Spatially restricted tumour-associated and host-associated immune drivers correlate with the recurrence sites of pancreatic cancer.

OBJECTIVE: Most patients with pancreatic ductal adenocarcinoma (PDAC) will experience recurrence after resection. Here, we investigate spatially organised immune determinants of PDAC recurrence. DESIGN: PDACs (n=284; discovery cohort) were classified according to recurrence site as liver (n=93/33%), lung (n=49/17%), local (n=31/11%), peritoneal (n=38/13%) and no-recurrence (n=73/26%). Spatial compartments were identified by fluorescent imaging as: pancytokeratin (PanCK)+CD45- (tumour cells); CD45+PanCK- (leucocytes) and PanCK-CD45- (stromal cells), followed by transcriptomic (72 genes) and proteomic analysis (51 proteins) for immune pathway targets. Results from next-generation sequencing (n=194) were integrated. Finally, 10 tumours from each group underwent immunophenotypic analysis by multiplex immunofluorescence. A validation cohort (n=109) was examined in parallel. RESULTS: No-recurrent PDACs show high immunogenicity, adaptive immune responses and are rich in pro-inflammatory chemokines, granzyme B and alpha-smooth muscle actin+ fibroblasts. PDACs with liver and/or peritoneal recurrences display low immunogenicity, stemness phenotype and innate immune responses, whereas those with peritoneal metastases are additionally rich in FAP+ fibroblasts. PDACs with local and/or lung recurrences display interferon-gamma signalling and mixed adaptive and innate immune responses, but with different leading immune cell population. Tumours with local recurrences overexpress dendritic cell markers whereas those with lung recurrences neutrophilic markers. Except the exclusive presence of RNF43 mutations in the no-recurrence group, no genetic differences were seen. The no-recurrence group exhibited the best, whereas liver and peritoneal recurrences the poorest prognosis. CONCLUSIONS: Our findings demonstrate distinct inflammatory/stromal responses in each recurrence group, which might affect dissemination patterns and patient outcomes. These findings may help to inform personalised adjuvant/neoadjuvant and surveillance strategies in PDAC, including immunotherapeutic modalities.

Current standards of surgical management of gastric cancer: an appraisal.

PURPOSE: Gastric cancer (GC) is the fifth most common malignancy worldwide and portends a grim prognosis due to a lack of appreciable improvement in 5-year survival. We aimed to analyze the available literature and summarize the current standards of surgical care for curative and palliative intent treatment of GC. METHODS: We conducted a systematic search on the PubMed database for studies on the management of GC. RESULTS: Endoscopic resection is an acceptable treatment option for T1a tumors. The role of optimal resection margin for GC remains unclear. D2 lymph node dissection remains the standard of care with splenectomy needed selectively for splenic hilum involvement. A distal pancreatic resection should be avoided. The advantage of bursectomy and omentectomy in GC surgery is not clear. Multi-visceral resection may be considered for locally advanced GC in carefully selected patients. Minimally invasive approaches are non-inferior to open surgery. Surgery should be abandoned prior even in metastatic GC within the frame of multimodal therapy approach. CONCLUSION: Various trials have conclusively shown improved patient outcomes when well-established surgical standards are followed.

Surgical Outcomes After Neoadjuvant Chemoradiation Followed by Curative Surgery in Patients With Esophageal Cancer: An Intergroup Phase III Trial of the Swiss Group for Clinical Cancer Research (SAKK 75/08).

OBJECTIVE: To assess the impact of surgical technique in regard to morbidity and mortality after neoadjuvant treatment for esophageal cancer. BACKGROUND: The SAKK trial 75/08 was a multicenter phase III trial (NCT01107639) comparing induction chemotherapy followed by chemoradiation and surgery in patients with locally advanced esophageal cancer. METHODS: Patients in the control arm received induction chemotherapy with cisplatin and docetaxel, followed by concomitant chemoradiation therapy with cisplatin, docetaxel, and 45Gy. In the experimental arm, the same regimen was used with addition of cetuximab. After completion of neoadjuvant treatment, patients underwent esophagectomy. The experimental arm received adjuvant cetuximab. Surgical outcomes and complications were prospectively recorded and analyzed. RESULTS: Total of 259 patients underwent esophagectomy. Overall complication rate was 56% and reoperation rate was 15% with no difference in complication rates for transthoracic versus transhiatal resections (56% vs 54%, P = 0.77), nor for video assisted thoracic surgeries (VATS) versus open transthoracic resections (67% vs 55%, P = 0.32). There was a trend to higher overall complication rates in squamous cell carcinoma versus adenocarcinoma (65% vs 51%, P = 0.035), and a significant difference in ARDS in squamous cell carcinoma with 14% versus 2% in adenocarcinoma (P = 0.0002). For patients with involved lymph nodes, a lymph node ratio of ≥0.1 was an independent predictor of PFS (HR 2.5, P = 0.01) and OS (HR 2.2, P = 0.03). CONCLUSIONS: This trial showed no difference in surgical complication rates between transthoracic and transhiatal resections. For patients with involved lymph nodes, lymph node ratio was an independent predictor of progression free survival and overall survival.

