Metastatic Ductal Eccrine Adenocarcinoma with Excellent Response to Immunotherapy

Eccrine carcinoma, a subtype of which is ductal eccrine adenocarcinoma (DEA), is a rare cutaneous malignancy. For metastatic eccrine carcinoma, there are very limited data to guide treatment. Conventional chemotherapy is of limited benefit and there is only a small body of evidence for the use of immunotherapy in non-DEA eccrine carcinomas. We report the first case of metastatic DEA treated with a multimodality approach including surgery, radiotherapy, and immunotherapy, with an excellent prolonged response to pembrolizumab, and provide a review of the literature on pathological and management aspects for this rare tumour subtype. A 60-year-old male with a history of pT1N0M0 left scalp DEA, managed 2 years prior with excision and adjuvant radiotherapy, represented with a symptomatic right pontine metastasis. Imaging demonstrated intracranial, pulmonary, and hilar disease; biopsy of the cranial and lung lesions showed metastatic adenocarcinoma, morphologically similar to the previously resected scalp DEA. The patient was treated with stereotactic resections of his pontine metastases and adjuvant cranial radiotherapy, then commenced on immunotherapy with pembrolizumab. The patient has completed 21 months of pembrolizumab with a significant radiological response of the pulmonary and hilar disease and nil evidence of intracranial recurrence or further metastases. In this case report, we provide the first evidence of efficacy of immunotherapy in metastatic DEA, demonstrating an excellent and prolonged response of metastatic DEA to pembrolizumab. Further research is required to better establish the role of immunotherapy within the management protocol for this uncommon but aggressive tumour subtype

Limits and Degenerations of Unitary Conformal Field Theories

In the present paper, degeneration phenomena in conformal field theories are studied. For this purpose, a notion of convergent sequences of CFTs is introduced. Properties of the resulting limit structure are used to associate geometric degenerations to degenerating sequences of CFTs, which, as familiar from large volume limits of non-linear sigma models, can be regarded as commutative degenerations of the corresponding ``quantum geometries''. As an application, the large level limit of the A-series of unitary Virasoro minimal models is investigated in detail. In particular, its geometric interpretation is determined.Comment: 57 pages, no figures; minor clarifications and reference added; final version to appear in Commun. Math. Phy

Establishment of novel long-term cultures from EpCAM positive and negative circulating tumour cells from patients with metastatic gastroesophageal cancer

Circulating tumour cell (CTC) enumeration and profiling has been established as a valuable clinical tool in many solid malignancies. A key challenge in CTC research is the limited number of cells available for study. Ex vivo CTC culture permits expansion of these rare cell populations for detailed characterisation, functional assays including drug sensitivity testing, and investigation of the pathobiology of metastases. We report for the first time the establishment and characterisation of two continuous CTC lines from patients with gastroesophageal cancer. The two cell lines (designated UWG01CTC and UWG02CTC) demonstrated rapid tumorigenic growth in immunodeficient mice and exhibit distinct genotypic and phenotypic profiles which are consistent with the tumours of origin. UWG02CTC exhibits an EpCAM+, cytokeratin+, CD44+ phenotype, while UWG01CTC, which was derived from a patient with metastatic neuroendocrine cancer, displays an EpCAM−, weak cytokeratin phenotype, with strong expression of neuroendocrine markers. Further, the two cell lines show distinct differences in drug and radiation sensitivity which match differential cancer-associated gene expression pathways. This is strong evidence implicating EpCAM negative CTCs in metastasis. These novel, well characterised, long-term CTC cell lines from gastroesophageal cancer will facilitate ongoing research into metastasis and the discovery of therapeutic targets

Retrospective evaluation of the use of pembrolizumab in malignant mesothelioma in a real-world Australian population

