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Background Germline BRCA1-2 pathogenic variants (gBRCA1-2pv)-related pancreatic ductal adenocarcinoma (PDAC) showed increased sensitivity to DNA cross-linking agents. This study aimed at exploring safety profile, dose intensity, and activity of different chemotherapy regimens in this setting. Patients and methods gBRCA1-2pv PDAC patients of any age and clinical tumor stage who completed a first course of chemotherapy were eligible. A descriptive analysis of chemotherapy toxicity, dose intensity, response, and survival outcomes was performed. Results A total of 85 gBRCA1-2pv PDAC patients treated in 21 Italian centers between December 2008 and March 2021were enrolled. Seventy-four patients were assessable for toxicity and dose intensity, 83 for outcome. Dose intensity was as follows: nab-paclitaxel 72%, gemcitabine 76% (AG); cisplatin 75%, nab-paclitaxel 73%, capecitabine 73%, and gemcitabine 65% (PAXG); fluorouracil 35%, irinotecan 58%, and oxaliplatin 64% (FOLFIRINOX). When compared with the literature, grade 3-4 neutropenia, thrombocytopenia, and diarrhea were increased with PAXG, and unmodified with AG and FOLFIRINOX. RECIST responses were numerically higher with the three- (81%) or four-drug (73%) platinum-containing regimens that outperformed AG (41%) and oxaliplatin-based doublets (56%). Carbohydrate antigen 19.9 (CA19.9) reduction >89% at nadir was reported in two-third of metastatic patients treated with triplets and quadruplets, as opposed to 33% and 45% of patients receiving oxaliplatin-based doublets or AG, respectively. All patients receiving AG experienced disease progression, with a median progression-free survival (mPFS) of 6.4 months, while patients treated with platinum-containing triplets or quadruplets had an mPFS >10.8 months. Albeit still immature, data on overall survival seemed to parallel those on PFS. Conclusions Our data, as opposed to figures expected from the literature, highlighted that platinum-based regimens provoked an increased toxicity on proliferating cells, when dose intensity was maintained, or an as-expected toxicity, when dose intensity was reduced, while no change in toxicity and dose intensity was evident with AG. Furthermore, an apparently improved outcome of platinum-based triplets or quadruplets over other regimens was observed., Highlights • Nab-paclitaxel plus gemcitabine dose intensity and toxicity were as expected from the literature. • Toxicity with platinum-based triplets was unmodified to the price of consistently reduced dose intensity. • Dose intensity for platinum-based quadruplets was preserved to the price of greater hematological toxicity and diarrhea. • RECIST and CA19.9 responses were higher with platinum-based triplets and quadruplets in metastatic patients. • Longer progression-free and overall survival were observed with platinum-based three- and four-drug regimens in stage IV (AJCC/UICC TNM 8th Edition, 2017) patients.

The prognosis of pancreatic ductal adenocarcinoma is still the worst among solid tumors. In this review, a panel of experts addressed the main unanswered questions about the clinical management of this disease, with the aim of providing practical decision support for physicians. On the basis of the evidence available from the literature, the main topics concerning pancreatic cancer are discussed: the diagnosis, as the need for a pathological characterization and the role for germ-line and somatic molecular profiling; the therapeutic management of resectable disease, as the role of upfront surgery or neoadjuvant chemotherapy, the post-operative restaging and the optimal timing foradjuvant chemotherapy, the management of the borderline resectable and locally advanced disease; the metastatic disease and the role of surgery for the management of patients with isolated metastasis and the use of biomarkers of metastatic potential; the role of supportive care and the healthcare management of pancreatic ductal adenocarcinoma.