Three-Dimensional Primary Cell Culture: A Novel Preclinical Model for Pancreatic Neuroendocrine Tumors.

Molecular mechanisms underlying the development and progression of pancreatic neuroendocrine tumors (PanNETs) are still insufficiently understood. Efficacy of currently approved PanNET therapies is limited. While novel treatment options are being developed, patient stratification permitting more personalized treatment selection in PanNET is yet not feasible since no predictive markers are established. The lack of representative in vitro and in vivo models as well as the rarity and heterogeneity of PanNET are prevailing reasons for this. In this study, we describe an in vitro 3-dimensional (3-D) human primary PanNET culture system as a novel preclinical model for more personalized therapy selection. We present a screening platform allowing multicenter sample collection and drug screening in 3-D cultures of human primary PanNET cells. We demonstrate that primary cells isolated from PanNET patients and cultured in vitro form islet-like tumoroids. Islet-like tumoroids retain a neuroendocrine phenotype and are viable for at least 2 weeks in culture with a high success rate (86%). Viability can be monitored continuously allowing for a per-well normalization. In a proof-of-concept study, islet-like tumoroids were screened with three clinically approved therapies for PanNET: sunitinib, everolimus and temozolomide. Islet-like tumoroids display varying in vitro response profiles to distinct therapeutic regimes. Treatment response of islet-like tumoroids differs also between patient samples. We believe that the presented human PanNET screening platform is suitable for personalized drug testing in a larger patient cohort, and a broader application will help in identifying novel markers predicting treatment response and in refining PanNET therapy.

Challenges of students and residents of human medicine in the first four months of the fight against the Covid-19 pandemic - Implications for future waves and scenarios.

INTRODUCTION: In the fight against the Covid-19 pandemic, medical students and residents are expected to adapt and contribute in a healthcare environment characterized by ever-changing measures and policies. The aim of this narrative review is to provide a summary of the literature that addresses the challenges of students and residents of human medicine in the first 4 months of the fight against the Covid-19 pandemic in order to identify gaps and find implications for improvement within the current situation and for potential future scenarios. METHODS: We performed a systematic literature search and content analysis (CA) of articles available in English language that address the challenges of students and residents of human medicine in the first 4 months of the fight against the Covid-19 pandemic. RESULTS: We retrieved 82 articles from a wide range of journals, professional backgrounds and countries. CA identified five recurring subgroup topics: "faculty preparation", «uncertainties and mental health¼, «clinical knowledge¼, «rights and obligations¼ and «(self-) support and supply¼. Within these subgroups the main concerns of (re-)deployment, interruption of training and career, safety issues, transmission of disease, and restricted social interaction were identified as potential stressors that hold a risk for fatigue, loss of morale and burnout. DISCUSSION: Students and residents are willing and able to participate in the fight against Covid-19 when provided with appropriate deployment, legal guidance, safety measures, clinical knowledge, thorough supervision, social integration and mental health support. Preceding interviews to decide on reasonable voluntary deployment, the use of new technology and frequent feedback communication with faculties, educators and policymakers can further help with a successful and sustainable integration of students and residents in the fight against the pandemic. CONCLUSION: It is critical that faculties, educators and policymakers have a thorough understanding of the needs and concerns of medical trainees during pandemic times. Leaders should facilitate close communication with students and residents, value their intrinsic creativeness and regularly evaluate their needs in regards to deployment, knowledge aspects, safety measures, legal concerns and overall well-being.

[Neuroendocrine tumor of the pancreas: What is new?] / Neuroendokrine Tumore des Pankreas.

