without the need for CLND. It showed consistent results across validation. The nomogram could be used for patient counselling and might aid in adjuvant therapy decision-making. • Advances in treatment of sentinel node–positive melanoma prompt new stratification. • Outcome predictions are based on factors from the primary melanoma and sentinel node. • Predictions are presented in the form of a nomogram. • Models are successful in external validation using a large prospective German cohort. • Information on non-sentinel nodes after completion dissection is not necessary. [ABSTRACT FROM AUTHOR]

Cyclin A1 is a promising antigen for T cell therapy being selectively expressed in high-grade ovarian cancer (OC) and acute myeloid leukemia (AML) stem cells. For adoptive T cell therapy, a single epitope has to be selected, with high affinity to MHC class I and adequate processing and presentation by malignant cells to trigger full activation of specific T cells. In silico prediction with three algorithms indicated 13 peptides of Cyclin A1 9 to 11 amino acids of length to have high affinity to HLA-A*02:01. Ten of them proved to be affine in an HLA stabilization assay using TAP-deficient T2 cells. Their immunogenicity was assessed by repetitive stimulation of CD8+ T cells from two healthy donors with single-peptide-pulsed dendritic cells or monocytes. Intracellular cytokine staining quantified the enrichment of peptide-specific functional T cells. Seven peptides were immunogenic, three of them against both donors. Specific cell lines were cloned and used in killing assays to demonstrate recognition of endogenous Cyclin A1 in the HLA-A*02:01-positive AML cell line THP-1. Immunopeptidome analysis based on direct isolation of HLA-presented peptides by mass spectrometry of primary AML and OC samples identified four naturally presented epitopes of Cyclin A1. The immunopeptidome of HeLa cells transfected with Cyclin A1 and HLA-A*02:01 revealed six Cyclin A1-derived HLA ligands. Epitope p410–420 showed high affinity to HLA-A*02:01 and immunogenicity in both donors. It proved to be naturally presented on primary AML blast and provoked spontaneous functional response of T cells from treatment naïve OC and, therefore, warrants further development for clinical application. [ABSTRACT FROM AUTHOR]

Reliable and reproducible interpretation of molecular aberrations constitutes a bottleneck of precision medicine. Evidence-based decision management systems may improve rational therapy recommendations. To cope with an increasing amount of complex molecular data in the clinical care of patients with cancer, we established a workflow for the interpretation of molecular analyses. A specialized physician screened results from molecular analyses for potential biomarkers, irrespective of the diagnostic modality. Best available evidence was retrieved and categorized through establishment of an in-house database and interrogation of publicly available databases. Annotated biomarkers were ranked using predefined evidence levels and subsequently discussed at a molecular tumour board (MTB), which generated treatment recommendations. Subsequent translation into patient treatment and clinical outcomes were followed up. One hundred patients were discussed in the MTB between January 2016 and May 2017. Molecular data were obtained for 70 of 100 patients (50 whole exome/RNA sequencing, 18 panel sequencing, 2 immunohistochemistry (IHC)/microsatellite instability analysis). The MTB generated a median of two treatment recommendations each for 63 patients. Thirty-nine patients were treated: 6 partial responses and 12 stable diseases were achieved as best responses. Genetic counselling for germline events was recommended for seven patients. The development of an evidence-based workflow allowed for the clinical interpretation of complex molecular data and facilitated the translation of personalized treatment strategies into routine clinical care. The high number of treatment recommendations in patients with comprehensive genomic data and promising responses in patients treated with combination therapy warrant larger clinical studies. • Evidence-based, flexible workflow for the clinical interpretation of molecular data. • Application to complex data including whole-exome sequencing and RNA-Sequencing in clinical routine. • Initiation of targeted treatment in 39% of patients. • Promising responses in a subset of patients. • Standardisation of precision oncology workflows could help improve prospective trials. [ABSTRACT FROM AUTHOR]

Objective: Precision cancer medicine (PCM) aims at identifying tumor-driving molecular characteristics to improve therapy. Despite early successes for some cancers, the approach faces manifold challenges. Patients undergoing extensive molecular diagnostics (MD) may hope for personal benefit, although chances are small. In order to offer suitable support to this group, health-care professionals need to gain insight into patients' experience. Thus, this study sought to explore the expectations of cancer patients undergoing MD of their tumor.Methods: In two German Comprehensive Cancer Centers, 30 patients with advanced-stage cancer who had exhausted conventional treatment and had consented to extensive, research-oriented MD (whole-genome sequencing n = 24, panel sequencing n = 6) participated in semi-structured interviews. Following thematic content analysis by Kuckartz, the interview transcripts were coded for expectations of MD participation and topics closely related. Moreover, patients completed questionnaires on their sociodemographic characteristics, medical history, and psychosocial distress.Results: Patients reported to be expecting (a) an improvement of their treatment, (b) a contribution to research, and/or (c) additional insight to their own cancer. Further, they described to feel individually appreciated and to have a reason to maintain hope for cure or recovery by participating in MD.Conclusions: Molecular diagnostics participation led patients to feel treated in a more "personalized" way, allowing them a greater sense of control in their situation of severe illness. Oncologists and psycho-oncologists need to ensure comprehensive information and empathetic support for patients undergoing extensive MD to balance their expectations and actual chances of clinical benefit. [ABSTRACT FROM AUTHOR]