Purpose: We aimed to explore the role of drugs re-challenge at thedisease progression after a chemotherapy-free interval for pancreatic adenocarcinoma (PDAC) patients. Methods: We retrospectively analyzed the outcome of re-treatments at theprogression in two cohorts of advanced PDAC patients who had disease control (DC) and a treatment holiday ≥ 3months after upfront chemotherapy. Results: Between 2015 and 2019, 66 advanced PDAC patients (cohort A) had DC with nab-paclitaxel-based chemotherapy (i.e. AG or PAXG = cisplatin, nab-paclitaxel, gemcitabine, capecitabine). At the time of progressive disease (PD), 34 patients were re-treated with AG (A1) and 32 were treated with other regimens (A2). The median (m) duration of chemotherapy holiday was 6.1 and 5.9monthsin A1 and A2, respectively. Partial response (PR) and stable disease (SD) were found in 14 (41%) and 12 (35%) ofpatients in A1 and in 8 (25%) and 6 (19%) patients in A2. CA19-9 response was recorded in 23/33 evaluable patients (70%) in A1 and in 5/20 (25%) in A2. mPFS2 and mOS2, defined as the time between the second line of treatment start and the disease progression or death, were 4.8 and 12.2months in A1 and 3.9 and 8.4months in A2, respectively. Similarly, between 2006 and 2013, 64 patients (cohort B) had DC with upfront PEFG/PEXG/PDXG regimens (epirubicin or docetaxel, cisplatin, gemcitabine, capecitabine or 5-fluorouracil) and were re-treated at PD with either 4-drug (B1; N = 30) or other regimens (B2; N = 34), yielding a mOS2 of 10.9 and 7.2months, respectively. Conclusion: Our data endorse the strategy of resuming prior drugs after a chemotherapy holiday ≥ 3months in advanced PDAC patients who achieved a durable disease control after upfront treatments.

Summary Background Current treatment for metastatic pancreatic ductal adenocarcinoma includes combination chemotherapy, such as FOLFIRINOX or nab-paclitaxel plus gemcitabine. We investigated the activity of a novel four-drug regimen, consisting of cisplatin, nab-paclitaxel, capecitabine, and gemcitabine, compared with nab-paclitaxel plus gemcitabine, in the PACT-19 trial. Methods This single-centre, randomised, open-label, phase 2 trial was done in San Raffaele Hospital in Italy. We enrolled patients aged 18–75 years with pathologically confirmed stage IV pancreatic ductal adenocarcinoma who had received no previous chemotherapy and had Karnofsky performance status of at least 70. Patients were randomly assigned (1:1) by computer-generated permutated block randomisation (block size of four) stratified by baseline concentration of carbohydrate antigen 19-9 to PAXG (cisplatin 30 mg/m 2 , nab-paclitaxel 150 mg/m 2 , and gemcitabine 800 mg/m 2 on days 1 and 15 and oral capecitabine 1250 mg/m 2 on days 1–28 every 4 weeks), or nab-paclitaxel and gemcitabine alone (nab-paclitaxel 125 mg/m 2 and gemcitabine 1000 mg/m 2 on days 1, 8, and 15 every 4 weeks). The primary endpoint was the proportion of patients who were progression-free at 6 months, analysed in the intention-to-treat population. Data cutoff was on March 31, 2018. The safety population included all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT01730222, and is now closed. Findings Between April 22, 2014, and May 30, 2016, we randomly assigned 83 patients to treatment: 42 patients to PAXG and 41 patients to nab-paclitaxel plus gemcitabine. At 6 months, 31 (74%, 95% CI 58–86) of 42 patients in the PAXG group were alive and free from disease progression compared with 19 (46%, 31–63) of 41 patients in the nab-paclitaxel plus gemcitabine group. The most frequent grade 3 adverse events were neutropenia (12 [29%] of 42 in the PAXG group vs 14 [34%] of 41 in the nab-paclitaxel plus gemcitabine group), anaemia (nine [21%] vs nine [22%]), and fatigue (seven [17%] vs seven [17%]). The most common grade 4 adverse event was neutropenia (five [12%] in the PAXG group vs two [5%] in the nab-paclitaxel plus gemcitabine group). Two (5%) treatment-related deaths occurred in the nab-paclitaxel plus gemcitabine group compared with none in the PAXG group. Interpretation Despite the small sample size, our findings suggest that the PAXG regimen warrants further investigation in a phase 3 trial in patients with metastatic pancreatic ductal adenocarcinoma. Funding Celgene.

