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Background: Atypical EGFR mutations occur in 10%-30% of non-small-cell lung cancer (NSCLC) patients with EGFR mutations and their sensitivity to classical epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKI) is highly heterogeneous. Patients harboring one group of uncommon, recurrent EGFR mutations (G719X, 57681, L861Q) respond to EGFR-TKI. Exon 20 insertions are mostly insensitive to EGFR-TKI but display sensitivity to exon 20 inhibitors. Clinical outcome data of patients with very rare point and compound mutations upon systemic treatments are still sparse to date. Patients and methods: In this retrospective, multicenter study of the national Network Genomic Medicine (nNGM) in Germany, 856 NSCLC cases with atypical EGFR mutations including co-occurring mutations were reported from 12 centers. Clinical follow-up data after treatment with different EGFR-TKIs, chemotherapy and immune checkpoint inhibitors were available from 260 patients. Response to treatment was analyzed in three major groups: (i) uncommon mutations (G719X, 57681, L861Q and combinations), (ii) exon 20 insertions and (iii) very rare EGFR mutations (very rare single point mutations, compound mutations, exon 18 deletions, exon 19 insertions). Results: Our study comprises the largest thus far reported real-world cohort of very rare EGFR single point and compound mutations treated with different systemic treatments. We validated higher efficacy of EGFR-TKI in comparison to chemotherapy in group 1 (uncommon), while most exon 20 insertions (group 2) were not EGFR-TKI responsive. In addition, we found TKI sensitivity of very rare point mutations (group 3) and of complex EGFR mutations containing exon 19 deletions or L858R mutations independent of the combination partner. Notably, treatment responses in group 3 (very rare) were highly heterogeneous. Co-occurring TP53 mutations exerted a non-significant trend for a detrimental effect on outcome in EGFR-TKI-treated patients in groups 2 and

Aims: intraductal tubulopapillary neoplasm (ITPN)of the pancreas is a recently recognized pancreatictumor entity. Here we aimed to determine the mostimportant features with a systematic review coupledwith an integrated statistical approach.Methods and results: PubMed, SCOPUS, and Embasewere searched for studies reporting data on pancreaticITPN. The clinicopathological, immunohistochemical,and molecular data were summarized. Then a compre-hensive survival analysis and a comparative analysis ofthe molecular alterations of ITPN with those of pancre-atic ductal adenocarcinoma (PDAC) and intraductalpapillary mucinous neoplasm (IPMN) from referencecohorts (including the International Cancer GenomeConsortium- ICGC dataset and The Cancer GenomeAtlas, TCGA program) were conducted. The core find-ings of 128 patients were as follows: (i) Clinicopathologi-cal parameters: pancreatic head is the most commonsite; presence of an associated adenocarcinoma wasreported in 60% of cases, but with rare nodal metastasis.(ii) Immunohistochemistry: MUC1 (>90%) and MUC6(70%) were the most frequently expressed mucins. ITPNlacked the intestinal marker MUC2; unlike IPMN, it didnot express MUC5AC. (iii) Molecular landscape: Com-pared with PDAC/IPMN, the classic pancreatic driversKRAS,TP53,CDKN2A,SMAD4,GNAS,andRNF43were less altered in ITPN (P<0.001), whereasMCLamplifications,FGFR2fusions, andPI3KCAmutationswere commonly altered (P<0.001). (iv) Survival anal-ysis: ITPN with a “pure” branch duct involvementshowed the lowest risk of recurrence.Conclusion: ITPN is a distinct pancreatic neoplasmwith specific clinicopathological and molecular char-acteristics. Its recognition is fundamental for its clini-cal/prognostic implications and for the enrichment ofpotential targets for precision oncology., Fondazione Cariverona Oncology Biobank Project; Fondazione Italiana Malattie Pancreas; Italian Ministry of Health; Associazione Italiana Ricerca sul Cancro (AIRC)

Kidney transplantation leads to an increased risk of cancer. Melanoma is one of the most frequent neoplasms in kidney transplant recipients. Transplanted patients were excluded from trials with checkpoint inhibitors in melanoma. The authors performed a systematic review regarding the use of anti-PD1 and anti-CTLA4 agents in renal transplanted patients with melanoma. Thirty-four cases were included (24 progressive disease, eight partial responses and one stable disease) but no complete response were reported. Fourteen graft rejections were observed, especially with anti-PD1 agent. The median time from the start of immune-checkpoint inhibitor and rejection was 21 days. Response rate was similar between patients with rejection and patients without rejection. The benefit of immune-checkpoint inhibitors versus the risk of allograft rejection should be carefully weighted for each patient. A multidisciplinary approach should be considered to discuss the most appropriate treatment for every case, given the aggressiveness of melanoma in these subsets of patients.

