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Sinus histiocytosis with massive lymphadenopathy (SHML) or Rosai-Dorfman disease (RDD) was first described as a distinct clinicopathological entity by Rosai and Dorfman in 1969. SHML is commonly characterized by painless cervical lymphadenopathy, and its clinical course is generally benign and self-limiting. This disorder commonly involves the lymph nodes but may secondarily involve the skin. However, purely cutaneous disease without lymphadenopathy or internal organ involvement rarely occurs. In the absence of the massive lymphadenopathy that is characteristic of RDD, the diagnosis of purely cutaneous RDD may be complicated by the rare, nonspecific clinical appearance of skin lesions and the broad histopathological differential diagnosis of this disorder. A high level of suspicion of this disease on the part of the clinician or pathologist is often required. We present a case of cutaneous RDD associated with involvement of periodontal tissue.

Background: BRCA1/2 genes play a critical role in genome stability and DNA repair. In animal models, loss of cardiomyocyte-specific BRCA1/2 is associated with DNA damage, apoptosis, cardiac dysfunction, and mortality following anthracycline exposure. However, whether these preclinical findings translate to humans remains unclear., Objective: Assess the impact of germline BRCA1/2 (gBRCA1/2) status on anthracyclines-induced cardiotoxicity (AIC) in patients with early breast cancer and no prior anti-HER2 therapy., Methods: This single-center retrospective/prospective cohort study focused on early breast cancer patients, treated with anthracycline-based chemotherapy in the neo/adjuvant setting, no prior anti-HER2 therapy, and known gBRCA1/2 status, normal baseline left ventricular ejection fraction (LVEF), and no previous cardiovascular disease. Follow-up assessments involved myocardial dysfunction blood biomarkers (MDBB), transthoracic echocardiography (TTE), and quality of life (QoL) questionnaires. The primary objective was LVEF changes comparing BRCA1/2 mutation carriers (gBRCA1/2m) vs non-carriers (gBRCA1/2wt). Secondary objectives included differences in MDBB and QoL., Results: A total of 137 patients were included (103 gBRCA1/2wt and 34 gBRCA1/2m). Baseline characteristics were similar between groups. Compared to baseline, LVEF% reduction was -4.7[-12.0, 0.0] vs -9.5[-18.0, -5.0] in gBRCA1/2wt vs gBRCA1/2m, (P = .027). After adjusting for confounders, the difference in reduction in LVEF remained statistically significant at -4.5 [95%CI, -8.6, -0.4; P = .032]. No differences between MDBB (C-reactive protein, hsTnI, NT-proBNP, D-Dimer, ST-2, or Galectine-3) or QoL (MLHFQ and EQ5-D index) were detected., Conclusions: gBRCA1/2m patients could represent a higher-risk population for AIC. gBRCA1/2 status should be one of the factors to consider in deciding on adjuvant anthracycline necessity. This population could benefit from a cardio-oncology closer follow-up and cardioprotective strategies., (© The Author(s) 2024. Published by Oxford University Press.)

We present a family in which four individuals have been identified with the same likely pathogenic genetic alteration in the PIK3CA gene at the germinal level; specifically, c.1145G>A p.(Arg382Lys) missense type. The index case patient was diagnosed with multinodular goiter and breast cancer at 61 years old. Among the other three carrier relatives: one has been diagnosed with serous cystadenoma of the ovary and a thyroid nodule with no radiological suspicion of malignancy; the other two present multinodular goiter. Additionally, a sister of three of the carriers suffered from an ovarian teratoma, follicular thyroid carcinoma on multinodular goiter, and high-grade serous ovarian carcinoma. No direct mutation study was performed on her as she had died due to ovarian carcinoma. This finding suggests that the PIK3CA gene should be considered in Cowden-like families when no other gene mutations have been found. Furthermore, this report contributes to characterization of the clinical phenotype caused by mutations in PIK3CA , which may be shared with other hereditary breast and ovarian cancer syndromes.