Context Pancreatic cancer (PC) is characterized by a 5-year survival rate of 4%. The molecular mechanisms involved in the high tumorigenicity of PC are not yet well-known. Methods PC samples from 7 localized and advanced cases of pancreatic adenocarcinomas were collected by ultrasound-guided biopsy. Whole transcriptome RNA libraries were sequenced at 75x2 bp on a HiScanSQ Illumina platform. An average of 4.5x107 reads per sample were generated, with a mean read depth of 40. Sequences were mapped to the human genome (build hg19) and the single nucleotide variants (SNVs) were detected with SNVMix2 tool. The SNVs were compared with genetic variations databanks (dbSNP, 1000genomes, Cosmic) in order to highlight the novel variants. The non-synonimous SNVs were considered at the protein level and analyzed with SNPs&GO, in order to predict whether a variation is disease-related or neutral. Results Pancreatic adenocarcinomas exhibited a mean of 139 (range: 65-252) non-synonimous SNVs, of which 12 on average are potentially disease-related. We found mutations in oncogenes and tumor suppressor genes known to be related to pancreatic tumors, as 4/7 patients exhibited KRAS oncogenic variants (p.G12D, R or V) two of which carried also mutations either in SMAD4 or PIK3CA, one patient showed both TP53 and CDKN2A inactivating mutations and one a mutation in SMARCA4. Novel disease-related SNVs were found in genes regulating cell cycle progression and proliferation, apoptosis, TGFbeta and integrin-signaling, epithelial to mesenchymal transition and nucleotide excision repair. Of interest some genes were mutated in multiple patients, as CBLC that regulates intracellular signalling by multiple tyrosine kinase genes. Conclusions Next generation sequencing analysis, through the identification of the oncogenic alterations carried by tumor cells, can improve the understanding of pancreatic carcinogenesis and highlight new biomarkers for early diagnosis and potential therapeutic targets in pancreatic cancer., JOP. Journal of the Pancreas, Vol 13, N° 5S (2012): September (Suppl.) - p. 548-650

Introduction: The long-term results of pancreatic tumors resections are disappointing. In order to increase postoperative survival after resections by surgical control of liver metastasis and peritoneal dissemination no-touch techniques of PD were proposed. Methods: We investigated the results of no-touch PD for malignant periampullary tumors in 31 patients, treated in our clinic in the period of November 20082011 years. In 14 patients tumors of papilla of Vater (PV) were diagnosed, in 12 tumors of the pancreas, 1neuroendocrine tumor, in 3 patientstumors of bile ducts (BD), 1 – gastrointestinal stromal tumor (GIST) of the duodenum. In 19 patients pylorus-preserving PD were done, in 12standard PD. In 3 patients additional resections of the affected portal or superior mesenteric vein were done. Results: Duration of the operation was 440,4 +77,4 minutes (from 340 to 745). Mean blood loss was 575,0 + 320,1 ml (from minimal to 1800). Morbidity was 22,6% (7 patients). Mortality was zero. Median survival in the group of BD cancer patients was 21,5 month. 1and 2year survival in pancreatic cancer patients was 63,5%, maximal follow-up26 months. 1and 2year survival for PV cancer patients was 100%, 3year survival85,7%, disease free 3-year survival57,1%. Patient with GIST is alive 34 months after procedure with metastatic disease from second postoperative year. Patient with neuroendocrine tumor is alive without metastatic disease 26 months after operation. Conclusion: No-touch PD is safe procedure. Further investigations should be done to evaluate potential benefit of the procedure.

e14541 Background: The aim of the study was to determine prognostic factors for recurrence in resected pancreatic cancer. Methods: We analyzed retrospectively 47 patients who underwent pancreatic r...

Venous thromboembolism (VTE) may occur during the natural history of neoplastic disease and is a common cause of mortality and morbidity in cancer patients. Major risk factors for VTE in cancer patients include surgery, immobilization, hospitalization, and the administration of granulopoietic and/or erythropoietic (stimulatory) agents. Chemotherapy is a supplementary independent risk factor for VTE and the use of central venous catheters (CVC) in clinical practice has increased the risk of thromboembolic events. We conducted a retrospective study to evaluate CVC-related thrombosis and the VTE rate in 145 consecutive metastatic colorectal cancer patients. We observed only 2 cases of symptomatic CVC- related thrombotic events (1.38%) and 10 cases of thromboembolic events (6.9%) in our series. Only surgery for metastases was found to be significantly related to the development of VTE, with an incidence of 16.1% vs. 4.4 in patients who did not undergo surgery (p = 0.037). In addition, a history of VTE seems to be a supplementary risk factor for CVC-related thrombosis (p = 0.055).

