Effect of clinical status on survival in patients with borderline or locally advanced pancreatic adenocarcinoma.

OBJECTIVE: To determine the effect of clinical status (weight variation and performance status [PS]) at diagnosis and during induction treatment on resectability and overall survival (OS) rates in patients with borderline resectable (BRPC) or locally advanced pancreatic cancer (LAPC). METHODS: From 2005 to 2017, 454 consecutive patients were diagnosed with LAPC or BRPC. We evaluated the PS (0-1 or 2-3), body mass index at diagnosis, and weight loss (WL) > 5% at initial staging and after induction treatment and separated continuous weight loss (CWL) from weight stabilization. RESULTS: A total of 294 patients (64.8%) presented with WL, and 57 patients (12.6%) presented with a PS of 2-3. At restaging, 60 patients (13.2%) presented with CWL. Independent factors that poorly influenced the OS were a PS of 2-3 at diagnosis (P < .01), CWL at restaging (P < .01), and absence of resection (P < .01). Factors independently impeding resection were LAPC (P < .01), PS > 1 at diagnosis (P < .01), and CWL (P = .01). In total, 142 patients (31.3%) underwent pancreatectomy. Independent factors that poorly influenced the OS in the resected group were PS > 0 at diagnosis (P = .01) and obesity (P < .01). For the 312 unresected cancer patients (68.7%), CWL (P < .01) was identified as an independent factor that poorly influenced the OS. CONCLUSION: Clinical parameters that are easy to measure and monitor are independent factors of poor prognosis. The variation of weight during the induction treatment, more than WL at diagnosis, significantly precluded resection and was an independent factor of shorter OS in unresected patients.

Fukuoka-Negative Branch-Duct IPMNs: When to Worry? A Study from the French Surgical Association (AFC).

BACKGROUND: This study analyzed the pathologic findings for patients with Fukuoka-negative branch-duct intraductal papillary mucinous neoplasm (BD-IPMN) who theoretically were eligible for surveillance care with follow-up assessment, but instead underwent resection. METHODS: From January 2005 to December 2012, 820 patients underwent evaluation for IPMN. At initial staging, 319 patients had BD-IPMN, and 89 of these patients presented with Fukuoka-negative criteria. These 89 patients were included in this study. RESULTS: Of the 89 patients, 55 (62%) underwent pancreatectomy. After pathologic examination, the ultimate diagnosis was MT-IPMN for 20 (36%) of these patients (the MT group) and BD-IPMN for 35 (64%) of these patients (the BD group). The remaining 34 patients (38%) underwent enucleation. The patients in the MT group were more likely to be male (P = 0.01) and to have a higher rate of recent (< 1 year) diabetes mellitus diagnosis (P = 0.007) than the patients in the BD group. In the multivariate analysis, diabetes mellitus was independently associated with involvement of the main pancreatic duct (P = 0.05). Malignancy was diagnosed for 14 (16%) of the 89 patients. The rate of invasive IPMN was higher in the MT group than in the BD group (20% vs. 0%, P = 0.02). The 5-year overall survival rate was 100% for the BD group and 84% for the MT group (P = 0.02). For the male patients with diabetes mellitus, the rate of malignancy rose to 67%. CONCLUSIONS: For patients with a diagnosis of Fukuoka-negative BD-IPMN, resection should be considered primarily for male patients with a recent diabetes mellitus diagnosis.

A pancreatic zone at higher risk of fistula after enucleation.

BACKGROUND: To determine predictive factors of postoperative pancreatic fistula (POPF) in patients undergoing enucleation (EN). METHODS: From 2005 to 2017, 47 patients underwent EN and had magnetic resonance imaging available for precise analysis of tumor location. Three pancreatic zones were delimited by the right side of the portal vein and the main pancreatic head duct (zone #3 comprising the lower head parenchyma and the uncinate process). RESULTS: The mortality and morbidity rates were 0% and 62%, respectively. POPF occurred in 23 patients (49%) and was graded as B or C (severe) in 15 patients (32%). Four patients (8.5%) developed a postoperative hemorrhage, and 5 patients (11%) needed a reintervention. In univariate and multivariate analyses, the pancreatic zone was the unique predictive factor of overall (P = .048) or severe POPF (P = .05). We did not observe any difference in postoperative courses when comparing the EN achieved in zones #1 and #2. We noted a longer operative duration (P = .016), higher overall (P = .017) and severe POPF (P = .01) rates, and longer hospital stays (P = .04) when comparing the EN achieved in zone #3 versus that in zones #1 and #2. Patients who underwent EN in zone #3 had a relative risk of developing a severe POPF of 3.22 compared with patients who underwent EN in the two other pancreatic zones. CONCLUSION: Our study identifies the lower head parenchyma and the uncinate process as a high-risk zone of severe POPF after EN. Patients with planned EN in this zone could be selected and benefit from preoperative and/or intraoperative techniques to reduce the severe POPF rate.