Importance: RAD51C and RAD51D are involved in DNA repair by homologous recombination. Germline pathogenic variants (PVs) in these genes are associated with an increased risk of ovarian and breast cancer. Understanding the homologous recombination deficiency (HRD) status of tumors from patients with germline PVs in RAD51C/D could guide therapeutic decision-making and improve survival., Objective: To characterize the clinical and tumor characteristics of germline RAD51C/D PV carriers, including the evaluation of HRD status., Design, Setting, and Participants: This retrospective cohort study included 91 index patients plus 90 relatives carrying germline RAD51C/D PV (n = 181) in Spanish hospitals from January 1, 2014, to December 31, 2021. Genomic and functional HRD biomarkers were assessed in untreated breast and ovarian tumor samples (n = 45) from June 2022 to February 2023., Main Outcomes and Measures: Clinical and pathologic characteristics were assessed using descriptive statistics. Genomic HRD by genomic instability scores, functional HRD by RAD51, and gene-specific loss of heterozygosity were analyzed. Associations between HRD status and tumor subtype, age at diagnosis, and gene-specific loss of heterozygosity in RAD51C/D were investigated using logistic regression or the t test., Results: A total of 9507 index patients were reviewed, and 91 patients (1.0%) were found to carry a PV in RAD51C/D; 90 family members with a germline PV in RAD51C/D were also included. A total of 157 of carriers (86.7%) were women and 181 (55.8%) had received a diagnosis of cancer, mainly breast cancer or ovarian cancer. The most prevalent PVs were c.1026+5_1026+7del (11 of 56 [19.6%]) and c.709C>T (9 of 56 [16.1%]) in RAD51C and c.694C>T (20 of 35 [57.1%]) in RAD51D. In untreated breast cancer and ovarian cancer, the prevalence of functional and genomic HRD was 55.2% (16 of 29) and 61.1% (11 of 18) for RAD51C, respectively, and 66.7% (6 of 9) and 90.0% (9 of 10) for RAD51D. The concordance between HRD biomarkers was 91%. Tumors with the same PV displayed contrasting HRD status, and age at diagnosis did not correlate with the occurrence of HRD. All breast cancers retaining the wild-type allele were estrogen receptor positive and lacked HRD., Conclusions and Relevance: In this cohort study of germline RAD51C/D breast cancer and ovarian cancer, less than 70% of tumors displayed functional HRD, and half of those that did not display HRD were explained by retention of the wild-type allele, which was more frequent among estrogen receptor-positive breast cancers. Understanding which tumors are associated with RAD51C/D and HRD is key to identify patients who can benefit from targeted therapies, such as PARP (poly [adenosine diphosphate-ribose] polymerase) inhibitors.

BACKGROUND: Sequential nab-paclitaxel plus gemcitabine followed by modified FOLFOX-6 (oxaliplatin, leucovorin, and 5-fluorouracil) (nab-P/Gem-mFOLFOX) showed a good safety and clinical profile in metastatic pancreatic ductal adenocarcinoma (mPDAC) in the phase I SEQUENCE trial. METHODS: The safety and efficacy of sequential nab-P/Gem-mFOLFOX was compared with standard nab-paclitaxel plus gemcitabine (nab-P/Gem) as first-line treatment in a multi-institutional, randomized, open-label, phase II trial in patients with untreated mPDAC. We randomly assigned patients in a 1:1 ratio to receive nab-P/Gem on days 1, 8, and 15 followed by mFOLFOX on day 29 of a 6-week cycle (experimental group) or nab-P/Gem on days 1, 8, and 15 of a 4-week cycle (control group). The primary end point was the 12-month overall survival rate. RESULTS: A total of 157 patients were randomly assigned: 78 to nab-P/Gem-mFOLFOX and 79 to nab-P/Gem. Patients receiving nab-P/Gem-mFOLFOX had a 12-month overall survival of 55.3% (95% confidence interval [CI], 44.2 to 66.5) versus 35.4% (95% CI, 24.9 to 46) in the control group (P=0.02). Similarly, the 24-month survival was 22.4% (95% CI, 13 to 31.8) with nab-P/Gem-mFOLFOX versus 7.6% (95% CI, 1.8 to 13.4) with control treatment. The median overall survival was 13.2 months (95% CI, 10.1 to 16.2) with nab-P/Gem-mFOLFOX and 9.7 months (95% CI, 7.5 to 12) with nab-P/Gem (hazard ratio for death, 0.68; 95% CI, 0.48 to 0.95). The safety profile showed a higher incidence of grade 3 or higher neutropenia (35 of 76 vs. 19 of 79 patients, P=0.004), grade 3 or higher thrombocytopenia (18 of 78 vs. 6 of 79 patients, P=0.007), and two treatment-related deaths (2.6%) with nab-P/Gem-mFOLFOX compared with none with control treatment. CONCLUSIONS: Sequential nab-P/Gem-mFOLFOX showed a significantly higher 12-month survival when compared with the standard nab-P/Gem treatment; this came with greater treatment toxicity. (Funded by Celgene; EuCT number, 2014-005350-19; ClinicalTrials.gov number, NCT02504333.)

