Recurrent disease detection after resection of pancreatic ductal adenocarcinoma using a recurrence-focused surveillance strategy (RADAR-PANC): protocol of an international randomized controlled trial according to the Trials within Cohorts design.

BACKGROUND: Disease recurrence remains one of the biggest concerns in patients after resection of pancreatic ductal adenocarcinoma (PDAC). Despite (neo)adjuvant systemic therapy, most patients experience local and/or distant PDAC recurrence within 2 years. High-level evidence regarding the benefits of recurrence-focused surveillance after PDAC resection is missing, and the impact of early detection and treatment of recurrence on survival and quality of life is unknown. In most European countries, recurrence-focused follow-up after surgery for PDAC is currently lacking. Consequently, guidelines regarding postoperative surveillance are based on expert opinion and other low-level evidence. The recent emergence of more potent local and systemic treatment options for PDAC recurrence has increased interest in early diagnosis. To determine whether early detection and treatment of recurrence can lead to improved survival and quality of life, we designed an international randomized trial. METHODS: This randomized controlled trial is nested within an existing prospective cohort in pancreatic cancer centers in the Netherlands (Dutch Pancreatic Cancer Project; PACAP) and the United Kingdom (UK) (Pancreas Cancer: Observations of Practice and survival; PACOPS) according to the "Trials within Cohorts" (TwiCs) design. All PACAP/PACOPS participants with a macroscopically radical resection (R0-R1) of histologically confirmed PDAC, who provided informed consent for TwiCs and participation in quality of life questionnaires, are included. Participants randomized to the intervention arm are offered recurrence-focused surveillance, existing of clinical evaluation, serum cancer antigen (CA) 19-9 testing, and contrast-enhanced computed tomography (CT) of chest and abdomen every three months during the first 2 years after surgery. Participants in the control arm of the study will undergo non-standardized clinical follow-up, generally consisting of clinical follow-up with imaging and serum tumor marker testing only in case of onset of symptoms, according to local practice in the participating hospital. The primary endpoint is overall survival. Secondary endpoints include quality of life, patterns of recurrence, compliance to and costs of recurrence-focused follow-up, and the impact on recurrence-focused treatment. DISCUSSION: The RADAR-PANC trial will be the first randomized controlled trial to generate high level evidence for the current clinical equipoise regarding the value of recurrence-focused postoperative surveillance with serial tumor marker testing and routine imaging in patients after PDAC resection. The Trials within Cohort design allows us to study the acceptability of recurrence-focused surveillance among cohort participants and increases the generalizability of findings to the general population. While it is strongly encouraged to offer all trial participants treatment at time of recurrence diagnosis, type and timing of treatment will be determined through shared decision-making. This might reduce the potential survival benefits of recurrence-focused surveillance, although insights into the impact on patients' quality of life will be obtained. TRIAL REGISTRATION: Clinicaltrials.gov, NCT04875325 . Registered on May 6, 2021.

Value of routine intraoperative frozen sections of proximal bile duct margins in perihilar cholangiocarcinoma, a retrospective multicenter and matched case-control study.

BACKGROUND: Currently, the potential benefits of additional resection after positive proximal intraoperative frozen sections (IFS) in perihilar cholangiocarcinoma (pCCA) on residual disease and oncological outcome remain uncertain. Therefore, the aim of this study is to investigate the number of R0 resections after additional resection of a positive proximal IFS and the influence of additional resections on overall survival (OS) in patients with pCCA. MATERIALS AND METHODS: A retrospective, multicenter, matched case-control study was performed, including patients undergoing resection for pCCA between 2000 and 2019 at three tertiary centers. Primary outcome was the number of achieved 'additional' R0 resections. Secondary outcomes were OS, recurrence, severe morbidity and mortality. RESULTS: Forty-four out of 328 patients undergoing resection for pCCA had a positive proximal IFS. An additional resection was performed in 35 out of 44 (79.5%) patients, which was negative in 24 (68.6%) patients. Nevertheless, seven out of these 24 patients were eventually classified as R1 resection due to other positive resection margins. Therefore, 17 (48.6%) patients could be classified as "true" R0 resection after additional resection. Ninety-day mortality after R1 resections was high (25%) and strongly influenced OS. After correction for 90-day mortality, median OS after negative additional resection was 33 months (95%CI:29.5-36.5) compared to 30 months (95%CI:24.4-35.6) after initial R1 (P = 0.875) and 46 months (95%CI:32.7-59.3) after initial R0 (P = 0.348). CONCLUSION: There were only 17 patients (out of a total of 328 patients) that potentially benefitted from routine IFS. Additional resection for a positive IFS leading to R0 resection was not associated with improved long-term survival.