Transcriptomic analysis predicts survival and sensitivity to anticancer drugs of patients with a pancreatic adenocarcinoma.

A major impediment to the effective treatment of patients with pancreatic ductal adenocarcinoma (PDAC) is the molecular heterogeneity of this disease, which is reflected in an equally diverse pattern of clinical outcome and in responses to therapies. We developed an efficient strategy in which PDAC samples from 17 consecutive patients were collected by endoscopic ultrasound-guided fine-needle aspiration or surgery and were preserved as breathing tumors by xenografting and as a primary culture of epithelial cells. Transcriptomic analysis was performed from breathing tumors by an Affymetrix approach. We observed significant heterogeneity in the RNA expression profile of tumors. However, the bioinformatic analysis of these data was able to discriminate between patients with long- and short-term survival corresponding to patients with moderately or poorly differentiated PDAC tumors, respectively. Primary culture of cells allowed us to analyze their relative sensitivity to anticancer drugs in vitro using a chemogram, similar to the antibiogram for microorganisms, establishing an individual profile of drug sensitivity. As expected, the response was patient dependent. We also found that transcriptomic analysis predicts the sensitivity of cells to the five anticancer drugs most frequently used to treat patients with PDAC. In conclusion, using this approach, we found that transcriptomic analysis could predict the sensitivity to anticancer drugs and the clinical outcome of patients with PDAC.

Biliary complications after pancreaticoduodenectomy: skinny bile ducts are surgeons' enemies.

BACKGROUND: The aim of this study was to determine the incidence and predisposing factors of biliary complications (BCs) after pancreaticoduodenectomy (PD) and report our experience in managing these BCs. Pancreatic surgery, particularly PD, has benefited from improvements in operative techniques and postoperative care and is currently safer in terms of mortality. However, the morbidity associated with PD remains high, including frequent complications such as delayed gastric emptying and pancreatic fistulas. Rarer but important BCs are those that manifest as bile leaks (BLs) and biliary strictures (BSs). METHODS: Between April 2005 and December 2011, a total of 397 patients underwent PD at two centers. All data were retrospectively studied with respect to age, gender, pancreatic pathology, neoadjuvant treatment, preoperative biliary stenting, intraoperative data, postoperative pancreatic fistula, BL and BS rates, and mortality. The management of BCs was also analyzed. RESULTS: Thirty patients experienced a BC: 13 BLs (3.3 %) and 17 BSs (4.3 %). A thin bile duct (<5 mm), measured during surgery, was the only predisposing factor for developing a BL or a BS. The management of the BLs consisted of surveillance in six patients (46 %), percutaneous drainage of bilioma in four patients (31 %), and reintervention in three patients (23 %). No patient with a BS had surgery as the frontline treatment: the initial management consisted of an endoscopic procedure, a percutaneous procedure, or medical treatment. Four patients (23.5 %) underwent surgical treatment after failure of nonsurgical procedures. CONCLUSIONS: The only identified predictive factor of BC, either a BS or a BL, was a thin bile duct. Although the noninvasive technique was the treatment of choice initially, reintervention was required in almost 25 % of the cases.

Two-Year Results of Sleeve Gastrectomy Combined with Posterior Fundoplication for Obesity Patients with Gastroesophageal Reflux Disease.