Colorectal cancer (CRC) is one of the most common tumours worldwide, and 70% of CRC patients are over 65 years of age. However, the scientific evidence available for these patients is poor, as they are underrepresented in clinical trials. Therefore, a group of experts from the Oncogeriatrics Section of the Spanish Society of Medical Oncology (SEOM), the Spanish Cooperative Group for the Treatment of Digestive Tumours, (TTD) and the Multidisciplinary Spanish Group of Digestive Cancer (GEMCAD) have reviewed the scientific evidence available in older patients with CRC. This group of experts recommends a multidisciplinary approach and geriatric assessment (GA) before making a therapeutic decision because GA predicts the risk of toxicity and survival and helps to individualize treatment. In addition, elderly patients with localized CRC should undergo standard cancer resection, preferably laparoscopically. The indication for adjuvant chemotherapy (CT) should be considered based on the potential benefit, the risk of recurrence, the life expectancy and patient comorbidities. When the disease is metastatic, the possibility of radical treatment with surgery, radiofrequency (RF) or stereotactic body radiation therapy (SBRT) should be considered. The efficacy of palliative CT is similar to that seen in younger patients, but elderly patients are at increased risk of toxicity. Clinical trials should be conducted with the elderly population and include GAs and specific treatment plans., (© 2023. The Author(s).)

The serial analysis of cell-free DNA (cfDNA) enables minimally invasive monitoring of tumor evolution, providing continuous genetic information. PERSEIDA was an observational, prospective study assessing the cfDNA RAS ( KRAS / NRAS ) mutational status evolution in first-line, metastatic CRC, RAS wild-type (according to baseline tumor tissue biopsy) patients. Plasma samples were collected before first-line treatment, after 20 ± 2 weeks, and at disease progression. One hundred and nineteen patients were included (102 received panitumumab and chemotherapy as first-line treatment-panitumumab subpopulation). Fifteen (12.6%) patients presented baseline cfDNA RAS mutations ( n = 14 [13.7%], panitumumab subpopulation) (mutant allele fraction ≥0.02 for all results). No patients presented emergent mutations (cfDNA RAS mutations not present at baseline) at 20 weeks. At disease progression, 11 patients ( n = 9; panitumumab subpopulation) presented emergent mutations ( RAS conversion rate: 19.0% [11/58]; 17.7% [9/51], panitumumab subpopulation). In contrast, three (5.2%) patients presenting baseline cfDNA RAS mutations were RAS wild-type at disease progression. No significant associations were observed between overall response rate or progression-free survival and cfDNA RAS mutational status in the total panitumumab subpopulation. Although, in patients with left-sided tumors, a significantly longer progression-free survival was observed in cfDNA RAS wild-type patients compared to those presenting cfDNA RAS mutations at any time. Continuous evaluation of RAS mutations may provide valuable insights on tumor molecular dynamics that can help clinical practice.