Contains fulltext : 245166.pdf (Publisher’s version ) (Open Access), AIMS: Current guidelines for pathology reporting on pancreatic cancer differ in certain aspects, resulting in divergent reporting practices and a lack of comparability of data. Here, we report on a new international dataset for pathology reporting on resection specimens with cancer of the exocrine pancreas (ductal adenocarcinoma and acinar cell carcinoma). The dataset was produced under the auspices of the International Collaboration on Cancer Reporting (ICCR), which is a global alliance of major (inter)national pathology and cancer organisations. METHODS AND RESULTS: According to the ICCR's rigorous process for dataset development, an international expert panel consisting of pancreatic pathologists, a pancreatic surgeon and an oncologist produced a set of core and non-core data items based on a critical review and discussion of current evidence. Commentary was provided for each data item to explain the rationale for selecting it as a core or non-core element and its clinical relevance, and to highlight potential areas of disagreement or lack of evidence, in which case a consensus position was formulated. Following international public consultation, the document was finalised and ratified, and the dataset, which includes a synoptic reporting guide, was published on the ICCR website. CONCLUSIONS: This first international dataset for cancer of the exocrine pancreas is intended to promote high-quality, standardised pathology reporting. Its widespread adoption will improve the consistency of reporting, facilitate multidisciplinary communication, and enhance the comparability of data, all of which will help to improve the management of pancreatic cancer patients.

Contains fulltext : 245166.pdf (Publisher’s version ) (Open Access), AIMS: Current guidelines for pathology reporting on pancreatic cancer differ in certain aspects, resulting in divergent reporting practices and a lack of comparability of data. Here, we report on a new international dataset for pathology reporting on resection specimens with cancer of the exocrine pancreas (ductal adenocarcinoma and acinar cell carcinoma). The dataset was produced under the auspices of the International Collaboration on Cancer Reporting (ICCR), which is a global alliance of major (inter)national pathology and cancer organisations. METHODS AND RESULTS: According to the ICCR's rigorous process for dataset development, an international expert panel consisting of pancreatic pathologists, a pancreatic surgeon and an oncologist produced a set of core and non-core data items based on a critical review and discussion of current evidence. Commentary was provided for each data item to explain the rationale for selecting it as a core or non-core element and its clinical relevance, and to highlight potential areas of disagreement or lack of evidence, in which case a consensus position was formulated. Following international public consultation, the document was finalised and ratified, and the dataset, which includes a synoptic reporting guide, was published on the ICCR website. CONCLUSIONS: This first international dataset for cancer of the exocrine pancreas is intended to promote high-quality, standardised pathology reporting. Its widespread adoption will improve the consistency of reporting, facilitate multidisciplinary communication, and enhance the comparability of data, all of which will help to improve the management of pancreatic cancer patients.

Contains fulltext : 245166.pdf (Publisher’s version ) (Open Access), AIMS: Current guidelines for pathology reporting on pancreatic cancer differ in certain aspects, resulting in divergent reporting practices and a lack of comparability of data. Here, we report on a new international dataset for pathology reporting on resection specimens with cancer of the exocrine pancreas (ductal adenocarcinoma and acinar cell carcinoma). The dataset was produced under the auspices of the International Collaboration on Cancer Reporting (ICCR), which is a global alliance of major (inter)national pathology and cancer organisations. METHODS AND RESULTS: According to the ICCR's rigorous process for dataset development, an international expert panel consisting of pancreatic pathologists, a pancreatic surgeon and an oncologist produced a set of core and non-core data items based on a critical review and discussion of current evidence. Commentary was provided for each data item to explain the rationale for selecting it as a core or non-core element and its clinical relevance, and to highlight potential areas of disagreement or lack of evidence, in which case a consensus position was formulated. Following international public consultation, the document was finalised and ratified, and the dataset, which includes a synoptic reporting guide, was published on the ICCR website. CONCLUSIONS: This first international dataset for cancer of the exocrine pancreas is intended to promote high-quality, standardised pathology reporting. Its widespread adoption will improve the consistency of reporting, facilitate multidisciplinary communication, and enhance the comparability of data, all of which will help to improve the management of pancreatic cancer patients.