INTRODUCTION: Currently, gastroesophageal reflux disease (GERD) is the main side effect after sleeve gastrectomy (SG), causing discomfort and potential long-term risks. Surgical techniques combining fundoplication with SG are being evaluated to limit postoperative GERD. METHODS: This single-center retrospective study evaluated patients who underwent SG with posterior fundoplication in the context of GERD between 2018 and 2021, with postoperative follow-up up to 24 months. The results were compared to a control group (ratio 1 to 4) who had SG without fundoplication. Observed total weight loss (TWL) was compared to predicted TWL using the Sophia multinational study's machine learning-based calculator. RESULTS: The series included 22 patients (mean body mass index 44.4 kg/m2) with GERD conditions: GERD symptoms (n = 15), hiatal hernia (n = 6), esophagitis (n = 7), and Barrett's esophagus (n = 5). Two patients required reoperation, including one for valve perforation. At 2 years, GERD was present in three patients (13.6%), including two who regularly took proton pump inhibitors. Compared to the control group (n=88), the frequency of GERD persisting at 2 years was significantly reduced in the SG with fundoplication group (p=0.05). The TWL at 12 and 24 months was 27.7% and 26.1%, respectively, with no significant difference compared to the weight predicted by the model, nor compared to the control group. CONCLUSION: The combination of posterior fundoplication with SG can be proposed in patients with GERD who have a contraindication to Roux-en-Y gastric bypass. Specific morbidity may exist at the beginning of the experience.

[Benefits of bariatric surgery on weight loss, development of comorbidities and mortality]. / Bénéfices de la chirurgie bariatrique sur la perte pondérale, l'évolution des comorbidités et la mortalité.

BENEFITS OF BARIATRIC SURGERY ON WEIGHT LOSS, DEVELOPMENT OF COMORBIDITIES AND MORTALITY Bariatric surgery, mainly sleeve gastrectomy (SG) and gastric bypass (GBP) in France, induces a greater and more durable weight loss than current treatments in cases of morbid or severe obesity with co-morbidity. Bariatric surgery can also improve, or even put into remission, most of the pathologies associated with obesity, such as type 2 diabetes, sleep apnea, arterial hypertension, dyslipidemia... An improvement in the quality of life and life expectancy of patients after bariatric surgery has been observed, even considering the operative risk and the discomfort generated by these procedures. The differences in efficacy, risk and discomfort at short and long term between SG and GPB do not allow to define a procedure of choice at the present time. The great effectiveness of bariatric surgery on diabetes associated with obesity, corresponding to the metabolic surgery concept, will probably lead to an extension of the operative indications.

BÉNÉFICES DE LA CHIRURGIE BARIATRIQUE SUR LA PERTE PONDÉRALE, L'ÉVOLUTION DES COMORBIDITÉS ET LA MORTALITÉ Les interventions de chirurgie bariatrique, majoritairement sleeve gastrectomie (SG) et bypass gastrique (BPG) en France, induisent une perte de poids plus importante et plus durable que les traitements courants, en cas d'obésité morbide ou sévère avec comorbidité(s). La chirurgie bariatrique permet aussi d'améliorer, voire de mettre en rémission, la plupart des pathologies associées à l'état d'obésité, comme le diabète de type 2, les apnées du sommeil, l'hypertension artérielle, les dyslipidémies… on observe une amélioration de la qualité et de l'espérance de vie des patients après chirurgie bariatrique, malgré le risque opératoire et les contraintes engendrées par ces interventions. Entre SG et BPG, les différences d'efficacité, de risque et de contraintes à court et long termes ne permettent pas, à l'heure actuelle, de définir une procédure de choix. La grande efficacité de la chirurgie bariatrique sur le diabète associé à l'obésité, correspondant à une véritable chirurgie métabolique, conduit à réfléchir sur l'extension des indications opératoires.

Feasibility of Conversion of a New Bariatric Fully Endoscopic Bypass Procedure to Bariatric Surgery: a Porcine Pilot Study.