Objective: To compare colorectal cancer (CRC) incidences in carriers of pathogenic variants of the MMR genes in the PLSD and IMRC cohorts, of which only the former included mandatory colonoscopy surveillance for all participants., Methods: CRC incidences were calculated in an intervention group comprising a cohort of confirmed carriers of pathogenic or likely pathogenic variants in mismatch repair genes (path&#95;MMR) followed prospectively by the Prospective Lynch Syndrome Database (PLSD). All had colonoscopy surveillance, with polypectomy when polyps were identified. Comparison was made with a retrospective cohort reported by the International Mismatch Repair Consortium (IMRC). This comprised confirmed and inferred path&#95;MMR carriers who were first- or second-degree relatives of Lynch syndrome probands., Results: In the PLSD, 8,153 subjects had follow-up colonoscopy surveillance for a total of 67,604 years and 578 carriers had CRC diagnosed. Average cumulative incidences of CRC in path&#95;MLH1 carriers at 70 years of age were 52% in males and 41% in females; for path&#95;MSH2 50% and 39%; for path&#95;MSH6 13% and 17% and for path&#95;PMS2 11% and 8%. In contrast, in the IMRC cohort, corresponding cumulative incidences were 40% and 27%; 34% and 23%; 16% and 8% and 7% and 6%. Comparing just the European carriers in the two series gave similar findings. Numbers in the PLSD series did not allow comparisons of carriers from other continents separately. Cumulative incidences at 25 years were < 1% in all retrospective groups., Conclusions: Prospectively observed CRC incidences (PLSD) in path&#95;MLH1 and path&#95;MSH2 carriers undergoing colonoscopy surveillance and polypectomy were higher than in the retrospective (IMRC) series, and were not reduced in path&#95;MSH6 carriers. These findings were the opposite to those expected. CRC point incidence before 50 years of age was reduced in path&#95;PMS2 carriers subjected to colonoscopy, but not significantly so., (© 2022. The Author(s).)

Background: Deregulation of FGF19-FGFR4 signaling is found in several cancers, including hepatocellular carcinoma (HCC), nominating it for therapeutic targeting. FGF401 is a potent, selective FGFR4 inhibitor with antitumor activity in preclinical models. This study was designed to determine the recommended phase 2 dose (RP2D), characterize PK/PD, and evaluate the safety and efficacy of FGF401 alone and combined with the anti-PD-1 antibody, spartalizumab., Methods: Patients with HCC or other FGFR4/KLB expressing tumors were enrolled. Dose-escalation was guided by a Bayesian model. Phase 2 dose-expansion enrolled patients with HCC from Asian countries (group1), non-Asian countries (group2), and patients with other solid tumors expressing FGFR4 and KLB (group3). FGF401 and spartalizumab combination was evaluated in patients with HCC., Results: Seventy-four patients were treated in the phase I with single-agent FGF401 at 50 to 150 mg. FGF401 displayed favorable PK characteristics and no food effect when dosed with low-fat meals. The RP2D was established as 120 mg qd. Six of 70 patients experienced grade 3 dose-limiting toxicities: increase in transaminases (n = 4) or blood bilirubin (n = 2). In phase 2, 30 patients in group 1, 36 in group 2, and 20 in group 3 received FGF401. In total, 8 patients experienced objective responses (1 CR, 7 PR; 4 each in phase I and phase II, respectively). Frequent adverse events (AEs) were diarrhea (73.8%), increased AST (47.5%), and ALT (43.8%). Increase in levels of C4, total bile acid, and circulating FGF19, confirmed effective FGFR4 inhibition. Twelve patients received FGF401 plus spartalizumab. RP2D was established as FGF401 120 mg qd and spartalizumab 300 mg Q3W; 2 patients reported PR., Conclusions: At biologically active doses, FGF401 alone or combined with spartalizumab was safe in patients with FGFR4/KLB-positive tumors including HCC. Preliminary clinical efficacy was observed. Further clinical evaluation of FGF401 using a refined biomarker strategy is warranted., Trial Registration: NCT02325739 ., (© 2022. The Author(s).)

