Management of Pathogenic CDH1 Variant Carriers Within the FREGAT Network: A Multicentric Retrospective Study.

OBJECTIVE: To describe the management of pathogenic CDH1 variant carriers (pCDH1vc) within the FREGAT (FRench Eso-GAsTric tumor) network. Primary objective focused on clinical outcomes and pathological findings, Secondary objective was to identify risk factor predicting postoperative morbidity (POM). BACKGROUND: Prophylactic total gastrectomy (PTG) remains the recommended option for gastric cancer risk management in pCDH1vc with, however, endoscopic surveillance as an alternative. METHODS: A retrospective observational multicenter study was carried out between 2003 and 2021. Data were reported as median (interquartile range) or as counts (proportion). Usual tests were used for univariate analysis. Risk factors of overall and severe POM (ie, Clavien-Dindo grade 3 or more) were identified with a binary logistic regression. RESULTS: A total of 99 patients including 14 index cases were reported from 11 centers. Median survival among index cases was 12.0 (7.6-16.4) months with most of them having peritoneal carcinomatosis at diagnosis (71.4%). Among the remaining 85 patients, 77 underwent a PTG [median age=34.6 (23.7-46.2), American Society of Anesthesiologists score 1: 75%] mostly via a minimally invasive approach (51.9%). POM rate was 37.7% including 20.8% of severe POM, with age 40 years and above and low-volume centers as predictors ( P =0.030 and 0.038). After PTG, the cancer rate on specimen was 54.5% (n=42, all pT1a) of which 59.5% had no cancer detected on preoperative endoscopy (n=25). CONCLUSIONS: Among pCDH1vc, index cases carry a dismal prognosis. The risk of cancer among patients undergoing PTG remained high and unpredictable and has to be balanced with the morbidity and functional consequence of PTG.

Can we classify ampullary tumours better? Clinical, pathological and molecular features. Results of an AGEO study.

BACKGROUND: Ampullary adenocarcinoma (AA) originates from either intestinal (INT) or pancreaticobiliary (PB) epithelium. Different prognostic factors of recurrence have been identified in previous studies. METHODS: In 91 AA patients of the AGEO retrospective multicentre cohort, we evaluated the centrally reviewed morphological classification, panel markers of Ang et al. including CK7, CK20, MUC1, MUC2 and CDX2, the 50-gene panel mutational analysis, and the clinicopathological AGEO prognostic score. RESULTS: Forty-three (47%) of the 91 tumours were Ang-INT, 29 (32%) were Ang-PB, 18 (20%) were ambiguous (Ang-AMB) and one could not be classified. Among these 90 tumours, 68.7% of INT tumours were Ang-INT and 78.2% of PB tumours were Ang-PB. MUC5AC expression was detected in 32.5% of the 86 evaluable cases. Among 71 tumours, KRAS, TP53, APC and PIK3CA were the most frequently mutated genes. The KRAS mutation was significantly more frequent in the PB subtype. In multivariate analysis, only AGEO prognostic score and tumour subtype were associated with relapse-free survival. Only AGEO prognostic score was associated with overall survival. CONCLUSIONS: Mutational analysis and MUC5AC expression provide no additional value in the prognostic evaluation of AA patients. Ang et al. classification and the AGEO prognostic score were confirmed as a strong prognosticator for disease recurrence.

Lymph node metastases in splenic flexure colon cancer: Is subtotal colectomy warranted?