Extended Resections for Advanced Gallbladder Cancer: Results from a Nationwide Cohort Study.

BACKGROUND: Extended resections (i.e., major hepatectomy and/or pancreatoduodenectomy) are rarely performed for gallbladder cancer (GBC) because outcomes remain inconclusive. Data regarding extended resections from Western centers are sparse. This Dutch, multicenter cohort study analyzed the outcomes of patients who underwent extended resections for locally advanced GBC. METHODS: Patients with GBC who underwent extended resection with curative intent between January 2000 and September 2018 were identified from the Netherlands Cancer Registry. Extended resection was defined as a major hepatectomy (resection of ≥ 3 liver segments), a pancreatoduodenectomy, or both. Treatment and survival data were obtained. Postoperative morbidity, mortality, survival, and characteristics of short- and long-term survivors were assessed. RESULTS: The study included 33 patients. For 16 of the patients, R0 resection margins were achieved. Major postoperative complications (Clavien Dindo ≥ 3A) occurred for 19 patients, and 4 patients experienced postoperative mortality within 90 days. Recurrence occurred for 24 patients. The median overall survival (OS) was 12.8 months (95% confidence interval, 6.5-19.0 months). A 2-year survival period was achieved for 10 patients (30%) and a 5-year survival period for 5 patients (15%). Common bile duct, liver, perineural and perivascular invasion and jaundice were associated with reduced survival. All three recurrence-free patients had R0 resection margins and no liver invasion. CONCLUSION: The median OS after extended resections for advanced GBC was 12.8 months in this cohort. Although postoperative morbidity and mortality were significant, long-term survival (≥ 2 years) was achieved in a subset of patients. Therefore, GBC requiring major surgery does not preclude long-term survival, and a subgroup of patients benefit from surgery.

Role of diagnostic laparoscopy in patients with suspicion of colorectal peritoneal metastases to evaluate suitability for cytoreductive surgery with hyperthermic intraperitoneal chemotherapy.

Background: The aim of the present study was to determine the feasibility and safety of performing diagnostic laparoscopy (DLS) routinely in patients with suspicion of colorectal peritoneal metastases (PM) to evaluate suitability for cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS + HIPEC). Methods: Data for consecutive patients who underwent DLS between 2012 and 2018 were extracted retrospectively from an institutional database. The primary outcome was the degree of visibility of the abdominal cavity during DLS. Good laparoscopic evaluation of the abdominal cavity was defined as visibility of at least the regions of the diaphragm, pelvis and small bowel. Secondary outcomes were reasons for perioperative exclusion for CRS + HIPEC, major postoperative complications (Clavien-Dindo grade III or above) and difference in overall survival (OS) between patients deemed suitable or unsuitable for CRS + HIPEC. Kaplan-Meier analyses were performed. Results: Some 184 patients were analysed. Good laparoscopic evaluation was possible in 138 patients (75·0 per cent), and 24 (13·0 per cent) had conversion to an open procedure. Ninety-three patients (50·5 per cent) were excluded for CRS + HIPEC, most commonly because of absence of colorectal PM (34 patients, 37 per cent) or extensive disease (Peritoneal Cancer Index 20 or above) (33 patients, 35 per cent). Major complications occurred in five patients (2·7 per cent), with no postoperative deaths. Median OS was significantly decreased in patients who were excluded due to extensive disease (14 (95 per cent c.i. 10 to 18) months) compared with patients suitable for CRS + HIPEC (36 (27 to 45) months) (P < 0·001). Conclusion: Routinely performing DLS in patients with suspicion of colorectal PM to evaluate suitability for CRS + HIPEC is feasible and safe, avoiding the morbidity of an unnecessary laparotomy in patients with extensive disease.