Background: VCN-01 is an oncolytic adenovirus (Ad5 based) designed to replicate in cancer cells with dysfunctional RB1 pathway, express hyaluronidase to enhance virus intratumoral spread and facilitate chemotherapy and immune cells extravasation into the tumor. This phase I clinical trial was aimed to find the maximum tolerated dose/recommended phase II dose (RP2D) and dose-limiting toxicity (DLT) of the intravenous delivery of the replication-competent VCN-01 adenovirus in patients with advanced cancer., Methods: Part I: patients with advanced refractory solid tumors received one single dose of VCN-01. Parts II and III: patients with pancreatic adenocarcinoma received VCN-01 (only in cycle 1) and nab-paclitaxel plus gemcitabine (VCN-concurrent on day 1 in Part II, and 7 days before chemotherapy in Part III). Patients were required to have anti-Ad5 neutralizing antibody (NAbs) titers lower than 1/350 dilution. Pharmacokinetic and pharmacodynamic analyses were performed., Results: 26% of the patients initially screened were excluded based on high NAbs levels. Sixteen and 12 patients were enrolled in Part I and II, respectively: RP2D were 1×10 13 viral particles (vp)/patient (Part I), and 3.3×10 12 vp/patient (Part II). Fourteen patients were included in Part III: there were no DLTs and the RP2D was 1×10 13 vp/patient. Observed DLTs were grade 4 aspartate aminotransferase increase in one patient (Part I, 1×10 13  vp), grade 4 febrile neutropenia in one patient and grade 5 thrombocytopenia plus enterocolitis in another patient (Part II, 1×10 13  vp). In patients with pancreatic adenocarcinoma overall response rate were 50% (Part II) and 50% (Part III). VCN-01 viral genomes were detected in tumor tissue in five out of six biopsies (day 8). A second viral plasmatic peak and increased hyaluronidase serum levels suggested replication after intravenous injection in all patients. Increased levels of immune biomarkers (interferon-γ, soluble lymphocyte activation gene-3, interleukin (IL)-6, IL-10) were found after VCN-01 administration., Conclusions: Treatment with VCN-01 is feasible and has an acceptable safety. Encouraging biological and clinical activity was observed when administered in combination with nab-paclitaxel plus gemcitabine to patients with pancreatic adenocarcinoma., Trial Registration Number: NCT02045602., Competing Interests: Competing interests: MB-P, MF-S, AM-B, MVM, EB, CB and MC are employees, and RS is consultant for VCN Biosciences. MC and RAle are co-inventors of one patent application concerning the expression of hyaluronidase by oncolytic adenoviruses and both have ownership interest in VCN Biosciences. RG-C has provided scientific advice and/or received honoraria or funding for continuous medical education from AAA, Advanz Pharma, Amgen, Bayer, BMS, HMP, Ipsen, Merck, Midatech Pharma, MSD, Novartis, PharmaMar, Pfizer, Pierre Fabre, Roche, Servier and Sanofi, and has received research support from Pfizer, BMS and MSD., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is largely unresponsive to checkpoint inhibitors. Blockade of the CXCR4/CXCL12 axis increases intratumoral trafficking of activated T cells while restraining immunosuppressive elements. This study evaluates dual blockade of CXCR4 and PD1 with chemotherapy in PDAC., Patients and Methods: Multicenter, single-arm, phase II study to evaluate the safety and efficacy of motixafortide and pembrolizumab combined with chemotherapy in patients with de novo metastatic PDAC and disease progression on front-line gemcitabine-based therapy (NCT02826486). Subjects received a priming phase of motixafortide daily on days 1-5, followed by repeated cycles of motixafortide twice a week; pembrolizumab every 3 weeks; and nanoliposomal irinotecan, fluorouracil, and leucovorin every 2 weeks (NAPOLI-1 regimen). The primary objective was objective response rate (ORR). Secondary objectives included overall survival (OS), progression-free survival (PFS), disease control rate (DCR), safety, and tolerability., Results: A total of 43 patients were enrolled. The ORR according to RECISTv1.1 was 21.1% with confirmed ORR of 13.2%. The DCR was 63.2% with median duration of clinical benefit of 5.7 months. In the intention-to-treat population, median PFS was 3.8 months and median OS was 6.6 months. The triple combination was safe and well tolerated, with toxicity comparable with the NAPOLI-1 regimen. Notably, the incidence of grade 3 or higher neutropenia and infection was 7%, lower than expected for this chemotherapy regimen., Conclusions: Triple combination of motixafortide, pembrolizumab, and chemotherapy was safe and well tolerated, and showed signs of efficacy in a population with poor prognosis and aggressive disease., (©2021 American Association for Cancer Research.)