Introduction: Cancer is the second most common cause of mortality and morbidity in Kidney Transplant Recipients (KTRs). Immunosuppression can influence the efficacy of cancer treatment and modification of the immunosuppressive regimen may restore anti-neoplastic immune responses improving oncologic prognosis. However, patients and transplant physicians are usually reluctant to modify immunosuppression, fearing rejection and potential graft loss. Due to the lack of extensive and recognised data supporting how to manage the immunosuppressive therapy in KTRs, in the context of immunotherapy, chemotherapy, radiotherapy and loco-regional treatments, a Consensus Conference was organised under the auspices of the European Society of Organ Transplantation and the Italian Society of Organ Transplantation. The conference involved a multidisciplinary group of transplant experts in the field across Europe. Methods: The overall process included a) the formulation of 12 specific questions based on the PICO methodology, b) systematic literature review and summary for experts for each question, c) a two-day conference celebration and the collection of experts' agreements. The conference was articulated in three sessions: “Immunosuppressive therapy and immunotherapy”, “Systemic therapy”, “Integrated Therapy”, while the final experts' agreement was collected with a televoting procedure and defined according to the majority criterion. Results: Twenty-six European experts attended the conference and expressed their vote. A total of 14 statements were finally elaborated and voted. Strong agreement was found for ten statements, moderate agreement for two, moderate disagreement for one and uncertainty for the last one. Conclusions: The consensus statements provide guidance to transplant physicians caring for kidney transplant recipients with cancer and indicate key aspects that need to be addressed by future clinical research.

We aimed to investigate the relation between largest lesion diameter, prostate-specific antigen density (PSA-D), age, and the detection of clinically significant prostate cancer (csPCa) using first-time targeted biopsy (TBx) in men with Prostate Imaging—Reporting and Data System (PI-RADS) 3 index lesions. A total of 292 men (2013–2019) from two referral centers were included. A multivariable logistic regression analysis was performed. The discrimination and clinical utility of the built model was assessed by the area under the receiver operation curve (AUC) and decision curve analysis, respectively. A higher PSA-D and higher age were significantly related to a higher risk of detecting csPCa, while the largest index lesion diameter was not. The discrimination of the model was 0.80 (95% CI 0.73–0.87). When compared to a biopsy-all strategy, decision curve analysis showed a higher net benefit at threshold probabilities of ≥2%. Accepting a missing ≤5% of csPCa diagnoses, a risk-based approach would result in 34% of TBx sessions and 23% of low-risk PCa diagnoses being avoided. In men with PI-RADS 3 index lesions scheduled for first-time TBx, the balance between the number of TBx sessions, the detection of low-risk PCa, and the detection of csPCa does not warrant a biopsy-all strategy. To minimize the risk of missing the diagnosis of csPCa but acknowledging the need of avoiding unnecessary TBx sessions and overdiagnosis, a risk-based approach is advisable.

Background Technical advancement and availability of high-throughput analysis has advanced molecular subtyping of most cancers. Thus, new possibilities for precision oncology have emerged. Aim Therefore, we aimed to collect data regarding availability and use of next generation sequencing (NGS) for urothelial cancer within the uropathology working group of the German Society of Pathology. Methods We collected data by questionnaires and additionally asked for sequencing results of bladder cancers in the participating institutions. Results A total of 13 university-affiliated institutes of pathology took part in the survey. All university institutes offer NGS-based molecular panel diagnostics and provide panels covering between 15 and 170 genes. Altogether, only 20 bladder cancers were sequenced in routine diagnostics and for 10 cancers potential targeted treatment options were available. Discussion So far, despite availability of NGS diagnostics at university institutes of pathology, only few bladder cancer samples have been sequenced. Based on current data from the molecular subtyping of bladder cancers, we recommend a step-by-step protocol with basic immunohistochemistry analysis and subsequent subtype-dependent analyses, e.g., alterations of the fibroblast growth factor receptors (FGFR) or comprehensive gene panel analyses.

