First-Line everolimus and cisplatin in patients with advanced extrapulmonary neuroendocrine carcinoma:a nationwide phase 2 single-arm clinical trial

BACKGROUND: Extrapulmonary neuroendocrine carcinoma (EP-NEC) are an aggressive subgroup of neuroendocrine neoplasms (NEN). Advanced EP-NEC is generally treated with platinum-based cytotoxic regimens, but progressive disease occurs rapidly, resulting in a poor prognosis. Genetic alterations in the mammalian target for rapamycin (mTOR) pathway have been identified in NEN, providing a rationale for treatment with the mTOR-inhibitor everolimus. METHODS: A prospective phase 2 single-arm study included patients with advanced EP-NEC from three Dutch NEN expertise centres between March 2016 and January 2020. Treatment consisted of cisplatin 75 mg/m(2) every 3 weeks in combination with daily everolimus 7.5 mg for a maximum of six cycles, followed by maintenance everolimus until disease progression. Primary endpoint was disease control rate (DCR), defined as the sum of overall response rate (ORR) plus the rate of stable disease according to RECIST 1.1, assessed at 9-week intervals. Toxicity was evaluated according to CTCAE version 5.0. RESULTS: Thirty-nine patients, with a median age of 64 years (range: 28–74), of whom 20 (51%) were male, were enrolled. DCR was 82.1% (95% confidence interval (CI): 66.4–92.4), with an ORR of 58.9% (CI: 42.1–74.4). Median duration of response was 6.4 (CI: 5.8–7.0) months and median progression-free survival was 6.0 (CI: 4.3–7.8) months. Three patients (8%) had durable responses lasting  > 12 months. Median overall survival was 8.7 (CI: 7.8–9.6) months. Most common grade 3/4 toxicities were haematological (36%) and renal (21%). CONCLUSION: Everolimus in combination with cisplatin is an effective first-line treatment option for advanced EP-NEC, especially in highly selected patients. TRIAL REGISTRATION: Clinicaltrials.gov, NCT02695459, https://clinicaltrials.gov/ct2/show/NCT02695459

Postoperative Radiotherapy in Stage I-III Merkel Cell Carcinoma

BACKGROUND: Postoperative radiotherapy (PORT) is currently recommended for the treatment of Merkel cell carcinoma. Nevertheless, deviations occur frequently due to the generally elderly and frail patient population. We aimed to evaluate the influence of PORT on survival in stage I-III MCC patients treated in the Netherlands. METHODS: Patients were included retrospectively between 2013 and 2018. Fine-Gray method was used for cumulative incidence of recurrence and MCC-related survival, cox regression was performed for overall survival (OS). Analyses were performed in patients with clinical (sentinel node biopsy [SN] not performed) stage I/II (c-I/II-MCC), pathologic (SN negative) stage I/II (p-I/II-MCC) and stage III MCC (III-MCC), separately. Propensity score matching (PSM) was performed to assess confounding by indication. RESULTS: In total 182 patients were included, 35 had p-I/II-MCC, 69 had c-I/II-MCC and 78 had III-MCC. Median follow up time was 53.5 (IQR 33.4-67.4), 30.5 (13.0-43.6) and 29.3 (19.3-51.0) months, respectively. Multivariable analysis showed PORT to be associated with less recurrences and improved OS, but not with MCC-related survival. In stage III-MCC, extracapsular extension (sub-distribution hazard [SDH] 4.09, p=0.012) and PORT (SDH 0.45, p=0.044) were associated with recurrence, and ≥4 positive lymph nodes (SDH 3.24, p=0.024) were associated with MCC-related survival. CONCLUSIONS: PORT was associated with less recurrences and improved OS in patients with stage I-III MCC, but not with improved MCC-related survival. Trends in OS benefit are likely to be caused by selection bias suggesting further refinement of criteria for PORT is warranted, for instance by taking life expectancy into account