Context Pancreatic cancer cells produce various proteases involved in invasion, angiogenesis and metastatic spread. Gabexate mesylate (GM), a serine protease inhibitor, may reduce invasive capabilities and enhance chemotherapy effects. Objective To evaluate the effect of treatment with GM and gemcitabine (GEM), alone or combined. Materials and methods Studies have been performed on cancer cell lines PANC-1, SW1990 and endothelial cell EA.hy926. Treatment consisted of GM (50-100 µM for 24 h), alone or followed by GEM (250 µM for 24 h). Aspects studied included: cell viability (MTT assay), cell invasiveness and migration (Boyden chambers chemoinvasion and chemotaxis assay), angiogenesis (endothelial tube formation assay) and VEGF levels (ELISA) in EA.hy926 cell, MMP-2 and MMP-9 activity (gelatin zymography). Results Cell viability: this parameter decreased by 40% with GM alone only in EA.hy926 cells (P

Context We report a case of clinical benefit and RP with GemOx in patient with cystadenocarcinoma of pancreas with ovarian metastasis. Case report In July 2008 a 42-year-old woman complained of abdominal pain and constipation. The CT scan and the MR showed the presence of two bilateral ovarian mass with pancreatic extension. The patient arrived then to our hospital and ECOG PS was 2. She underwent bilateral ovarian and womb resection. During surgery peritoneal carcinosis, a pancreatic mass and multiple abdominal lesions were found. Multiple biopsies of pancreatic lesion and other abdominal lesions documented mucinous cystadenocarcinoma of pancreas, with ovarian and peritoneal metastases. In December 2008 the patient started chemotherapy (CHT) with gemcitabine 1000 mg/m2/dL and oxaliplatin 100 mg/m2/d2 every 2 weeks (GemOx). After 6 cycles of CHT a CT scan showed a stable disease. Clinical conditions were good (ECOG 0) so we decided to continue the medical treatment with other 6 cycles of CHT. In August 2009 a CT scan showed a reduction of the abdominal mass, and a surgical resection was then possible. The patient underwent distal pancreatic resection, regional lymphadenectomy and splenectomy. Pathologic examination documented biliopancreatic well differentiated adenocarcinoma. Surgical margins presented malignant cells and mucoid areas without cells. After surgery we decided to continue CHT with gemcitabine as "adjuvant treatment" for other 3 cycles, CT scan showed no disease, clinical conditions were good and the patient stopped the treatment. Actually there is no evidence or relapse. Conclusion As reported in literature, GemOx is associated with improvement in PFS and clinical benefit in patient with advanced pancreatic cancer. This is an interesting case where GemOx leaded inoperable pancreatic cancer to a operable cancer.

Context Pancreatic ductal adenocarcinoma is generally associated with a dismal prognosis even after curative pancreatic resection. Recently, some authors have reported cohort of patients with long survival. Case report A 60-year-old woman underwent pancreaticoduodenectomy (PD) for pancreatic head mass on May 1996. Pathological examination showed a well differentiated ductal adenocarcinoma of 2.5 cm in diameter, limited within the pancreatic gland (T2); loco-regional lymph node metastases (N1) were present and the resection margin was free from carcinoma (R0). The postoperative course was uneventful and 5 weeks after surgery the patient began adjuvant therapy with gemcitabine plus CDDP for 6 cycles. The patient was clinically and CT followed every 3 months for the first year and every 6 months subsequently. Thirteen years later (December 2009), due to an impaired glucose tolerance, without other symptoms, a CT scan showed a cystic lesion with septa of 45 mm in diameter localized in the tail of the pancreas. A FDG-PET resulted positive and on January 2010, the patient underwent surgery. The operation consisted in an en-bloc resection of body-tail of the pancreas, spleen, left adrenal gland and a part of the gastric wall. Pathological examination showed moderately differentiated pancreatic adenocarcinoma, biliopancreatic and intestinal type, invading the peripancreatic fat tissue but without invasion of the gastric wall and adrenal gland (T3); no lymph node metastases (N0) were present. Resections margin were also free from cancer cells (R0). The pathological characteristics of the mass suggest the hypothesis of a pancreatic adenocarcinoma arising from an intraductal papillary mucinous neoplasm (IPMN). The postoperative course was uneventful and at present the patient fourteen years after the first operation is in good general health and cancer free. Conclusion The long-term survival of our patient is probably due to a "non correct" pathological diagnosis at the first operation because IPMNs were not well known. This is also supported by the fact that the IPMN was pathologically diagnosed after the second surgical approach and it is possible that these lesions are slow-growing and may recur in other sites of the pancreatic gland.