Neuroendocrine tumor of the pancreas: What is new? Abstract. Neuroendocrine neoplasms are a rare and heterogeneous group of tumors with very different clinical presentations. Accordingly, they are initially difficult to recognize in clinical practice and diagnosis is often delayed. The necessary diagnostic steps include radiological and functional / nuclear medicine examinations to determine the extent of the primary tumor on the one hand and the presence of metastases on the other. If indicated, tissue sampling / biopsy is indicated. The resulting treatments include surgical resection, treatment with somatostatin analogues or multimodal therapy concepts, depending on the type and spread of the tumor and the symptoms. The therapy of patients with NET must be discussed at an interdisciplinary tumor board at a specialized center.

Is There a Role for Surgery in Patients with Neuroendocrine Tumors of the Esophagus? A Contemporary View from the NCDB.

BACKGROUND: Esophageal neuroendocrine tumors (eNETs) are exceedingly rare, aggressive and have a poor prognosis. Treatment guidelines are ill-defined and mainly based on evidence from case reports and analogous experiences drawn from similar disease sites. METHODS: The NCDB was reviewed for histologically confirmed stage I-III, primary eNETs from 2006 to 2014. Patients were grouped into whether or not they underwent primary tumor resection. Univariate, multivariable, and full bipartite propensity score (PS) adjusted Cox regression analyses were used to assess overall and relative survival differences. RESULTS: A total of 250 patients were identified. Mean age was 65.0 (standard deviation [SD] 11.9) years, and 174 (69.6%) patients were male. Most patients had stage III disease (n = 136, 54.4%), and the most common type of NET was small cell eNET (n = 111, 44.4%). Chemotherapy was used in 186 (74.4%), radiation therapy in 178 (71.2%), and oncological resection was performed in 69 (27.6%) patients. Crude 2-year survival rates were higher in the operated (57.3%) compared with the nonoperated group (35.2%; p < 0.001). The survival benefit held true after multivariable adjustment (hazard ratio [HR] 0.47, 95% confidence interval [CI] 0.32-0.69, p < 0.001). After full bipartite PS adjustment analysis, survival was longer for patients who received a surgical resection compared with those who did not (HR 0.48, 95% CI 0.31-0.75, p = 0.003) with a corresponding 2-year overall survival rate of 63.3% (95% CI 52.0-77.2) versus 38.8% (95% CI 30.9-48.8), respectively. CONCLUSIONS: Multimodal treatment that includes surgery is associated with better overall survival for eNETs. Additional research is needed to more definitively identify patients who benefit from esophagectomy and to establish an appropriate treatment algorithm.

Preservation of Epstein-Barr virus status and mismatch repair protein status along the metastatic course of gastric cancer.

AIMS: Epstein-Barr virus (EBV) in-situ hybridisation and mismatch repair (MMR) protein immunohistochemistry identifies two subgroups of gastric cancer (GC) with high immunogenicity and likelihood for response to immune check-point inhibition. As tumour biology may change during the metastatic course, which can negatively influence the success of therapeutic decisions made on primary tissue, we investigated the consistency of GC EBV and MMR status within primary tumours and metastases. METHODS AND RESULTS: We investigated a cohort of 415 primary resected GC, including 111 cases with corresponding distant metastases and 297 cases with lymph node metastases. Tumours were analysed by EBV in-situ hybridisation and MLH1, PMS2, MSH2 and MSH6 immunohistochemistry using tissue microarray technique. Primary tumours were grouped as EBV-positive MMR-proficient, EBV-negative MMR-deficient and EBV-negative MMR-proficient. Eleven of 415 (2.7%) of primary tumours were EBV-positive MMR-proficient, whereas 49 of 415 (11.8%) of tumours were EBV-negative MMR-deficient. EBV and MMR protein status showed full concordance with that of the primary tumours. MMR-deficient tumours were of lower pT-category (P < 0.001), had fewer lymph node metastases [24 of 49 (49%) versus 273 of 361 (75.6%) cases; P < 0.001] and a lower rate of distant metastases [six of 49 (12.2%) versus 105 of 366 (28.7%) cases; P = 0.015]. CONCLUSION: We demonstrate a strong correlation of EBV and MMR status between primary tumours, lymph node and distant metastases in a large series of primary resected GC. The cases showed the expected frequency of EBV-positive MMR-deficient and EBV-negative MMR-proficient tumours. We conclude that tissue testing for molecular subtyping for therapeutic decision-making can be reliably performed on primary tumours and metastases in GC.

Performance of a factory-calibrated, real-time continuous glucose monitoring system during elective abdominal surgery.