Background: Although occasioned through different mechanisms, the potential neurotoxicity and also haematological toxicity of nab-paclitaxel and oxaliplatin-based chemotherapy regimen were studied in this trial, which aimed to determine the maximum-tolerated dose (MTD) and to evaluate safety and efficacy of the combination in a sequential regimen of nab-paclitaxel, gemcitabine (GEM) and modified FOLFOX (mFOLFOX) in untreated patients with metastatic pancreatic ductal adenocarcinoma (PDAC)., Materials and Methods: Treatment consisted of nab-paclitaxel (125/100 mg/m 2 ) plus GEM (1000/800 mg/m 2 ) on days 1, 8 and 15, followed by mFOLFOX (oxaliplatin [85/75/65 mg/m 2 ], 5-FU bolus [400/300/200 mg/m 2 ], 5-FU infusion [2400/2000/1600 mg/m 2 ]) on day 28, of a 42-day cycle. Patients were enrolled at the highest dose level with a subsequent 3 + 3 dose de-escalation plan., Results: Eleven patients (median age = 61, 64% with performance status [PS] = 1) were eligible. All patients received the highest dose level. No de-escalation was needed. A dose-limiting toxicity was reported, an upper gastrointestinal haemorrhage. The MTD was nab-paclitaxel 125 mg/m 2 , GEM 1000 mg/m 2 , oxaliplatin 85 mg/m 2 , 5-FU bolus 400 mg/m 2 and 5-FU infusion 2400 mg/m 2 . Common all-grade toxicities were neutropenia (73%), anaemia (55%), thrombocytopenia (55%) and asthenia (55%). Other relevant toxicities were paraesthesia (46%), nausea (36%), dysesthesia (27%) and pyrexia (27%). Objective response rate was 50% and disease control rate was 80%., Conclusions: The regimen of nab-paclitaxel plus GEM followed by mFOLFOX showed favourable safety and tolerability profiles with significant anti-tumor activity. More data are being achieved in a randomised phase II trial, to confirm efficacy rates and dismiss long-term neurotoxicity concerns regarding the sequencing of nab-paclitaxel and oxaliplatin., Competing Interests: Conflict of interest statement Alfredo Carrato has received advisory board honoraria from Merck, Roche, MSD, Pfizer, Bayer, Shire, Servier, Celgene and Amgen. J. M. Vieitez has received grants from Celgene, outside the submitted work. E. Aranda has received honoraria for advisory role from Amgen, Bayer, Celgene, Merck, Roche, Sanofi. All other authors have declared no conflicts of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Purpose: 5-Fluorouracil/leucovorin, oxaliplatin, irinotecan (FOLFOXIRI) plus bevacizumab is more effective than doublets plus bevacizumab as first-line therapy for metastatic colorectal cancer, but is not widely used because of concerns about toxicity and lack of predictive biomarkers. This study was designed to explore the role of circulating tumour cell (CTC) count as a biomarker to select patients for therapy with FOLFOXIRI-bevacizumab., Patients and Methods: VISNÚ-1 was a multicentre, open-label, randomised, phase III study in patients with previously untreated, unresectable, metastatic colorectal carcinoma and ≥3 CTC/7.5 mL blood. Patients received bevacizumab 5 mg/kg plus FOLFOXIRI (irinotecan 165 mg/m 2 , oxaliplatin 85 mg/m 2 , leucovorin 400 mg/m 2 and 5-fluorouracil 3200 mg/m 2 ) or FOLFOX (oxaliplatin 85 mg/m 2 , leucovorin 400 mg/m 2 , 5-fluorouracil 400 mg/m 2 then 2400 mg/m 2 ) by intravenous administration every 2 weeks. The primary outcome was progression-free survival (PFS)., Results: The intention-to-treat population comprised 349 patients (FOLFOXIRI-bevacizumab, n=172; FOLFOX-bevacizumab, n=177). Median PFS was 12.4 months (95% CI 11.2 to 14.0) with FOLFOXIRI bevacizumab and 9.3 months (95% CI 8.5 to 10.7) with FOLFOX-bevacizumab (stratified HR, 0.64; 95% CI 0.49 to 0.82; p=0.0006). Grade≥3 adverse events were more common with FOLFOXIRI-bevacizumab 85.3% vs 75.1% with FOLFOX-bevacizumab (p=0.0178). Treatment-related deaths occurred in 8 (4.7%) and 6 (3.4%) patients, respectively., Conclusions: First-line FOLFOXIRI-bevacizumab significantly improved PFS compared with FOLFOX-bevacizumab in patients with metastatic colorectal cancer and ≥3 CTCs at baseline, which indicate a poor prognosis. CTC count may be a useful non-invasive biomarker to assist with the selection of patients for intensive first-line therapy., Competing Interests: Competing interests: EA has done consulting or advisory roles for Amgen, Bayer, Celgene, Merck, Roche and Sanofi. JMV has done consulting or advisory roles for Amgen, Roche, Servier, received research funding from Amgen and Roche, done expert testimonies for Servier, and received travel, accommodation, and expenses from Amgen, Bristol-Myers Squibb, Roche, and Servier. AG-E has received travel, accommodation, and expenses from Amgen, Merck, Roche and Servier. BG has done consulting or advisory roles for Celgene and Sanofi, received research funding from Amgen, Celgene, Erytech Pharma, Gilead Sciences, Lilly, Parexel, and Sanofi, and travel, accommodation, and expenses from Amgen, Celgene, Roche, Sanofi and Servier. JJR-Z has done consulting or advisory roles for Amgen, Archimedes, Bayer, Ipsen, Merck, Novartis, Pfizer, Prostrakan, Roche, Sanofi, and Servier, and received travel, accommodation, and expenses from Amgen, Bayer, Ipsen, Merck, Novartis, Prostrakan, Roche, Sanofi, and Servier. CG-P has received travel, accommodation, and expenses from Sanofi/Aventis. RG-C declares having provided scientific advice and/or received honoraria from AAA, Amgen, Bayer, Bristol-Myers Squibb, Ipsen, Lilly, Merck, MSD, Novartis, PharmaMar, Pfizer, Roche and Sanofi, and has received research support from Bristol-Myers Squibb and Pfizer. MJS has done consulting or advisory roles for Amgen, Merck, Roche, Sanofi and Servier, and received travel, accommodation, and expenses from Amgen, Merck and Roche. ALCM has received travel, accommodation and expenses from Amgen. RLL has stock and other ownership interests in MTrap and Nasasbiotech SL, has done consulting or advisory roles for Bayer, Bristol-Myers Squibb, Janssen, Lilly, MSD, and Roche, done speakers’ bureaus for Novartis and Roche, received institutional research funding from Lilly, Merck, and Roche, and received travel, accommodation, and expenses from Pierre Fabre, Roche and Tesaro. JS has done speaking honoraria for Ipsen, Lilly, Merck, MSD, Pfizer, Roche, Shire, and Servier, advisory roles for Amgen, Bayer, Bristol-Myers Squibb, Celgene, Ipsen, Merck, Roche, Sanofi, and Servier, and received travelling and accommodation support from Ipsen and Merck. ED-R has done consulting or advisory roles for Amgen, Bayer, Genomica, Merck Serono and Servier, speakers’ bureaus for MSD and Servier, and received research funding from Amgen, AstraZeneca, Merck Serono, Roche and Sysmex. SGC, ASS, PG-A, FR, GAQ-A, EGF, MSF and BG declare no potential conflicts of interest., (© Author (s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ on behalf of the European Society for Medical Oncology.)