PURPOSE: Bariatric endoscopic procedures are emerging as alternatives to bariatric surgical procedures. This study aimed to assess if a natural orifice transluminal endoscopic surgery (NOTES) bariatric procedure could be converted to a surgical duodenal-jejunal bypass (DJB) or sleeve gastrectomy (SG). MATERIALS AND METHODS: This 12-week prospective study compared 4 test pigs to 3 control (no procedures) pigs aged 3 months at baseline. The test pigs received a fully endoscopic NOTES-based bypass including measurement of the bypassed limb and creation of a gastrojejunal anastomosis (GJA) using gastrojejunal lumen-apposing metal stents (GJ-LAMS) at Week 0, placement of a duodenal exclusion device (DED) at Week 2, and randomization to DJB or SG surgery at Week 8 with subsequent 4-week follow-up. At Week 12, the pigs were sacrificed and necropsy was performed. RESULTS: Endoscopic procedures were technically successful. One pig did not receive a DED due to early GJ-LAMS migration leading to premature closure of the GJA. At Week 8, all 4 pigs were doing well, and the remaining 3 GJ-LAMS and 3 DEDs were uneventfully endoscopically removed. Two one-anastomosis DJB were performed, and 2 SG were performed, closing in one case the site of the previous GJA. The surgical procedures were technically feasible and uneventful during follow-up. Necropsy assessments showed no local or peritoneal inflammation or abscess and no leakage or fistula. CONCLUSION: An endoscopic bariatric bypass can be transitioned to a one-anastomosis duodenal-jejunal bypass or sleeve gastrectomy, without complications.

French survey on a cohort of emergency general surgery modifications induced by lockdown of the SARS-CoV-2 pandemic.

PURPOSE: The brutal COVID-19 pandemic has majorly impacted populations and health systems, and surgeons have observed dramatic changes in their daily clinical activities. A survey of French digestive surgeons was conducted to assess these changes. METHODS: An electronic survey was sent to French digestive and general surgeons in the Societe Francaise de Chirurgie Digestive (SFCD) to assess the surgeons' daily activity during the pandemic and investigate changes in patients' management. The care deviations were classified as delay of management, modification of strategy, or modification of organization, and the impact of these changes on patients was evaluated by the surgeon's estimation of loss of chance. RESULTS: A major reduction in surgical elective activity was observed in 50 (75%) of the 67 hospitals that responded. Of these, 48 hospitals (71.6%) reported receiving SARS-CoV-2 patients. A deviation from usual care was observed in 10% of patients admitted for emergency general surgery. Among 140 patients presenting a deviation from usual care, 74 (52.9%) had delayed management, 53 (37.9%) had a modification of strategy, and 64 (45.7%) had a modification of organization. Medical treatment instead of surgical treatment was decided for 37 (26.4%) patients, resulting in a high loss of chance for 6 patients. Delays (p < 0.001) and a switch from surgical to medical treatment (p = 0.002) were independently correlated with overall loss of chance based on multivariate analysis. CONCLUSION: This study highlighted the deviations in general emergency surgery patients and provided implications for the solutions that should be implemented during a new health crisis.

Surgery of small bowel melanoma metastases in the era of efficient medical therapies: a retrospective cohort study.

Surgery of small bowel melanoma metastases has to be reconsidered in the era of targeted treatments and immunotherapy. To retrospectively assess context and outcomes of small bowel melanoma metastases resections. All consecutive melanoma patients who underwent resection of small bowel metastases between 2011 and 2017, in a single referral center, were retrospectively analyzed through melanoma-specific survival (MSS). A total of 20 patients were included with a 47.8 months median follow-up. Before small bowel surgery, eight patients (40%) were asymptomatic while seven had anemia and five patients had abdominal pain. All resections were decided on tumor boards except for three surgeries performed in the emergency setting. In the whole cohort, MSS was 89.5 months with 50% of patients alive at the study endpoint. We classified surgical indications in three groups: (1) surgery as a pivotal treatment for mono- or oligo-metastases limited to the small bowel (n = 6); (2) salvage surgery for symptomatic patients in order to preserve their chances to switch to an active line of medical treatment (n = 8); and (3) surgery of small bowel dissociated metastatic progression for patients otherwise controlled (n = 6), aiming at keeping patients with the same treatment or active follow-up. In these three situations, the objective of surgery was usually met, and most patients had a long median MSS after surgery: 70.3 months, 89.5 months and 72.4 months, respectively. Although medical treatments have dramatically improved survival in metastatic melanoma, surgical control of life-threatening localization like small bowel metastases is often a condition for long survival.

Establishment of a pancreatic adenocarcinoma molecular gradient (PAMG) that predicts the clinical outcome of pancreatic cancer.