Introduction: We investigated the efficacy and toxicity of pembrolizumab in patients with mesothelioma from a real-world Australian population. We aimed to determine clinical factors and predictive biomarkers that could help select patients who are likely to benefit from pembrolizumab. Method: Patients with mesothelioma who were treated with pembrolizumab as part of the Insurance and Care New South Wales compensation scheme were included. Clinical information was collected retrospectively. Tumor biomarkers such as programmed death-ligand 1 (PD-L1), BAP1, and CD3-positive (CD3+) tumor-infiltrating lymphocytes (TILs) were examined using archival formalin-fixed paraffin-embedded tumor samples. Results: A total of 98 patients were included with a median age of 70 years (range, 46–91 y); 92% were men; 76% had epithelioid subtype; 21% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0. Pembrolizumab was used as second-line or subsequent-line treatment in 94 patients and as first-line treatment in four patients. The overall response rate was 18%, and the disease control rate was 56%. The median progression-free survival (PFS) was 4.8 months (95% confidence interval: 3.6–6.2), and the median overall survival (OS) was 9.5 months (95% confidence interval: 6.6–13.7). Immune-related adverse events occurred in 27% of patients, of which nine (9%) were of grade 3 or higher. In the multivariable analysis, factors independently associated with longer PFS included baseline ECOG status of 0 (median PFS: 12 mo versus 4 mo, p < 0.01) and PD-L1 tumor proportion score of greater than or equal to 1% (median PFS: 6 mo versus 4 mo, p < 0.01). Baseline platelet count of less than or equal to 400 × 109/liter was independently associated with longer PFS and OS (median PFS: 6 mo versus 2 mo, p = 0.05; median OS: 10 mo versus 4 mo, p = 0.01), whereas lack of pretreatment dexamethasone was independently associated with OS but not PFS (median OS: 10 mo versus 3 mo, p = 0.01). The odds of response were higher for patients with baseline ECOG status of 0 (p = 0.02) and with greater than or equal to 5% CD3+ TILs in the tumor (p < 0.01). PD-L1 expression, BAP1 loss, and CD3+ TILs in the stroma were not significantly associated with the overall response rate. Conclusions: Immunotherapy is a reasonable treatment option for patients with mesothelioma. Our results are comparable to other clinical trials investigating pembrolizumab in mesothelioma in terms of response. Good performance status assessment remains the most robust predictor for patient outcomes. CD3+ TILs in the tumor may help select patients that are likely to respond to pembrolizumab, whereas factors such as PD-L1 expression, baseline platelet count, and lack of pretreatment dexamethasone may help predict survival outcomes from pembrolizumab treatment

Integrative analysis of multimodal mass spectrometry data in MZmine 3

3 Pág.We thank Christopher Jensen and Gauthier Boaglio for their contributions to the MZmine codebase. We thank Jianbo Zhang and Zachary Russ for their donations to MZmine development. The MZmine 3 logo was designed by the Bioinformatics & Research Computing group at the Whitehead Institute for Biomedical Research. T.P. is supported by Czech Science Foundation (GA CR) grant 21-11563M and by the European Union’s Horizon 2020 research and innovation programme under Marie Skłodowska-Curie grant agreement 891397. Support for P.C.D. was from US NIH U19 AG063744, P50HD106463, 1U24DK133658 and BBSRC-NSF award 2152526. T.S. acknowledges funding by Deutsche Forschungsgemeinschaft (441958208). M. Wang acknowledges the US Department of Energy Joint Genome Institute ( https://ror.org/04xm1d337 , a DOE Office of Science User Facility) and is supported by the Office of Science of the US Department of Energy operated under subcontract No. 7601660. E.R. and H.H. thank Wen Jiang (HILICON AB) for providing the iHILIC Fusion(+) column for HILIC measurements. M.F., K.D. and S.B. are supported by Deutsche Forschungsgemeinschaft (BO 1910/20). L.-F.N. is supported by the Swiss National Science Foundation (project 189921). D.P. was supported through the Deutsche Forschungsgemeinschaft (German Research Foundation) through the CMFI Cluster of Excellence (EXC-2124 — 390838134 project-ID 1-03.006_0) and the Collaborative Research Center CellMap (TRR 261 - 398967434). J.-K.W. acknowledges the US National Science Foundation (MCB-1818132), the US Department of Agriculture, and the Chan Zuckerberg Initiative. MZmine developers have received support from the European COST Action CA19105 — Pan-European Network in Lipidomics and EpiLipidomics (EpiLipidNET). We acknowledge the support of the Google Summer of Code (GSoC) program, which has funded the development of several MZmine modules through student projects. We thank Adam Tenderholt for introducing MZmine to the GSoC program.Peer reviewe