We assessed the performance of the factory-calibrated, sixth-generation continuous glucose monitoring (CGM) system Dexcom G6® (DexCom Inc., San Diego, California) during elective abdominal surgery. Twenty adults with (pre)diabetes undergoing abdominal surgery (>2 hours; 15 men, age 69 ± 13 years, glycated haemoglobin 53 ± 14 mmol/mol) wore the sensor from 1 week prior to surgery until hospital discharge. From induction of anaesthesia until 2 hours post-surgery, reference capillary glucose values were obtained every 20 minutes using the Accu-Chek® Inform II meter (Roche Diabetes Care, Mannheim, Germany). The primary endpoint was the mean absolute relative difference (ARD) between sensor and reference method during this period. In total, 1207 CGM/reference pairs were obtained. In the peri-operative period (523 pairs), mean ± SD and median (interquartile range [IQR]) ARD were 12.7% ± 8.7% and 9.9 (6.3;15.9)%, respectively, and 67.4% of sensor readings were within International Organization of Standardization 15197:2013 limits. CGM overestimated reference glucose by 1.1 ± 0.8 mmol/L (95% limits of agreement -0.5;2.7 mmol/L). Clarke error grid zones A or B contained 99.2% of pairs (A: 78.8%; B: 20.4%). The median (IQR) peri-operative sensor availability was 98.6 (95.9;100.0)%. No clinically significant adverse events occurred. In conclusion, the Dexcom G6 device showed consistent and acceptable accuracy during elective abdominal surgery, opening new avenues for peri-operative glucose management.

No Difference in Survival between Neo-Adjuvant Chemotherapy and Neo-Adjuvant Chemoradiation Therapy in Gastric Cardia Cancer Patients: A Contemporary View from the National Cancer Database.

INTRODUCTION: Both neo-adjuvant chemoradiation therapy (NACRT) and neo-adjuvant chemotherapy (NAC), in addition to surgical resection of gastric cardia cancer, improves survival outcomes. We assessed whether NACRT or NAC had superior overall survival (OS) and relative survival (RS) outcomes using the National Cancer Database (NCDB). METHODS: The NCDB from 2006 to 2014 was reviewed to identify non-metastatic adult gastric cardia cancer patients who underwent surgical resection and received NACRT or NAC. Advanced statistical models were applied to assess survival outcomes. RESULTS: Of the 5,371 patients included, 4,520 (84.2%) were male, the mean age was 61.2 years (SD 10.0), 4,229 (78.7%) underwent NACRT, and 1,142 (21.3%) underwent NAC. NACRT patients more often had an R0 resection compared to NAC (91.4 vs. 86.6%, p < 0.001, respectively). Univariate 5-year OS rates were 40.0% (95% CI 38.2-41.8) for NACRT and 40.1% (37.0-43.6) for NAC (p = 0.302). No differences in OS for NAC vs. NACRT were found after multivariable analysis (hazard ratio [HR] 0.95, 95% CI 0.86-1.05, p = 0.290). There were no survival differences after stepwise, propensity score, RS analyses, nor after near-far-matching (HR 0.94, 95% CI 0.82-1.07, p = 0.332). CONCLUSIONS: NAC or NACRT yield the same survival outcome for patients with resectable gastric cardia cancer. These data support the need for randomized controlled trials comparing the 2 regimens head-to-head.

Role of lymphadenectomy, adjuvant chemotherapy, and treatment at high-volume centers in patients with resected pancreatic cancer-a distinct view on lymph node yield.

PURPOSE: While the importance of lymphadenectomy is well-established for patients with resectable pancreatic cancer, its direct impact on survival in relation to other predictive factors is still ill-defined. METHODS: The National Cancer Data Base 2006-2015 was queried for patients with resected pancreatic adenocarcinoma (stage IA-IIB). Patients were dichotomized into the following two groups, those with 1-14 resected lymph nodes and those with ≥ 15. Optimal number of resected lymph nodes and the effect of lymphadenectomy on survival were assessed using various statistical modeling techniques. Mediation analysis was performed to differentiate the direct and indirect effect of lymph node resection on survival. RESULTS: A total of 21,912 patients were included; median age was 66 years (IQR 59-73), 48.9% were female. Median number of resected lymph nodes was 15 (IQR 10-22), 10,163 (46.4%) had 1-14 and 11,749 (53.6%) had ≥ 15 lymph nodes retrieved. Lymph node positivity increased by 4.1% per lymph node up to eight examined lymph nodes, and by 0.6% per lymph node above eight. Five-year overall survival was 17.9%. Overall survival was better in the ≥ 15 lymph node group (adjusted HR 0.91, CI 0.88-0.95, p < 0.001). On a continuous scale, survival improved with increasing LNs collected. Patients who underwent adjuvant chemotherapy and were treated at high-volume centers had improved overall survival compared with their counterparts (adjusted HR 0.59, CI 0.57-0.62, p < 0.001; adjusted HR 0.86, CI 0.83-0.89, p < 0.001, respectively). Mediation analysis revealed that lymphadenectomy had only 18% direct effect on improved overall survival, while 82% of its effect were mediated by other factors like treatment at high-volume hospitals and adjuvant chemotherapy. DISCUSSION: While higher number of resected lymph nodes increases lymph node positivity and is associated with better overall survival, most of the observed survival benefit is mediated by chemotherapy and treatment at high-volume centers.