BACKGROUND: A significant gap in pancreatic ductal adenocarcinoma (PDAC) patient's care is the lack of molecular parameters characterizing tumours and allowing a personalized treatment. METHODS: Patient-derived xenografts (PDX) were obtained from 76 consecutive PDAC and classified according to their histology into five groups. A PDAC molecular gradient (PAMG) was constructed from PDX transcriptomes recapitulating the five histological groups along a continuous gradient. The prognostic and predictive value for PMAG was evaluated in: i/ two independent series (n = 598) of resected tumours; ii/ 60 advanced tumours obtained by diagnostic EUS-guided biopsy needle flushing and iii/ on 28 biopsies from mFOLFIRINOX treated metastatic tumours. FINDINGS: A unique transcriptomic signature (PAGM) was generated with significant and independent prognostic value. PAMG significantly improves the characterization of PDAC heterogeneity compared to non-overlapping classifications as validated in 4 independent series of tumours (e.g. 308 consecutive resected PDAC, uHR=0.321 95% CI [0.207-0.5] and 60 locally-advanced or metastatic PDAC, uHR=0.308 95% CI [0.113-0.836]). The PAMG signature is also associated with progression under mFOLFIRINOX treatment (Pearson correlation to tumour response: -0.67, p-value < 0.001). INTERPRETATION: PAMG unify all PDAC pre-existing classifications inducing a shift in the actual paradigm of binary classifications towards a better characterization in a gradient. FUNDING: Project funding was provided by INCa (Grants number 2018-078 and 2018-079, BACAP BCB INCa_6294), Canceropole PACA, DGOS (labellisation SIRIC), Amidex Foundation, Fondation de France, INSERM and Ligue Contre le Cancer.

Distinct epigenetic landscapes underlie the pathobiology of pancreatic cancer subtypes.

Recent studies have offered ample insight into genome-wide expression patterns to define pancreatic ductal adenocarcinoma (PDAC) subtypes, although there remains a lack of knowledge regarding the underlying epigenomics of PDAC. Here we perform multi-parametric integrative analyses of chromatin immunoprecipitation-sequencing (ChIP-seq) on multiple histone modifications, RNA-sequencing (RNA-seq), and DNA methylation to define epigenomic landscapes for PDAC subtypes, which can predict their relative aggressiveness and survival. Moreover, we describe the state of promoters, enhancers, super-enhancers, euchromatic, and heterochromatic regions for each subtype. Further analyses indicate that the distinct epigenomic landscapes are regulated by different membrane-to-nucleus pathways. Inactivation of a basal-specific super-enhancer associated pathway reveals the existence of plasticity between subtypes. Thus, our study provides new insight into the epigenetic landscapes associated with the heterogeneity of PDAC, thereby increasing our mechanistic understanding of this disease, as well as offering potential new markers and therapeutic targets.

Pancreatic Adenocarcinoma Therapeutic Targets Revealed by Tumor-Stroma Cross-Talk Analyses in Patient-Derived Xenografts.

Preclinical models based on patient-derived xenografts have remarkable specificity in distinguishing transformed human tumor cells from non-transformed murine stromal cells computationally. We obtained 29 pancreatic ductal adenocarcinoma (PDAC) xenografts from either resectable or non-resectable patients (surgery and endoscopic ultrasound-guided fine-needle aspirate, respectively). Extensive multiomic profiling revealed two subtypes with distinct clinical outcomes. These subtypes uncovered specific alterations in DNA methylation and transcription as well as in signaling pathways involved in tumor-stromal cross-talk. The analysis of these pathways indicates therapeutic opportunities for targeting both compartments and their interactions. In particular, we show that inhibiting NPC1L1 with Ezetimibe, a clinically available drug, might be an efficient approach for treating pancreatic cancers. These findings uncover the complex and diverse interplay between PDAC tumors and the stroma and demonstrate the pivotal role of xenografts for drug discovery and relevance to PDAC.

A pancreatic ductal adenocarcinoma subpopulation is sensitive to FK866, an inhibitor of NAMPT.