Patient-Derived Organoid Models of Human Neuroendocrine Carcinoma

Gastroenteropancreatic neuroendocrine carcinoma (GEP-NEC) is a poorly understood disease with limited treatment options. A better understanding of this disease would greatly benefit from the availability of representative preclinical models. Here, we present the potential of tumor organoids, three-dimensional cultures of tumor cells, to model GEP-NEC. We established three GEP-NEC organoid lines, originating from the stomach and colon, and characterized them using DNA sequencing and immunohistochemistry. Organoids largely resembled the original tumor in expression of synaptophysin, chromogranin and Ki-67. Models derived from tumors containing both neuroendocrine and non-neuroendocrine components were at risk of overgrowth by non-neuroendocrine tumor cells. Organoids were derived from patients treated with cisplatin and everolimus and for the three patients studied, organoid chemosensitivity paralleled clinical response. We demonstrate the feasibility of establishing NEC organoid lines and their potential applications. Organoid culture has the potential to greatly extend the repertoire of preclinical models for GEP-NEC, supporting drug development for this difficult-to-treat tumor type

Blood Transcript Profiling for the Detection of Neuroendocrine Tumors: Results of a Large Independent Validation Study

Background: Available neuroendocrine biomarkers are considered to have insufficient accuracy to discriminate patients with gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs) from healthy controls. Recent studies have demonstrated a potential role for circulating neuroendocrine specific transcripts analysis—the NETest—as a more accurate biomarker for NETs compared to available biomarkers. This study was initiated to independently validate the discriminative value of the NETest as well as the association between tumor characteristics and NETest score.Methods: Whole blood samples from 140 consecutive GEP-NET patients and 113 healthy volunteers were collected. Laboratory investigators were blinded to the origin of the samples. NETest results and chromogranin A (CgA) levels were compared with clinical information including radiological imaging to evaluate the association with tumor characteristics.Results: The median NETest score in NET patients was 33 vs. 13% in controls (p < 0.0001). The NETest did not correlate with age, gender, tumor location, grade, load, or stage. Using the cut-off of 14% NETest sensitivity and specificity were 93 and 56%, respectively, with an AUC of 0.87. The optimal cut-off for the NETest in our population was 20%, with sensitivity 89% and specificity 72%. The upper limit of normal for CgA was established as 100 μg/l. Sensitivity and specificity of CgA were 56 and 83% with an AUC of 0.76. CgA correlated with age (rs = 0.388, p < 0.001) and tumor load (rs = 0.458, p < 0.001).Conclusions: The low specificity of the NETest precludes its use as a screening test for GEP-NETs. The superior sensitivity of the NETest over CgA (93 vs. 56%; p < 0.001), irrespective of the stage of the disease, emphasize its potential as a marker of disease presence in follow up as well as an indicator for residual disease after surgery

Аксіологічні виміри душпастирства у творах Іоана Золотоустого

Стаття Світлани Білоус "Аксіологічні виміри душпастирства у творах Іоана Золотоустого" присвячена пошуку джерел духовної опіки над людиною, витоки яких автор бачить у християнському середньовіччі. Життя і творча спадщина Іоана Золотоустого – яскравий приклад пояснення сутності й визначення ціннісної природи душпастирювання крізь призму поняття священства.Статья Светланы Билоус "Аксиологические измерения душпастирства в произведениях Іоана Золотоустого" посвящена поиску источников духовной опеки над человеком, истоки которіх автор видит в христианском средневековье. Жизнь и творческое наследство Иоанна Золотоустого – яркий пример объяснения сущности и определение ценностной природы душпастирства сквозь призму понятия священства.The article by Svitlana Bilous "Axiological dimensions of priesthood in the Ioan Zolotoustyi’s works" is dedicated to finding sources of spiritual care over a human, the origin of which the author sees in the Christian Middle Ages. The life and literary heredity of Ioan Zolotoustyi is a brilliant pattern of explaining the essence and definition of valuable ​​nature of pastoral care through the prism of the concept of the priesthood