Recurrence Patterns and Long-term Results After Induction Chemotherapy, Chemoradiotherapy, and Curative Surgery in Patients With Locally Advanced Esophageal Cancer.

OBJECTIVE: The long-term follow up data of 2 prospective phase II trials is reported (NCT00072033, NCT00445861), which investigated neoadjuvant chemoradiation followed by surgery in patients with esophageal carcinoma. Postoperative complications as well as prognostic factors and patterns of relapse during long-term observation are shown. SUMMARY OF BACKGROUND DATA: Long-term follow-up is often missing in the complex setting of multimodal treatments of esophageal carcinoma; this leads to rather undifferentiated follow-up guidelines for this tumor entity. METHODS: In the first trial, patients received induction chemotherapy followed by chemoradiation and surgery. In the second trial, cetuximab was added to the same neoadjuvant treatment concomitant with induction chemotherapy and chemoradiation. RESULTS: Eighty-two patients underwent surgery; the median follow-up time was 6.8 and 6.4 years, respectively. Fifty-five percent were diagnosed with adenocarcinoma, 80% clinically node-positive, 68% received transthoracic esophagectomy, and 32% transhiatal or transmediastinal resection. Five patients died postoperatively in-hospital due to complications (6%). The median overall survival was 4.3 years, and the median event-free survival was 2.7 years. Patients with adenocarcinoma rarely relapsed after a 3-year event-free survival. Whereas patients with residual tumor cells after neoadjuvant therapy primarily experienced relapse within the first 2 postoperative years, this in contrast to several patients with complete remission who also experienced late relapses 4 years after surgery. CONCLUSION: After curative surgery in a multimodal setting, the histological type and the response to neoadjuvant therapy predicted the time frame of relapse; this knowledge may influence further follow-up guidelines for esophageal carcinoma.

Clinical Outcome After Rectal Replacement With Side-to-End, Colon-J-Pouch, or Straight Colorectal Anastomosis Following Total Mesorectal Excision: A Swiss Prospective, Randomized, Multicenter Trial (SAKK 40/04).

OBJECTIVE: To compare, in a phase 3, prospective, randomized, multi-center clinical trial functional outcome of reconstruction procedures following total mesorectal excision (TME). SUMMARY BACKGROUND DATA: Intestinal continuity reconstruction following TME is accompanied by postoperative defecation dysfunctions known as "anterior resection syndrome." Commonly used reconstruction techniques are straight colorectal anastomosis (SCA), colon J -pouch (CJP), and side-to-end anastomosis (SEA). Comparison of their functional outcomes in prospective, randomized, multi-center studies, including long-term assessments, is lacking. METHODS: Patients requiring TME for histologically proven rectal tumor, with or without neoadjuvant treatment, age ≥ 18 years, normal sphincter function without history of incontinence, any pretreatment staging or adenoma, expected R0-resection, were randomized for standardized SCA, CJP, or SEA procedures. Primary endpoint was comparison of composite evacuation scores 12 months after TME. Comparison of composite evacuation and incontinence scores at 6, 18 and 24 months after surgery, morbidity, and overall survival represented secondary endpoints. Analysis was based on "per protocol" (PP) population, fully complying with trial requirements, and intention-to treat (ITT) population. RESULTS: Three hundred thirty-six patients from 15 hospitals were randomized. PP population included 257 patients (JCP = 63; SEA = 95; SCA = 99). Composite evacuation scores of PP and ITT populations did not show statistically significant differences among the 3 groups at any time point. Similarly, composite incontinence scores for PP and ITT populations showed no statistically significant difference among the 3 trial arms at any time point. CONCLUSIONS: Within boundaries of investigated procedures, surgeons in charge may continue to perform reconstruction of intestinal continuity following TME at their technical preference.