BACKGROUND AND OBJECTIVES: Tumors of the splenic flexure (TSF) can be associated with metastatic lymph nodes (LN) along the left colic pedicle, but also along the superior mesenteric vessels. We aimed to detail the anatomical distribution of metastatic LNs in patients undergoing elective subtotal colectomy for TSF. METHOD: Between 2000 and 2016, 65 patients were included. At pathological analysis, LNs were classified into two groups: locoregional LN (along the left colic artery) and distant LN (along the middle colic, right colic, and ileocolic arteries). RESULTS: The median number of LNs examined was 20. Eighteen patients (27%) were pN+. Among them, six (33% of pN+ patients and 9% of the series) had at least one positive distant LN. All these patients had a positive distant LN along the right colic artery. These patients had a significantly advanced stage and more positive LNs than the others (stage III-IV: 100% vs 22%, P = 0.0009 and 6 [3-15] vs 0 [0-15], P < 0.0001, respectively). The presence of synchronous metastases was predictor of metastatic distant LNs (P = 0.042). CONCLUSION: Elective subtotal colectomy for TSF allows to discover distant positive LNs in nearly 10% of patients. For those having TSF and synchronous metastatic disease enable to resection, subtotal colectomy should be recommended.

Neoadjuvant FOLFOX 4 versus FOLFOX 4 with Cetuximab versus immediate surgery for high-risk stage II and III colon cancers: a multicentre randomised controlled phase II trial--the PRODIGE 22--ECKINOXE trial.

BACKGROUND: In patients with high risk stage II and stage III colon cancer (CC), curative surgery followed by adjuvant FOLFOX-4 chemotherapy has become the standard of care. However, for 20 to 30% of these patients, the current curative treatment strategy of surgical excision followed by adjuvant chemotherapy fails either to clear locoregional spread or to eradicate distant micrometastases, leading to disease recurrence. Preoperative chemotherapy is an attractive concept for these CCs and has the potential to impact upon both of these causes of failure. Optimum systemic therapy at the earliest possible opportunity may be more effective at eradicating distant metastases than the same treatment given after the delay and immunological stress of surgery. Added to this, shrinking the primary tumor before surgery may reduce the risk of incomplete surgical excision, and the risk of tumor cell shedding during surgery. METHODS/DESIGN: PRODIGE 22--ECKINOXE is a multicenter randomized phase II trial designed to evaluate efficacy and feasibility of two chemotherapy regimens (FOLFOX-4 alone and FOLFOX-4 + Cetuximab) in a peri-operative strategy in patients with bulky CCs. Patients with CC deemed as high risk T3, T4 and/or N2 on initial abdominopelvic CT scan are randomized to either colectomy and adjuvant chemotherapy (control arm), or 4 cycles of neoadjuvant chemotherapy with FOLFOX-4 (for RAS mutated patients). In RAS wild-type patients a third arm testing FOLFOX+ cetuximab has been added prior to colectomy. Patients in the neoadjuvant chemotherapy arms will receive postoperative treatment for 4 months (8 cycles) to complete their therapeutic schedule. The primary endpoint of the study is the histological Tumor Regression Grade (TRG) as defined by Ryan. The secondary endpoints are: treatment strategy safety (toxicity, primary tumor related complications under chemotherapy, peri-operative morbidity), disease-free and recurrence free survivals at 3 years, quality of life, carcinologic quality and completeness of the surgery, initial radiological staging and radiological response to neoadjuvant chemotherapy, and the correlation between histopathological and radiological response. Taking into account a 50% prevalence of CC without RAS mutation, accrual of 165 patients is needed for this Phase II trial. TRIAL REGISTRATION: NCT01675999 (ClinicalTrials.gov).

Appendiceal adenocarcinoma, diagnosed after acute perforated appendicitis: Potential contribution of HIPEC.