Molecular and Clinical Biomarkers in Gastrointestinal Cancer

Biomarkers are critically important in clinical oncology. In addition to providing valuable prognostic information, biomarkers assist in patient risk assessment, prediction of response to treatment, and monitoring progress of disease, all key factors in improving the individualisation and delivery of treatment. Furthermore, biomarkers provide insight into the mechanisms of cancer and identify novel targets for therapeutic agents. This thesis investigates both molecular biomarkers in gastroesophageal cancer and clinical biomarkers in colon cancer and identifies several molecular targets and clinical markers of interest

Pancreatitis and Biliary Obstruction Secondary to Duodenal Metastasis from Rapidly Progressing Lung Adenocarcinoma Treated with Common Bile Duct Stenting

Non-small cell lung cancer (NSCLC) is characterised by diffuse metastases, with common sites being the brain, liver, bones, and adrenal glands. Small bowel metastasis from NSCLC is a rare phenomenon, particularly in patients with an adenocarcinoma histology. We report the case of a 56-year-old lung adenocarcinoma patient with a duodenal metastasis diagnosed on FDG/PET-CT and confirmed on duodenal biopsy. Although initially asymptomatic, he subsequently presented with obstructive jaundice secondary to rapid local disease progression at the duodenal metastasis, requiring endoscopic intervention for biliary drainage. He was commenced on single agent pembrolizumab, with disease response on subsequent follow-up. This case highlights a rare case of gastrointestinal metastasis from NSCLC requiring endoscopic intervention due to rapid progression of the disease at the site of metastasis

Systemic treatment in advanced biliary cancers: a multicenter Australian analysis and review

Aim: While first-line palliative chemotherapy (CT1) improves survival and quality of life in advanced biliary cancer (ABC), there is no randomized evidence to support second-line chemotherapy (CT2) in ABC. We aim to explore to role of CT2 in ABC. Methods: We performed a retrospective review of all patients who received one or more lines of chemotherapy for ABC at four Australian cancer centers between 2008 and 2011. A Cox proportional hazard model was developed to determine the impact of clinicopathologic variables on overall survival (OS) from time of progression on CT1. Results: We identified 73 patients who received palliative chemotherapy for ABC. Twenty-five patients (34%) received two or more lines of chemotherapy. Patients with a preserved performance status on progression on first-line chemotherapy (CT1) were more likely to receive second-line chemotherapy (CT2) (P \u3c 0.001). Disease control rate with CT2 was 36%, and mean progression-free survival was 3.2 months (95% confidence interval 1.5-4.9 months). The following variables were significant in the univariate analysis of OS from time of progression on CT1: lines of chemotherapy (P = 0.0001), Eastern Cooperative Oncology Group performance status at progression on CT1 (P \u3c 0.0001) and disease control with CT1 (P = 0.027). Lines of chemotherapy received and performance status remained significant in the multivariate analysis for OS from progression on CT1. Conclusion: Second-line chemotherapy is feasible in a subset of patients with ABC. Even after accounting for confounding variables, CT2 appears to increase OS in ABC, although we are unable to exclude other unmeasured factors such as tumor biology. These findings warrant further evaluation with prospective trials

High body mass index is associated with an increased overall survival in rectal cancer