Quality of Life After Total Mesorectal Excision and Rectal Replacement: Comparing Side-to-End, Colon J-Pouch and Straight Colorectal Reconstruction in a Randomized, Phase III Trial (SAKK 40/04).

BACKGROUND: Functional outcomes of different reconstruction techniques have an impact on patients' quality of life (QoL), but information on long-term QoL is lacking. We compared QoL among three reconstruction techniques after total mesorectal excision (TME). METHODS: Quality of life was assessed within a randomized, multicenter trial comparing rectal surgery using side-to-end anastomosis (SEA), colon J-pouch (CJP), and straight colorectal anastomosis (SCA) by the Functional Assessment of Cancer Therapy-Colorectal scale (FACT-C) before randomization and every 6 months up to 2 years post-TME. The primary QoL endpoint was the change in the Trial Outcome Index (TOI), including the FACT-C subscales of physical and functional well-being and colorectal cancer symptoms (CSS), from baseline to month 12. Pair-wise comparisons of changes from baseline (presurgery) to each timepoint between the three arms were analyzed by Mann-Whitney tests. RESULTS: For the QoL analysis, 257 of 336 randomized patients were in the per protocol evaluation (SEA = 95; CJP = 63; SCA = 99). Significant differences between the reconstruction techniques were found for selected QoL scales up to 12 months, all in favor of CJP. Patients with SEA or SCA reported a clinically relevant deterioration for TOI and CSS at 6 months, those with SCA for CSS also at 12 months after TME. Patients with CJP remained stable. CONCLUSIONS: Although the three reconstruction techniques differ in their effects on QoL at months 6 and 12, these differences did not persist over the whole observation period of 24 months. Patients with a colon J-pouch may benefit with respect to QoL in the short-term.

Neoadjuvant Treatment for Borderline Resectable Pancreatic Ductal Adenocarcinoma.

One of the main reasons for the dismal prognosis of pancreatic ductal adenocarcinoma (PDAC) is its late diagnosis. At the time of presentation, only approximately 15-20% of all patients with PDAC are considered resectable and around 30% are considered borderline resectable. A surgical approach, which is the only curative option, is limited in borderline resectable patients by local involvement of surrounding structures. In borderline resectable pancreatic cancer (BRPC), neoadjuvant treatment regimens have been introduced with the rationale to downstage and downsize the tumor in order to enable resection and eliminate -microscopic distant metastases. However, there are no official guidelines for the preoperative treatment of BRPC. In the majority of cases, patients are administered -Gemcitabine-based or FOLFIRINOX-based chemotherapy regimens with or without radiation. Radiologic restaging after neoadjuvant therapy has to be judged with caution when it comes to predict tumor response and resectability, since inflammation induced by neoadjuvant therapy may mimic solid tumor. Patients who do not show any disease progression during neoadjuvant therapy should be offered surgical exploration, since a high percentage is likely to undergo resection with negative margins (R0) and, thus, achieve improved overall survival although imaging judged it unlikely. Despite the promising new approaches of neoadjuvant treatment regimens during the last 2 decades, surgery remains the first choice if the tumor appears to be primary resectable at the time of diagnosis. At present, there are no international guidelines regarding the preoperative treatment of BRPC. Therefore, in order to standardize and adjust neoadjuvant treatment in the future, new guidelines have to be determined on the basis of upcoming prospective randomized studies.

Tumour budding in pancreatic cancer revisited: validation of the ITBCC scoring system.