INTRODUCTION: Treatment of peritoneal metastasis from appendicular adenocarcinoma consists of cyto-reductive surgery (CRS) and Hyperthermic IntraPEritoneal Chemotherapy (HIPEC). In case of acute appendicular syndrome (AAS) the tumor is likely to be perforated. In that case, there is no treatment recommendation. We propose CRS and HIPEC. MATERIALS AND METHOD: We listed 21 consecutive patients who were addressed for discovery of appendiceal adenocarcinoma. The emergency surgery was performed in a primary-care hospital. We evaluated the therapeutic algorithms, per operative decision, survival and recurrent rate. RESULTS: Among the 21 patients, 4 patients were diagnosed as synchronous appendicular peritoneal metastasis, and underwent CRS and HIPEC. The other 17 patients with diagnosis of adenocarcinoma on anatomopathological samples, without peritoneal metastasis during appendectomy, were addressed. Between them 2 patients were denied CRS. Among the 15 operated patients, 8 patients had no peritoneal metastasis discovery during surgery, and therefore underwent prophylactic CRS and HIPEC. Peritoneal metastasis were discovered for the other 7 patients, who also underwent CRS and HIPEC. For the prophylactic group, the recurrence rate is 12,5 %, overall survival (OS) is 100 %. The rate of grade III-IV surgical complications after CRS and HIPEC was 36 % among the 19 patients who underwent surgery. CONCLUSION: In case of appendectomy in emergency situations for perforated adenocarcinoma, half of the patients may have peritoneal metastasis. In case of non-identified peritoneal metastasis during CRS, performing a prophylactic HIPEC seems to be associated with an encouraging rate of peritoneal disease free situation at 5 years.

Active surveillance for low-grade appendiceal mucinous neoplasm (LAMN).

Objectives: Due to the scarcity of low-grade appendiceal mucinous neoplasm (LAMN), there is an absence of systematized guidelines concerning its management, especially after incidental finding on an appendiceal specimen. In this study, we evaluate the active surveillance (AS) strategy adopted for a series of patients diagnosed with LAMN on resection specimens who were considered to have a low risk of pseudomyxoma progression. Methods: Thirty patients were included between April 2014 and July 2021, with a female majority and a median follow-up period of 3.1 years. The inclusion criteria were as follows: LAMN diagnosis on appendiceal specimens, confirmed in an expert center, limited extra-appendiceal mucin resected and localized around the appendix, normal biology (CEA, CA199, CA125) and normal abdominopelvic MRI. AS included physical exam (trocar scar), biology and MRI, 6 months postoperatively, then yearly for 10 years. Results: As an initial surgery, 77 % had an appendectomy as their initial intervention, 17 % had a cecectomy, and 6 % had a right colectomy. After follow-up, 87 % of patients showed no sign of disease progression by MRI, while 13 % progressed to PMP. MRI performed in the first postoperative year predicted the disease prognosis in 97 % of patients. Conclusions: The AS strategy, based on MRI, is a valid option after incidental LAMN diagnosis.

Local prolactin is a target to prevent expansion of basal/stem cells in prostate tumors.

Androgen-independent recurrence is the major limit of androgen ablation therapy for prostate cancer. Identification of alternative pathways promoting prostate tumor growth is thus needed. Stat5 has been recently shown to promote human prostate cancer cell survival/proliferation and to be associated with early prostate cancer recurrence. Stat5 is the main signaling pathway triggered by prolactin (PRL), a growth factor whose local production is also increased in high-grade prostate cancers. The first aim of this study was to use prostate-specific PRL transgenic mice to address the mechanisms by which local PRL induces prostate tumorogenesis. We report that (i) Stat5 is the major signaling cascade triggered by local PRL in the mouse dorsal prostate, (ii) this model recapitulates prostate tumorogenesis from precancer lesions to invasive carcinoma, and (iii) tumorogenesis involves dramatic accumulation and abnormal spreading of p63-positive basal cells, and of stem cell antigen-1-positive cells identified as a stem/progenitor-like subpopulation. Because basal epithelial stem cells are proposed to serve as tumor-initiating cells, we challenged the relevance of local PRL as a previously unexplored therapeutic target. Using a double-transgenic approach, we show that Delta1-9-G129R-hPRL, a competitive PRL-receptor antagonist, prevented early stages of prostate tumorogenesis by reducing or inhibiting Stat5 activation, cell proliferation, abnormal basal-cell pattern, and frequency or grade of intraepithelial neoplasia. This study identifies PRL receptor/Stat5 as a unique pathway, initiating prostate tumorogenesis by altering basal-/stem-like cell subpopulations, and strongly supports the importance of further developing strategies to target locally overexpressed PRL in human prostate cancer.