Background Technical advancement and availability of high-throughput analysis has advanced molecular subtyping of most cancers. Thus, new possibilities for precision oncology have emerged. Aim Therefore, we aimed to collect data regarding availability and use of next generation sequencing (NGS) for urothelial cancer within the uropathology working group of the German Society of Pathology. Methods We collected data by questionnaires and additionally asked for sequencing results of bladder cancers in the participating institutions. Results A total of 13 university-affiliated institutes of pathology took part in the survey. All university institutes offer NGS-based molecular panel diagnostics and provide panels covering between 15 and 170 genes. Altogether, only 20 bladder cancers were sequenced in routine diagnostics and for 10 cancers potential targeted treatment options were available. Discussion So far, despite availability of NGS diagnostics at university institutes of pathology, only few bladder cancer samples have been sequenced. Based on current data from the molecular subtyping of bladder cancers, we recommend a step-by-step protocol with basic immunohistochemistry analysis and subsequent subtype-dependent analyses, e.g., alterations of the fibroblast growth factor receptors (FGFR) or comprehensive gene panel analyses.

BaCKGroUNd: Non-melanoma skin cancers (NmSC) are the most common epithelial malignancies in organ transplantation recipients (otrs). in italy, incidence rates of post-transplantation NmSC are approximately 5% after 5 years and 10% after 10 years since organ transplantation. the objective was to describe risk factors associated with NmSC in a cohort of renal and liver transplant recipients, in a single-center longitudinal study. metHodS: renal and liver transplant patients, who underwent transplantation between June 1985 and december 2015, were visited for the first time or followed-up in a dedicated outpatient clinic every six months until July 2016. reSUltS: We included 356 renal and 76 liver transplant patients. 108 otrs (25.6%) presented 299 NmSC. 74 patients developed actinic keratosis (17.1%), 36 patients squamous cell carcinoma (8.5%), and 52 patients basal cell carcinoma (12.3%). time from transplantation and kidney transplant were the main risk factors for NmSC. Higher incidences of all NmSC were observed in patients >60 years, males and smokers, while decreased incidences were detected in individuals with higher educational levels. Multiple logistic regression models confirmed that male gender (rr 3.3, P=0.001), cigarette smoking (rr 2.0, P=0.026), light eye color (rr 2.9, P=0.001) and family history of cancer (rr 1.8, P=0.042) were independently associated with NmSC. CoNClUSioNS: dermatological follow-up is important in otrs, due to the higher risk of tumors and mainly NmSC. Clinical and environmental factors, including cigarette smoking, are useful in characterizing otr with higher risk of NmSC.

One-step nucleic acid amplification (OSNA) is used to intraoperatively detect sentinel lymph node metastases in breast cancer. OSNA has also been proposed in endometrial cancer, but evidence in this regard is unclear to define the diagnostic accuracy of OSNA in detecting lymph node metastases in endometrial cancer. A systematic review and meta-analysis was performed by searching 8 electronic databases from their inception to March 2019 for studies testing the diagnostic accuracy of OSNA in detecting sentinel lymph node metastasis in endometrial cancer. Pathologic ultrastaging was the reference standard. Sensitivity, specificity, positive and negative likelihood ratio (LR+ and LR-), diagnostic odds ratio (DOR) and area under the curve (AUC) on SROC curve were calculated. Four studies with 237 patients and 691 lymph nodes were included. OSNA showed sensitivity = 0.88, specificity = 0.93, LR + =17.95, LR- = 0.15, DOR = 191.23 and high diagnostic accuracy (AUC = 0.959). OSNA appears as a highly accurate tool for intraoperative assessment of sentinel lymph node in endometrial cancer.

Leser-Trélat Sign (LTS) is a rare paraneoplastic syndrome characterized by the sudden eruption of multiple seborrheic keratoses in patients with internal malignancy, commonly localized in the gastrointestinal tract. We report an 80-year-old female patient showing a rapid increase in the number and size of seborrheic keratosis associated with the diagnosis of a cutaneous nodular melanoma (Breslow thickness: 4.5 mm) located on the right flank. After the excision of melanoma, subsequent staging procedures resulted negative, moreover no evidence of melanoma recurrence and no changes of the seborrheic keratoses was detected after a follow-up of 52 months. Although the association between melanoma and Leser Trelat sign is rare, an accurate skin examination with the aid of dermatoscopy searching for undiagnosed skin cancers, should be suggested in patient with sudden eruption of keratosis seborrheic to early diagnose and treat a possible melanoma.