© Journal of Gastrointestinal Oncology. All rights reserved. Background: The impact of increased body mass index (BMI) on clinical outcomes in locoregional rectal cancer is unknown. Methods: This is a retrospective cohort study which included 453 consecutive rectal cancer patients undergoing definitive treatment, with confirmed stage I, II or III rectal adenocarcinoma. The association of BMI at diagnosis with overall survival (OS), cancer specific survival (CSS) and disease-free survival (DFS) was explored, controlling for key covariates using multivariable analyses. BMI as defined by the World Health Organization (WHO) is as follows: BMI \u3c18.5-underweight; 18.5-24.9-normal; 25.0-29.9-pre-obesity; \u3e30-obese. Results: Overweight and obese patients had significantly better OS than underweight/normal weight patients (5-year OS 80% for overweight, 77% for obese, and 65% for underweight/normal weight patients, P=0.02). High BMI (\u3e25) was significantly associated with improved OS in univariate [0.62 (0.4-0.8) P=0.007] and multivariable [0.65 (0.4-0.9) P=0.023] analyses. When stratified by stage, high BMI was associated with improved OS in stage III patients (P=0.0009), but not stage II (P=0.21) or stage I (0.54). High BMI was also significantly associated with improved CSS in univariate (HR 0.62, P=0.048) and multivariable analyses (HR 0.58, P=0.03). Conclusions: In our study a BMI greater than 25 is significantly associated with a longer OS and CSS in patients with locoregional rectal cancer. These findings may be due to the reduced metabolic capacity for non-obese patients to deal with rectal cancer treatment as well as the burden of disease, however further research is needed to evaluate this

Efficacy and safety of cosibelimab, an anti-PD-L1 antibody, in metastatic cutaneous squamous cell carcinoma

Immune checkpoint inhibitors; Immunotherapy; Skin neoplasmsInhibidors de punt de control immunitari; Immunoteràpia; Neoplàsies de la pellInhibidores de puntos de control inmunitario; Inmunoterapia; Neoplasias de la pielBackground Programmed cell death receptor-1 (PD-1)-blocking antibodies are approved to treat metastatic or locally advanced cutaneous squamous cell carcinoma (CSCC) cases ineligible for curative surgery or radiation. Notwithstanding, some patients experience inadequate responses or severe immune-related adverse events (AEs), indicating the need for improved therapies. Cosibelimab is a high-affinity programmed cell death-ligand 1 (PD-L1)-blocking antibody that activates innate and adaptive immunity by blocking PD-L1 interaction with PD-1 and B7-1 receptors. It is an unmodified immunoglobulin G1 subtype with a functional Fc domain capable of inducing antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. Here, we present results of the pivotal study of patients with metastatic CSCC from an open-label, multicenter, multiregional, multicohort, phase 1 trial of cosibelimab. Methods In this trial, participants with metastatic CSCC received cosibelimab 800 mg intravenously every 2 weeks. Primary endpoint was objective response rate (ORR) by independent central review using Response Evaluation Criteria in Solid Tumors, V.1.1. Secondary endpoints included duration of response (DOR) and safety. Results Objective response was observed in 37 of 78 participants (47.4% (95% CI: 36.0% to 59.1%)), with median follow-up of 15.4 months (range: 0.4 to 40.5) as of data cut-off. Median DOR was not reached (range: 1.4+ to 34.1+ months), with response ongoing in 73.0% of participants. Common treatment-emergent AEs (≥15%) were fatigue (26.9%), rash (16.7%), and anemia (15.4%). Eighteen participants (23.1%) experienced immune-related AEs (grade 3: n=2 (2.6%); no grade 4/5). No treatment-related deaths were reported. Conclusions Cosibelimab demonstrated clinically meaningful ORR and DOR and was associated with a manageable safety profile. Trial registration number NCT03212404.This study was funded by Checkpoint Therapeutics