YpN0 rectal cancer patients with sterilized lymph nodes after neoadjuvant chemoradiotherapy are of greater risk of recurrence.

BACKGROUND: Indication for adjuvant chemotherapy in ypN0 rectal cancer patients after chemoradiotherapy (CRT) is debated. The clinical significance of the presence of sterilized lymph nodes (LNS) in ypN0 patients remains to be determined. AIMS: To assess the prognostic value of LNS in ypN0 rectal cancers after neoadjuvant CRT. METHODS: From 2006-2016, 235 patients underwent TME surgery for non-metastatic mid-low rectal cancer after CRT. A lymph node was considered sterilized if there were signs of treatment response (fibrosis, necrosis or mucus) without residual tumor cells. RESULTS: 180 patients (77%) were classified ypN0 and 55 (23%) ypN+. LNS was present in 20 patients (9%). In ypN0 patients, 5-year OS was similar between patients with and without LNS. In contrast, 5-year DFS was significantly lower in ypN0/LNS + patients (58% vs. 78%, p = 0.043) and was similar to those staged ypN+. In multivariate analysis, two factors were independent predictors of DFS: mesorectal grading (OR = 3.14; 95%CI: 1.10-8.34; p = 0.033) and the presence of LNS (OR = 3.93, 95% CI: 1.06-11.81, p = 0.042) CONCLUSION: The presence of LNS in ypN0 rectal cancer after neoadjuvant CRT is associated with an increased risk of recurrence and may be taken into account for the discussion of adjuvant chemotherapy.

Temsirolimus-induced glomerulopathy.

A 58-year-old man with advanced renal cell carcinoma developed grade 3 proteinuria (8.5 g/24 h) without microscopic hematuria or renal insufficiency five days after temsirolimus infusion. Kidney biopsy revealed ischemic glomeruli and focal segmental glomerulosclerosis lesion. Proteinuria level decreased to 2.80 g per day two weeks after temsirolimus withdrawal. Clinicians should be aware to this complication.

Oxalate nephropathy is a major cause of kidney injury in surgically treated pancreatic adenocarcinoma patients.

BACKGROUND: Despite new therapeutics, the prognosis for pancreatic cancer remains poor. Pancreatic surgery is a therapeutic option in non-metastatic forms. The consequences for renal function are poorly described. METHODS: Patients who underwent surgery for pancreatic cancer between 1 January 2010 and 1 January 2017 and who experienced kidney biopsy in the Pitié-Salpêtrière Hospital were analysed. RESULTS: Two hundred and ninety-four patients had pancreatic surgery during the period of analysis and five of them had a kidney biopsy (mean ± SD 20 months ±13.6 months after surgery) during the post-operative follow-up. Among these patients, three exhibited oxalate nephropathy (ON), indicating that the prevalence of ON in patients with pancreatectomy is at least 1%. ON may be insidious, with chronic renal failure without urinary abnormalities. All patients had a high oxalate-to-creatinine ratio in urine sample. Renal function improved after specific management of ON in two patients. Pancreaticoduodenectomy may represent a higher risk of ON than left pancreatectomy. CONCLUSION: Although rare and underestimated, ON appears to be a real risk after pancreatic resection. Early detection may preserve renal function.

Association of Primary Resistance to Immune Checkpoint Inhibitors in Metastatic Colorectal Cancer With Misdiagnosis of Microsatellite Instability or Mismatch Repair Deficiency Status.