Treating pancreatic cancer is extremely challenging due to multiple factors, including chemoresistance and poor disease prognosis. Chemoresistance can be explained by: the presence of a dense stromal barrier leading to a lower vascularized condition, therefore limiting drug delivery; the huge intra-tumoral heterogeneity; and the status of epithelial-to-mesenchymal transition. These factors are highly variable between patients making it difficult to predict responses to chemotherapy. Nicotinamide phosphoribosyl transferase (NAMPT) is the main enzyme responsible for recycling cytosolic NAD+ in hypoxic conditions. FK866 is a noncompetitive specific inhibitor of NAMPT, which has proven anti-tumoral effects, although a clinical advantage has still not been demonstrated. Here, we tested the effect of FK866 on pancreatic cancer-derived primary cell cultures (PCCs), both alone and in combination with three different drugs typically used against this cancer: gemcitabine, 5-Fluorouracil (5FU) and oxaliplatin. The aims of this study were to evaluate the benefit of drug combinations, define groups of sensitivity, and identify a potential biomarker for predicting treatment sensitivity. We performed cell viability tests in the presence of either FK866 alone or in combination with the drugs above-mentioned. We confirmed both inter- and intra-tumoral heterogeneity. Interestingly, only the in vitro effect of gemcitabine was influenced by the addition of FK866. We also found that NAMPT mRNA expression levels can predict the sensitivity of cells to FK866. Overall, our results suggest that patients with tumors sensitive to FK866 can be identified using NAMPT mRNA levels as a biomarker and could therefore benefit from a co-treatment of gemcitabine plus FK866.

Deciphering the cellular source of tumor relapse identifies CD44 as a major therapeutic target in pancreatic adenocarcinoma.

It has been commonly found that in patients presenting Pancreatic Ductal Adenocarcinoma (PDAC), after a period of satisfactory response to standard treatments, the tumor becomes non-responsive and patient death quickly follows. This phenomenon is mainly due to the rapid and uncontrolled development of the residual tumor. The origin and biological characteristics of residual tumor cells in PDAC still remain unclear. In this work, using PDACs from patients, preserved as xenografts in nude mice, we demonstrated that a residual PDAC tumor originated from a small number of CD44+ cells present in the tumor. During PDAC relapse, proliferating CD44+ cells decrease expression of ZEB1, while overexpressing the MUC1 protein, and gain morphological and biological characteristics of differentiation. Also, we report that CD44+ cells, in primary and residual PDAC tumors, are part of a heterogeneous population, which includes variable numbers of CD133+ and EpCAM+ cells. We confirmed the propagation of CD44+ cells in samples from cases of human relapse, following standard PDAC treatment. Finally, using systemic administration of anti-CD44 antibodies in vivo, we demonstrated that CD44 is an efficient therapeutic target for treating tumor relapse, but not primary PDAC tumors. We conclude that CD44+ cells generate the relapsing tumor and, as such, are themselves promising therapeutic targets for treating patients with recurrent PDAC.

A subgroup of pancreatic adenocarcinoma is sensitive to the 5-aza-dC DNA methyltransferase inhibitor.

Pancreatic Ductal Adenocarcinoma (PDAC) is a disease with a great heterogeneity in the response to treatments. To improve the responsiveness to treatments there are two different approaches, the first one consist to develop new and more efficient drugs that intent to cure all patients and the second one is to use already-approved drugs, alone or in combination, but selecting beforehand the most sensitive patients. In this work we explored the efficiency of the second possibility. We developed a collection of 17 PDAC samples collected by Endoscopic Ultrasound-Guided Fine-Needle Aspiration (EUS-FNA) or surgery and preserved as xenografts and as primary cultures. This collection was characterized at molecular level by a transcriptomic analysis using an Affymetrix approach. In this paper we present data demonstrating that a subgroup of PDAC responds to low doses of 5-aza-dC. These tumors show a specific RNA expression profile that could serve as a marker, but there is no correlation with Dnmt1, Dnmt3A or Dnmt3B expression. Responder tumors corresponded to well-differentiated samples and longer survival patients. In conclusion, we present data obtained with the well-known drug 5-aza-dC as a proof of concept that a drug that seems to be inefficient in solid tumors in general could be applicable to a particular subgroup of patients with PDAC.

Recurrent spontaneous pneumomediastinum in an adult.

Spontaneous pneumomediastinum (SP) is defined as the presence of free air in mediastinal space without any apparent cause. This rare entity is most likely to occur in young males often related to an episode of vomiting, asthma or sustained physical activity. SP usually resolves spontaneously in few days of treatment based on rest and analgesia. Complications are extremely rare. Its recurrence has been poorly reported but seems exceptional. We present a case of recurrent SP occurring in a 21-year-old male with a mental deficiency. The recurrence occurred after a free-interval of 12 months. We proposed a literature review.