AIMS: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with rising incidence. Biomarkers that would help the prognostic stratification of patients are needed urgently. Although tumour budding (BD) is a strong and independent prognostic factor in PDAC it is not included in histopathology reports, due partly to the lack of a standardised scoring system. The aim of the present work is to assess the reliability and reproducibility of the BD scoring system proposed recently by the International Tumour Budding Consensus Conference (ITBCC) 2016 in a well-characterised PDAC cohort (n = 120) with complete clinicopathological and follow-up information. METHODS AND RESULTS: BD was scored independently by two pathologists on haematoxylin and eosin-stained PDAC sections by assessing the densest budding area at ×20 magnification (one hot-spot, 0.785 mm2 ), regardless of intra- or peritumoural localisation, and assigned to four categories: BD0: no buds; BD1: one to four buds; BD2: five to nine buds; and BD3: ≥ 10 buds. Findings were correlated to patient and tumour characteristics and interobserver agreement was assessed. The weighted kappa value for BD category was 0.62 (0.5-0.73), indicating strong agreement. Increasing BD category (BD3 versus BD0-2) correlated with higher grade (P = 0.002) and shorter overall [OS, P < 0.0001, hazard ratio (HR) = 3.234, 95% confidence interval (CI) = 1.95-5.37] and disease-free survival (DFS, P = 0.0135, HR = 1.974, 95% CI = 1.15-3.39). BD (BD3 versus BD0-2) was an independent prognostic factor for OS and DFS, after adjusting for tumour-node-metastasis (TNM) stage by using both the 8th American Joint Committee on Cancer (AJCC) edition (OS: P = 0.0031, HR = 2.298, 95% CI = 1.32-0.99; DFS: P = 0.0458, HR = 1.713, 95% CI = 1.01-2.91) and the 7th AJCC edition (OS: P < 0.0001, HR = 2.795,95% CI = 1.71-4.57 and DFS: P = 0.00786, HR = 1.643, 95% CI = 0.95-2.86). CONCLUSIONS: ITBCC scoring is a simple, reliable and reproducible method to evaluate BD in PDAC and facilitates its documentation in histopathology reports, allowing the prognostic stratification of PDAC patients.

Comparison of glucagon-like peptide-1 receptor (GLP-1R) PET/CT, SPECT/CT and 3T MRI for the localisation of occult insulinomas: evaluation of diagnostic accuracy in a prospective crossover imaging study.

PURPOSE: Benign insulinomas are the most prevalent cause of endogenous hyperinsulinaemic hypoglycaemia (EHH) in adults, and because of their small size are difficult to localise. The purpose of the study was to test the diagnostic accuracy and clinical impact of glucagon-like peptide-1 receptor (GLP-1R) PET/CT using 68Ga-DOTA-exendin-4 in consecutive adult patients referred for localisation of insulinomas. The results were compared with 111In-DOTA-exendin-4 SPECT/CT, study-MRI and previously performed external CT and/or MRI (prior external CT/MRI). METHODS: We prospectively enrolled patients with neuroglycopenic symptoms due to EHH. GLP-1R PET/CT, SPECT/CT and study-MRI were performed in a randomised, crossover order within 3-4 days. The reference standard was surgery with histology and treatment outcome. RESULTS: From January 2014 until March 2017, 52 patients were recruited. All imaging and invasive procedures before recruitment identified suspicious lesions in 46.2% of patients. GLP-1R PET/CT, SPECT/CT and study-MRI detected suspicious lesions in 78.8%, 63.5% and 63.4% of patients, respectively. In 38 patients, conclusive histology was available for final analysis. Accuracy (95% confidence interval) for PET/CT, SPECT/CT, study-MRI and prior external CT/MRI was 93.9% (87.8-97.5%), 67.5% (58.1-76.0%), 67.6% (58.0-76.1%) and 40.0% (23.9-57.9%), respectively (all P values < 0.01, except comparison of SPECT/CT and study-MRI with a P value = 1.0). Impact on clinical management was 42.3%, 32.7% and 33.3% for PET/CT, SPECT/CT and study-MRI, respectively. Percentage reading agreement was 89.5%, 75.7%, and 71.1% for PET/CT, SPECT/CT and study-MRI, respectively. CONCLUSION: 68Ga-DOTA-exendin-4 PET/CT performed significantly better than 111In-DOTA-exendin-4 SPECT/CT and MRI in the localisation of benign insulinomas and should be considered in patients where localisation fails with CT/MRI ( ClinicalTrials.gov , NCT02127541).

Functional Outcomes After Rectal Resection for Deep Infiltrating Pelvic Endometriosis: Long-term Results.