Background: We evaluated the antitumor activity and safety of avelumab, a human anti--PD-L1 IgG1 antibody, as first-line switch-maintenance (1 L-mn) or second-line (2 L) treatment in patients with advanced gastric/gastroesophageal cancer (GC/GEJC) previously treated with chemotherapy. Methods: In a phase 1b expansion cohort, patients without (1 L-mn) or with (2 L) disease progression following first-line chemotherapy for advanced GC/GEJC received avelumab 10 mg/kg intravenously every 2 weeks. Endpoints included best overall response, progression-free survival (PFS), overall survival (OS), and safety. Results: Overall, 150 patients were enrolled (1 L-mn, n = 90; 2 L, n = 60) and median follow-up in the 1 L-mn and 2 L subgroups was 36.0 and 33.7 months, respectively. The confirmed objective response rate was 6.7% in both subgroups (95% CI, 2.5-13.9% and 1.8-16.2%, respectively), including complete responses in 2.2% of the 1 L-mn subgroup (n= 2). In the 1 L-mn and 2 L subgroups, median duration of response was 21.4months (95% CI, 4.0--not estimable) and 3.5months (95% CI, 2.8-8.3) and disease control rates were 56.7 and 28.3%, respectively. Median PFS in the 1 L-mn and 2 L subgroups was 2.8 months (95% CI, 2.3-4.1) and 1.4 months (95% CI, 1.3-1.5), with 6-month PFS rates of 23.0% (95% CI, 14.7-32.4%) and 7.9% (95% CI, 2.6-17.2%), andmedian OS was 11.1months (95% CI, 8.9-13.7) and 6.6 months (95% CI, 5.4-9.4), respectively. In the 1L-mn subgroup, median OS measured from start of 1 L chemotherapy was 18.7 months (95% CI, 15.4-20.6). Across both subgroups, 20.7% had an infusion-related reaction of any grade. Other common treatment-related adverse events (TRAEs) of any grade included fatigue (10.0%) and nausea (6.7%). Treatment-related serious adverse events occurred in 4.0% of patients. Overall, 8.7% had a grade≥3 TRAE, including 1 treatment-related death. Conclusion: Avelumab showed clinical activity and an acceptable safety profile in patients with GC/GEJC. [ABSTRACT FROM AUTHOR]

The impact of tumour mutational burden (TMB) on outcome with molecularly matched therapy is unknown. Higher TMB could predict resistance to molecularly matched therapy through co-occurring driver mutations. One hundred and four patients with advanced cancers underwent molecular profiling in the DKTK-MASTER program. Fifty-five patients received systemic therapy excluding immunotherapy. Patients with molecularly matched (n = 35) or non-molecularly informed therapy (n = 20) were analysed for TMB and survival. Results were validated in an independent cohort of patients receiving molecularly matched (n = 68) or non-molecularly informed therapy (n = 40). Co-occurring driver mutations and TMB were analysed in the exploratory cohort and The Cancer Genome Atlas (TCGA) datasets. Patients were stratified by the median TMB of 1.67 mutations per Megabase (mut/Mb) of 35 patients receiving molecularly matched therapy into TMB-high or TMB-low groups. Median overall survival (4 months [95% CI, 3.3–7.6] versus 12.8 months [95% CI, 10-not reached], p < 0.001) and progression-free survival (1.8 months [95% CI, 1.1–3.7] versus 7.9 months [95% CI, 2.8–17.0], p = 0.003) were significantly shorter in the TMB-high group compared to the TMB-low group. In the validation cohort, shorter OS and PFS were identified in the TMB-high group (TMB cut-off of 4 mut/Mb) treated with molecularly matched therapy. No differences were observed in patients receiving non-molecularly informed systemic therapy. A significant correlation between co-occurring driver mutations and TMB (n = 104, r = 0.78 [95% CI, 0.68–0.85], p < 0.001) was found in the exploratory cohort as well as the majority (24/33) of TCGA studies. A high TMB was associated with unfavourable outcome in patients receiving molecularly matched therapy, indicating untargeted resistance pathways. Therefore, TMB should be further investigated as a predictive biomarker in precision oncology programs. • Personalised cancer therapy lacks efficacy for a majority of patients. • Predictive biomarkers for the use of molecularly matched therapy warranted. • Role of tumour mutational burden for molecularly matched therapy unknown. • Analysis of TMB and molecularly matched therapy in two pan-cancer cohorts. • TMB associated with improved outcome with matched but not unmatched therapy. [ABSTRACT FROM AUTHOR]