IMPORTANCE: Primary resistance to immune checkpoint inhibitors is observed in 10% to 40% of patients with metastatic colorectal cancer (mCRC) displaying microsatellite instability (MSI) or defective mismatch repair (dMMR). OBJECTIVE: To investigate possible mechanisms underlying primary resistance to immune checkpoint inhibitors of mCRC displaying MSI or dMMR. DESIGN, SETTING, AND PARTICIPANTS: This post hoc analysis of a single-center, prospective cohort included 38 patients with mCRC diagnosed as MSI or dMMR by local laboratories and entered into trials of immune checkpoint inhibitors between January 1, 2015, and December 31, 2016. The accuracy of MSI or dMMR status was also assessed in a retrospective cohort comprising 93 cases of mCRC that were diagnosed as MSI or dMMR between January 1, 1998, and December 31, 2016, in 6 French hospitals. Primary resistance of mCRC was defined as progressive disease according to Response Evaluation Criteria in Solid Tumors criteria, 6 to 8 weeks after initiation of immune checkpoint inhibitors, without pseudo-progression. All tumor samples were reassessed for dMMR status using immunohistochemistry with antibodies directed against MLH1, MSH2, MSH6, and PMS2, and for MSI using polymerase chain reaction with pentaplex markers and with the HSP110 T17 (HT17) repeat. MAIN OUTCOMES AND MEASURES: The primary outcome was positive predictive value. RESULTS: Among the 38 patients (15 women and 23 men; mean [SD] age, 55.6 [13.7] years) in the study with mCRC displaying MSI or dMMR, primary resistance to immune checkpoint inhibitors was observed in 5 individuals (13%). Reassessment of the status of MSI or dMMR revealed that 3 (60%) of these 5 resistant tumors were microsatellite stable or displayed proficient mismatch repair. The positive predictive value of MSI or dMMR status assessed by local laboratories was therefore 92.1% (95% CI, 78.5%-98.0%). In the retrospective cohort of 93 patients (44 women and 49 men; mean [SD] age, 56.8 [18.3] years) without immune checkpoint inhibitor treatment, misdiagnosis of the MSI or dMMR status by local assessment was 10% (n = 9), with a positive predictive value of 90.3% (95% CI, 82.4%-95.0%). Testing for MSI with the HT17 assay confirmed the MSI or dMMR status in 2 of 4 cases showing discrepant results between immunohistochemistry and pentaplex polymerase chain reaction (ie, dMMR but microsatellite stable). CONCLUSIONS AND RELEVANCE: Primary resistance of mCRC displaying MSI or dMMR to immune checkpoint inhibitors is due mainly to misdiagnosis of their MSI or dMMR status. Larger studies are required to confirm these findings. Microsatellite instability or dMMR status should be tested routinely using both immunohistochemistry and polymerase chain reaction methods prior to treatment with immune checkpoint inhibitors.

hENT1 Testing in Pancreatic Ductal Adenocarcinoma: Are We Ready? A Multimodal Evaluation of hENT1 Status.

Gemcitabine is still one of the standard chemotherapy regimens for pancreatic ductal adenocarcinoma (PDAC). Gemcitabine uptake into tumor cells is mainly through the human equilibrative nucleoside transport 1 (hENT1). It was therefore proposed as a potential predictive biomarker of gemcitabine efficacy but reports are conflicting, with an important heterogeneity in methods to assess hENT1 expression. A multicenter cohort of 471 patients with a resected PDAC was used to assess simultaneously the predictive value of the 2 best described hENT1 antibodies (10D7G2 and SP120). Three additional antibodies and the predictive value of hENT1 mRNA were also tested on 251 and 302 patients, respectively. hENT1 expression was assessed in 54 patients with matched primary tumors and metastases samples. The 10D7G2 clone was the only hENT1 antibody whose high expression was associated with a prolonged progression free survival and overall survival in patients who received adjuvant gemcitabine. hENT1 mRNA level was also predictive of gemcitabine benefit. hENT1 status was concordant in 83% of the cases with the best concordance in synchronous metastases. The 10D7G2 clone has the best predictive value of gemcitabine benefit in PDAC patients. Since it is not commercially available, hENT1 mRNA level could represent an alternative to assess hENT1 status.

Immunological environment in colorectal cancer: a computer-aided morphometric study of whole slide digital images derived from tissue microarray.