No abstract available

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Contains fulltext : 200082.pdf (Publisher’s version ) (Open Access)

Evidence-based guidelines on the management of pancreatic cystic neoplasms (PCN) are lacking. This guideline is a joint initiative of the European Study Group on Cystic Tumours of the Pancreas, United European Gas

Contains fulltext : 200082.pdf (Publisher’s version ) (Open Access)

Contains fulltext : 200082.pdf (Publisher’s version ) (Open Access)

Evidence-based guidelines on the management of pancreatic cystic neoplasms (PCN) are lacking. This guideline is a joint initiative of the European Study Group on Cystic Tumours of the Pancreas, United European Gastroenterology, European Pancreatic Club, European-African Hepato-Pancreato-Biliary Association, European Digestive Surgery, and the European Society of Gastrointestinal Endoscopy. It replaces the 2013 European consensus statement guidelines on PCN. European and non-European experts performed systematic reviews and used GRADE methodology to answer relevant clinical questions on nine topics (biomarkers, radiology, endoscopy, intraductal papillary mucinous neoplasm (IPMN), mucinous cystic neoplasm (MCN), serous cystic neoplasm, rare cysts, (neo)adjuvant treatment, and pathology). Recommendations include conservative management, relative and absolute indications for surgery. A conservative approach is recommended for asymptomatic MCN and IPMN measuring <40 mm without an enhancing nodule. Relative indications for surgery in IPMN include a main pancreatic duct (MPD) diameter between 5 and 9.9 mm or a cyst diameter ≥40 mm. Absolute indications for surgery in IPMN, due to the high-risk of malignant transformation, include jaundice, an enhancing mural nodule >5 mm, and MPD diameter >10 mm. Lifelong follow-up of IPMN is recommended in patients who are fit for surgery. The European evidence-based guidelines on PCN aim to improve the diagnosis and management of PCN.

Several studies have shown a two- to five-fold increased risk of melanoma in organ transplant recipients (OTRs) due to chronic immunosuppression [1]. The reported standardized incidence ratio of melanoma in OTRs ranges from slightly above 1 [2] to 8.0 [3]. It is difficult to draw conclusions on the true relative risk of melanoma in OTRs because some studies reported only case series [4], while others analysed large data sets that were not designed for this purpose [5]. Here, we report the estimated [...]

Background Ewing's sarcoma (ES) is the second most common bone or soft-tissue sarcoma in childhood and adolescence and features a high propensity to metastasize. The six-transmembrane epithelial antigen of the prostate 1 (STEAP1) is a membrane-bound mesenchymal stem cell marker highly expressed in ES. Here, we investigated the role of STEAP1 as an immunohistological marker for outcome prediction in patients with ES. Patients and methods Membranous STEAP1 immunoreactivity was analyzed using immunohistochemistry in 114 primary pre-chemotherapy ES of patients diagnosed from 1983 to 2010 and compared with clinical parameters and patient outcome. Median follow-up was 3.85 years (range 0.43-17.51). Results A total of 62.3% of the ES samples displayed detectable STEAP1 expression with predominant localization of the protein at the plasma membrane. High membranous STEAP1 immunoreactivity was found in 53.5%, which correlated with better overall survival (P=0.021). Accordingly, no or low membranous STEAP1 expression was identified as an independent risk factor in multivariate analysis (hazard ratio 2.65, P=0.036). Conclusion High membranous STEAP1 expression predicts improved outcome and may help to define a specific subgroup of ES patients, who might benefit from adapted therapy regimens

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Background Ewing's sarcoma (ES) is the second most common bone or soft-tissue sarcoma in childhood and adolescence and features a high propensity to metastasize. The six-transmembrane epithelial antigen of the prostate 1 (STEAP1) is a membrane-bound mesenchymal stem cell marker highly expressed in ES. Here, we investigated the role of STEAP1 as an immunohistological marker for outcome prediction in patients with ES. Patients and methods Membranous STEAP1 immunoreactivity was analyzed using immunohistochemistry in 114 primary pre-chemotherapy ES of patients diagnosed from 1983 to 2010 and compared with clinical parameters and patient outcome. Median follow-up was 3.85 years (range 0.43-17.51). Results A total of 62.3% of the ES samples displayed detectable STEAP1 expression with predominant localization of the protein at the plasma membrane. High membranous STEAP1 immunoreactivity was found in 53.5%, which correlated with better overall survival (P=0.021). Accordingly, no or low membranous STEAP1 expression was identified as an independent risk factor in multivariate analysis (hazard ratio 2.65, P=0.036). Conclusion High membranous STEAP1 expression predicts improved outcome and may help to define a specific subgroup of ES patients, who might benefit from adapted therapy regimens