PURPOSE: Precision oncology depends on the availability of up-to-date, comprehensive, and accurate information about associations between genetic variants and therapeutic options. Recently, a number of knowledge bases (KBs) have been developed that gather such information on the basis of expert curation of the scientific literature. We performed a quantitative and qualitative comparison of Clinical Interpretations of Variants in Cancer, OncoKB, Cancer Gene Census, Database of Curated Mutations, CGI Biomarkers (the cancer genome interpreter biomarker database), Tumor Alterations Relevant for Genomics-Driven Therapy, and the Precision Medicine Knowledge Base. METHODS: We downloaded each KB and restructured their content to describe variants, genes, drugs, and gene-drug associations in a common format. We normalized gene names to Entrez Gene IDs and drug names to ChEMBL and DrugBank IDs. For the analysis of clinically relevant gene-drug associations, we obtained lists of genes affected by genetic alterations and putative drug therapies for 113 patients with cancer whose cases were presented at the Molecular Tumor Board (MTB) of the Charité Comprehensive Cancer Center. RESULTS: Our analysis revealed that the KBs are largely overlapping but also that each source harbors a notable amount of unique information. Although some KBs cover more genes, others contain more data about gene-drug associations. Retrospective comparisons with findings of the Charitè MTB at the gene level showed that use of multiple KBs may considerably improve retrieval results. The relative importance of a KB in terms of cancer genes was assessed in more detail by logistic regression, which revealed that all but one source had a notable impact on result quality. We confirmed these findings using a second data set obtained from an independent MTB. CONCLUSION: To date, none of the existing publicly available KBs on gene-drug associations in precision oncology fully subsumes the others, but all of them exhibit specific strengths and weaknesses. Consideration of multiple KBs, therefore, is essential to obtain comprehensive results. [ABSTRACT FROM AUTHOR]

Organoid cultures derived from colorectal cancer (CRC) samples are increasingly used as preclinical models for studying tumor biology and the effects of targeted therapies under conditions capturing in vitro the genetic make-up of heterogeneous and even individual neoplasms. While 3D cultures are initiated from surgical specimens comprising multiple cell populations, the impact of tumor heterogeneity on drug effects in organoid cultures has not been addressed systematically. Here we have used a cohort of well-characterized CRC organoids to study the influence of tumor heterogeneity on the activity of the KRAS/MAPK-signaling pathway and the consequences of treatment by inhibitors targeting EGFR and downstream effectors. MAPK signaling, analyzed by targeted proteomics, shows unexpected heterogeneity irrespective of RAS mutations and is associated with variable responses to EGFR inhibition. In addition, we obtained evidence for intratumoral heterogeneity in drug response among parallel “sibling” 3D cultures established from a single KRAS-mutant CRC. Our results imply that separate testing of drug effects in multiple subpopulations may help to elucidate molecular correlates of tumor heterogeneity and to improve therapy response prediction in patients. [ABSTRACT FROM AUTHOR]

Abstract Background Patients with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC) progressing on platinum-based chemotherapy have poor prognoses and limited therapeutic options. Programmed cell death-1 (PD-1) and its ligand 1 (PD-L1) are frequently upregulated in HNSCC. The international, multi-institutional, single-arm, phase II HAWK study (NCT02207530) evaluated durvalumab monotherapy, an anti-PD-L1 monoclonal antibody, in PD-L1-high patients with platinum-refractory R/M HNSCC. Patients and methods Immunotherapy-naïve patients with confirmed PD-L1-high tumour cell expression (defined as patients with ≥25% of tumour cells expressing PD-L1 [TC ≥ 25%] using the VENTANA PD-L1 [SP263] Assay) received durvalumab 10 mg/kg intravenously every 2 weeks for up to 12 months. The primary end-point was objective response rate; secondary end-points included progression-free survival (PFS) and overall survival (OS). Results Among evaluable patients (n = 111), objective response rate was 16.2% (95% confidence interval [CI], 9.9–24.4); 29.4% (95% CI, 15.1–47.5) for human papillomavirus (HPV)-positive patients and 10.9% (95% CI, 4.5–21.3) for HPV-negative patients. Median PFS and OS for treated patients (n = 112) was 2.1 months (95% CI, 1.9–3.7) and 7.1 months (95% CI, 4.9–9.9); PFS and OS at 12 months were 14.6% (95% CI, 8.5–22.1) and 33.6% (95% CI, 24.8–42.7). Treatment-related adverse events were 57.1% (any grade) and 8.0% (grade ≥3); none led to death. At data cut-off, 24.1% of patients remained on treatment or in follow-up. Conclusion Durvalumab demonstrated antitumour activity with acceptable safety in PD-L1-high patients with R/M HNSCC, supporting its ongoing evaluation in phase III trials in first- and second-line settings. In an ad hoc analysis, HPV-positive patients had a numerically higher response rate and survival than HPV-negative patients. Highlights • This study assessed durvalumab in patients with R/M HNSCC and PD-L1-high expression. • Patients had failed 1 platinum-based chemotherapeutic regimen in the R/M setting. • The ORR for all patients was 16.2% with a median OS of 7.1 months. • HPV-positive patients had a numerically higher response rate and longer survival. • Durvalumab showed antitumour activity with acceptable safety in the HAWK study. [ABSTRACT FROM AUTHOR]