Cancer research has moved from investigating tumour cells to including analysis of the tumour microenvironment as well. The aim of this study was to assess the cellular infiltrate of colorectal cancer (CRC) using computer-aided analysis of whole slide digital image derived from tissue microarray (TMA). TMA slides from 31 CRC patients were immunostained for forkhead box protein 3 (FOXP3) and immunomodulatory enzyme indoleamine 2,3-dioxygenase (IDO) at four sites: centre (C) and invasive front (F) of the tumour, proximal non-metastatic draining lymph node (N-), tumour-draining lymph node with metastasis (N+) and healthy mucosa at 10 cm from the cancer (M). We analysed the proportion of IDO+ tissue areas in the lamina propria or in the non-epithelial area of the lymph node and in epithelial cells in each site. The normal mucosa of patients operated on for benign disease was also analysed. The proportion (%) of FOXP3+ tissue area in C, F, N-, N+ and M were 2.3 ± 1.8, 2.6 ± 2.9, 6.0 ± 2.9, 14.2 ± 5.8 and 1.2 ± 0.8 (p < 0.001). The proportion (%) of IDO+ tissue area in the lamina propria of C, F, N-, N+ and M were 1.6 ± 3.1, 1.1 ± 1.3, 3.4 ± 2.5, 9.1 ± 8.5 and 6.7 ± 5.4 (p < 0.001). IDO+ tissue area in the lamina propria was not significantly different between healthy mucosa of patients with cancer than without (1.8 ± 3 vs 1.1 ± 0.95). The proportion of IDO positive tissue area in the epithelium was significantly higher in healthy mucosa of patients with cancer than without (5.4 ± 13.8 vs 2.1 ± 2.4). The FOXP3+ tissue area was increased in healthy mucosa of CRC patients in comparison with healthy mucosa of patients with colorectal resection for disease other than cancer: 1.20 ± 1.81 versus 0.81 ± 0.51 (p < 0.05). The proportion of IDO+ tissue area in lymph node (N-) was correlated with the proportion of FOXP3+ tissue area in tumour area (r = 0.44, p < 0.01). TMA technique permits simultaneous analysis of FOXP3+ and IDO+ cells at different sites including tumour, draining non-metastatic lymph node, metastatic lymph node and normal mucosa.

Cancer-related thrombotic microangiopathy secondary to Von Willebrand factor-cleaving protease deficiency.

Cancer-related thrombotic microangiopathy (TM) is a serious complication with a short-term life-threatening prognosis. This complication shares certain similarities with thrombotic thrombocytopenic purpura and hemolytic uremic syndrome, both characterized by circulating platelet aggregates containing ultralarge multimers of Von Willebrand factor (VWF). We report a case of cancer-related thrombotic microangiopathy secondary to disseminated metastatic cancer with undetectable serum Von Willebrand factor-cleaving protease activity and no evidence of serum inhibitory antibody. A concomitant decrease of Ca 19-9 level and hemolysis was observed during chemotherapy, in parallel with normalization of Von Willebrand factor-cleaving protease activity. The role of ultralarge multimers of Von Willebrand factor in platelet aggregation in the context of metastatic disease is discussed with respect to our findings in this case of cancer-related thrombotic microangiopathy.

Generalized Caseview applied to prostate cancer prognosis.

The interpretation of results of any study using large tables with series of numbers is always difficult. Generalized Case View Method (GCm) allows translating these tables of numbers into an image. The Method identifies each informational entity in the table with a 'pixel', forming what we call an 'infoxel'. The sum of all informational entities becomes an image, the Generalized Caseview. The method consists of two steps: the first one is to define the reference frame while the second is to visualize data through the reference frame. The 'infoxels' that constitute the reference frame should be organized according to three criteria: binary, nominal and ordinal. Here this method has been applied to visualize the results of a study about prostate cancer spread. This paper exemplifies the usefulness of associating a classical statistical tool with Generalized Caseview method to solve a biomedical problem.