BACKGROUND: Curative management of deep infiltrating endometriosis requires complete removal of all endometriotic implants. Surgical approach to rectal involvement has become a topic of debate given potential postoperative bowel dysfunction and complications. OBJECTIVE: This study aims to assess long-term postoperative evacuation and incontinence outcomes after laparoscopic segmental rectal resection for deep infiltrating endometriosis involving the rectal wall. DESIGN: This is a retrospective study of prospectively collected data. SETTINGS: This single-center study was conducted at the University Hospital of Bern, Switzerland. PATIENTS: Patients with deep infiltrating endometriosis involving the rectum undergoing rectal resection from June 2002 to May 2011 with at least 24 months follow-up were included. MAIN OUTCOME MEASURES: Aside from endometriosis-related symptoms, detailed symptoms on evacuation (points: 0 (best) to 21 (worst)) and incontinence (0-24) were evaluated by using a standardized questionnaire before and at least 24 months after surgery. RESULTS: Of 66 women who underwent rectal resection, 51 were available for analyses with a median follow-up period of 86 months (range: 26-168). Forty-eight patients (94%) underwent laparoscopic resection (4% converted, 2% primary open), with end-to-end anastomosis in 41 patients (82%). Two patients (4%) had an anastomotic insufficiency; 1 case was complicated by rectovaginal fistula. Dysmenorrhea, nonmenstrual pain, and dyspareunia substantially improved (p < 0.001 for all comparisons). Overall evacuation score increased from a median of 0 (range: 0-11) to 2 points (0-15), p = 0.002. Overall incontinence also increased from 0 (range: 0-9) to 2 points (0-9), p = 0.003. LIMITATIONS: This study was limited by its retrospective nature and moderate number of patients. CONCLUSIONS: Laparoscopic segmental rectal resection for the treatment of deep infiltrating endometriosis including the rectal wall is associated with good results in endometriotic-related symptoms, although patients should be informed about possible postoperative impairments in evacuation and incontinence. However, its clinical impact does not outweigh the benefit that can be achieved through this approach. See Video Abstract at http://links.lww.com/DCR/A547.

Selective survival advantage associated with primary tumor resection for metastatic gastric cancer in a Western population.

BACKGROUND: The prognosis of metastatic gastric cancer (GC) remains dismal, with a median survival of 10 months. Historically, primary tumor resection was not thought to confer any survival benefit. Although high-level data exist guiding treatment of metastatic GC for patients in the East, no such data exist for Western patients despite inherent ethnic differences in GC biology. METHODS: The 2006-2012 National Cancer Database was queried for adult patients with metastatic gastric adenocarcinoma. Patients were classified into those who underwent primary tumor resection and chemotherapy (PTRaC) and those who received chemotherapy only. Groups were propensity score matched, and survival was compared using advanced statistical modeling. RESULTS: A total of 7026 patients met the inclusion criteria: 6129 (87%) patients were treated with chemotherapy alone and 897 (13%) patients were treated with PTRaC. After multivariable adjustment, patients who underwent PTRaC had a significantly better overall survival (OS) than patients who received systemic therapy only (HR, 0.60; 95% CI, 0.56-0.64; p < 0.001). Following full bipartite propensity score-adjusted analysis, 2-year OS for patients who received chemotherapy only was 12.6% (95% CI, 11.7-13.5%), whereas it was 34.2% (95% CI, 31.3-37.5%) for patients who underwent PTRaC (HR for resection: 0.52; 95% CI, 0.47-0.57; p < 0.001). CONCLUSION: Our data suggest that there exists a subset of patients with metastatic GC for which PTRaC may improve OS. As significant uncertainty still remains, our results support the need for further prospective trials investigating the influence of palliative gastrectomy on survival among Western patients.

Open versus laparoscopic portal lymphadenectomy in gallbladder cancer: is there a difference in lymph node yield?

BACKGROUND: Gallbladder cancer (GBC) is the most common biliary tract malignancy. Because it commonly metastasizes via lymphatics, portal lymphadenectomy should be included in oncologic resections. This study aimed to compare the oncologic equivalence of the laparoscopic versus open technique by evaluating lymph node (LN) yield. METHODS: The 2010-2012 National Cancer Data Base identified patients who underwent laparoscopic or open resection of GBC with dedicated lymphadenectomy. LN yield was compared by resection method. Variables associated with LN yield ≥3 were identified. RESULTS: Of 1524 patients identified, 52% were intended to undergo laparoscopic surgery, with 20% of these patients converted to open. Collection of ≥3 LNs following open resection (47%) was higher than for laparoscopic resection (34%), p < 0.001. Operations performed at high-volume (aOR:1.74, p < 0.001) and/or academic centers (aOR:1.70, p = 0.024) had superior LN yield. LN yield was not associated with overall survival (aHR:0.93, p = 0.493). CONCLUSIONS: In this analysis of national data, LN yield following laparoscopic resection for GBC was significantly lower than following open resection. Open resection is more frequently performed at academic centers, possibly to assure adequate oncologic resection. Enforcing consensus guidelines for lymphadenectomy in gallbladder cancer will optimize outcomes as minimally invasive approaches evolve.