Antecedentes: El objetivo del presente estudio fue determinar la viabilidad y seguridad de realizar una laparoscopia diagnóstica (diagnostic laparoscopy, DLS) de rutina en pacientes con sospecha de metástasis peritoneal (peritoneal metastasis, PM) de origen colorrectal para evaluar la idoneidad para la cirugía citorreductora con quimioterapia intraperitoneal hipertérmica (cytoreductive surgery + hyperthermic intraperitoneal chemotherapy, CRS+HIPEC). Métodos: Los datos de los pacientes consecutivos que fueron sometidos a DLS entre 2012 y 2018 se obtuvieron retrospectivamente de una base de datos institucional. La visualización de al menos las regiones de los diafragmas, pelvis e intestino delgado se definió como una correcta evaluación laparoscópica de la cavidad abdominal. Los resultados secundarios fueron las complicaciones postoperatorias mayores (Clavien­Dindo grado ≥ III), razones para la exclusión perioperatoria para CRS+HIPEC y diferencia en supervivencia global (overall survival, OS) entre pacientes que se consideraron apropiados y no apropiados para CRS+HIPEC. Se realizaron análisis de Kaplan­Meier y análisis de riesgos proporcionales. Resultados: Se analizaron 181 pacientes. En 138 pacientes (75,0%) fue posible una adecuada evaluación laparoscópica, mientras que 24 casos (13%) fueron convertidos a un procedimiento abierto. Se excluyeron 93 (50,5%) pacientes para CRS+HIPEC, más comúnmente por la ausencia de PM colorrectales (36,6%) o enfermedad extensa (37,6%). En cinco pacientes aparecieron complicaciones mayores (2,7%), sin mortalidad postoperatoria. La mediana de la OS disminuyó de forma significativa en pacientes que fueron excluidos debido a enfermedad extensa (14 meses, i.c. del 95% 10­18) en comparación con pacientes idóneos para CRS+HIPEC (35 meses, i.c. del 95% 30­40, P < 0,0001). Conclusión: La realización rutinaria de DLS en pacientes con sospecha de PM de origen colorrectal para evaluar la idoneidad de la CRS+HIPEC es viable y segura. La morbilidad de una laparotomía innecesaria puede prevenirse en pacientes con enfermedad extensa o ausencia de PM colorrectales.

Primary umbilical endometriosis.

Cutaneous endometriosis is a rare condition, especially when it occurs without previous surgery. We report a case of a 27-year old woman with catamenial bleeding from her umbilicus. A MRI, cytological and pathological examination confirmed the diagnosis of endometriosis. We also present a brief review of the literature.

Oncogenic KRAS sensitises colorectal tumour cells to chemotherapy by p53-dependent induction of Noxa.

BACKGROUND: Oxaliplatin and 5-fluorouracil (5-FU) currently form the backbone of conservative treatment in patients with metastatic colorectal cancer. Tumour responses to these agents are highly variable, but the underlying mechanisms are poorly understood. Our previous results have indicated that oncogenic KRAS in colorectal tumour cells sensitises these cells to chemotherapy. METHODS: FACS analysis was used to determine cell-cycle distribution and the percentage of apoptotic and mitotic cells. A multiplexed RT-PCR assay was used to identify KRAS-controlled apoptosis regulators after exposure to 5-FU or oxaliplatin. Lentiviral expression of short-hairpin RNAs was used to suppress p53 or Noxa. RESULTS: Oncogenic KRAS sensitised colorectal tumour cells to oxaliplatin and 5-FU in a p53-dependent manner and promoted p53 phosphorylation at Ser37 and Ser392, without affecting p53 stabilisation, p21 induction, or cell-cycle arrest. Chemotherapy-induced expression of the p53 target gene Noxa was selectively enhanced by oncogenic KRAS. Suppression of Noxa did not affect p21 induction or cell-cycle arrest, but reduced KRAS/p53-dependent apoptosis after exposure to chemotherapy in vitro and in tumour xenografts. Noxa suppression did not affect tumour growth per se, but strongly reduced the response of these tumours to chemotherapy. CONCLUSION: Oncogenic KRAS determines the cellular response to p53 activation by oxaliplatin or 5-FU, by facilitating apoptosis induction through Noxa.

Prolonged portal triad clamping during liver surgery for colorectal liver metastases is associated with decreased time to hepatic tumour recurrence.

AIMS: The aim of this study was to evaluate the oncological outcome of portal triad clamping during hepatectomy in colorectal cancer patients. METHODS: 160 patients with colorectal liver metastases underwent a partial hepatectomy with curative intent. Data were collected in a prospective database and were retrospectively analyzed for time to liver recurrence (TTLiR) and time to overall recurrence (TTR). The prognostic significance of portal triad clamping of any type and severe ischemia due to prolonged portal triad clamping was determined by Cox regression models. RESULTS: TTLiR was reduced after clamping of any type, although not statistically significant (p=0.061). Severe ischemia due to prolonged portal triad clamping significantly decreased TTLiR (p=0.022), but not TTR. Furthermore, severe ischemia independently predicted TTLiR in a multivariable analysis (p=0.038). CONCLUSIONS: Severe ischemia due to prolonged portal triad clamping during hepatic resection for colorectal liver metastases appears to be associated with decreased TTLiR. Further research remains necessary to determine the causative effect of prolonged vascular clamping on liver tumour recurrence.