REIRRADIATION FOR HEAD-AND-NECK CANCER: DELICATE BALANCE BETWEEN EFFECTIVENESS AND TOXICITY

To analyze the effectiveness and toxicity of reirradiation (re-RT) for head-and-neck cancer. A retrospective data analysis was performed of 58 patients who underwent re-RT with curative intent. Re-RT was given as definitive treatment in 53% of patients, whereas salvage surgery preceded reirradiation in 47%. The median cumulative RT dose was 119 Gy (range, 76-140). Concurrent chemotherapy was administered with re-RT (CRT) in 57% of patients. Event-free survival was defined as survival without recurrence and without serious toxicity (≥Grade 3). Median follow-up was 57 months (range, 9-140). Locoregional (LR) control was 50% at 2 and 5 years. The 2-year and 5-year overall survival (OS) was 42% and 34%. The following factors were associated with improved OS: postoperative re-RT (vs. primary re-RT), treatment with RT only (vs. CRT) and interval >3 years between previous RT and re-RT. For patients treated with postoperative re-RT and definitive re-RT, the 5-year OS was 49% and 20%, respectively. Patients treated with CRT had a 5-year OS of 13%. Serious (late) toxicity ≥Grade 3 was observed in 20 of 47 evaluable patients (43%). Three cases of treatment-related death were recorded. The 2- and 5-year serious toxicity-free interval was 59% and 55%, respectively. Associated with increased risk of serious toxicity were CRT and higher re-RT dose. The event-free survival rates at 2 and 5 years were 34% and 31%, respectively. Re-RT in head-and-neck cancer is associated with poor survival rates of 13-20% in patients with inoperable disease treated with primary (chemo-) re-RT. For this subgroup, however, no other curative options are available. Long-term disease control and survival can be achieved in patients who receive re-RT as an adjunct to surgical resection. The rates of serious toxicity after re-RT are high, with an incidence of approximately 45% at 5 years. Approximately 1 in 3 patients survived re-RT without recurrence and severe complication

Prevalence of Sarcopenia and Impact on Survival in Patients with Metastatic Gastroenteropancreatic Neuroendocrine Tumours

Sarcopenia in patients with cancer is associated with adverse outcomes such as shorter survival. However, there exists little evidence regarding the prevalence of sarcopenia in patients with metastatic gastroenteropancreatic neuroendocrine tumours (GEP-NETs). Patients with a histologically confirmed newly diagnosed metastatic GEP-NET between 2006 and 2018, CT scan, and anthropometric data at diagnosis were included in this study. CT scans were analysed for the presence of sarcopenia and correlated with overall survival (OS). In total, 183 patients, 87 male (48%), with a median age of 62 years (IQR 52–68 years), were included. In 44 patients (24%), there was a pancreas NET, and in 136 patients, there was a small bowel NET (74%). Sarcopenia was present in 128 patients (69%) and unrelated to BMI (median 25.1). There were significant survival differences between patients with pancreatic and small bowel NETs at 86 vs. 141 months, respectively (p = 0.04). For patients with pancreatic NETs, the presence of sarcopenia was independently associated with shorter OS (HR 3.79 95% CI 1.1–13.03, p-value 0.035). A high prevalence of sarcopenia at the time of diagnosis of a metastatic GEP-NET was seen and associated with worse OS in patients with pancreatic NETs. Further research should focus on how to reverse sarcopenia and its impact on OS and/or quality of life

Prevalence of Sarcopenia and Impact on Survival in Patients with Metastatic Gastroenteropancreatic Neuroendocrine Tumours

Sarcopenia in patients with cancer is associated with adverse outcomes such as shorter survival. However, there exists little evidence regarding the prevalence of sarcopenia in patients with metastatic gastroenteropancreatic neuroendocrine tumours (GEP-NETs). Patients with a histologically confirmed newly diagnosed metastatic GEP-NET between 2006 and 2018, CT scan, and anthropometric data at diagnosis were included in this study. CT scans were analysed for the presence of sarcopenia and correlated with overall survival (OS). In total, 183 patients, 87 male (48%), with a median age of 62 years (IQR 52–68 years), were included. In 44 patients (24%), there was a pancreas NET, and in 136 patients, there was a small bowel NET (74%). Sarcopenia was present in 128 patients (69%) and unrelated to BMI (median 25.1). There were significant survival differences between patients with pancreatic and small bowel NETs at 86 vs. 141 months, respectively (p = 0.04). For patients with pancreatic NETs, the presence of sarcopenia was independently associated with shorter OS (HR 3.79 95% CI 1.1–13.03, p-value 0.035). A high prevalence of sarcopenia at the time of diagnosis of a metastatic GEP-NET was seen and associated with worse OS in patients with pancreatic NETs. Further research should focus on how to reverse sarcopenia and its impact on OS and/or quality of life