The elderly form a very heterogeneous group in relation to their general health state, degree of dependence, comorbidities, performance status, physical reserve and geriatric situation, so cancer treatment in the older patient remains a therapeutic challenge. The physiological changes associated with aging increase the risk of developing a serious toxicity induced by chemotherapy treatment, as well as other undesirable consequences as hospitalizations, dependence and non-compliance with treatment, that can negatively affect survival, quality of life and treatment efficacy. The use of hematopoietic growth factors and other active supportive interventions in the elderly can help prevent and/or alleviate these toxicities. However, we have little data on the efficacy and tolerance of support treatments in the older patient. The objective of this work is to review the most frequent toxicities of oncological treatments in the elderly and their management.

In the last 2 decades, clinical genetics on hereditary colorectal syndromes has shifted from just a molecular characterization of the different syndromes to the estimation of the individual risk of cancer and appropriate risk reduction strategies. In the last years, new specific therapies for some subgroups of patients have emerged as very effective alternatives. At the same time, germline multigene panel testing by next-generation sequencing (NGS) technology has become the new gold standard for molecular genetics.

microRNAs (miRNA) expression in colorectal (CR) primary tumours can facilitate a more precise molecular characterization. We identified and validated a miRNA profile associated with clinical and histopathological features that might be useful for patient stratification. In situ hybridization array using paraffin-embedded biopsies of CR primary tumours were used to screen 1436 miRNAs. 17 miRNAs were selected for validation by quantitative reverse transcription polymerase chain reaction (qRT-PCR) ( n = 192) and were further correlated with clinical and histopathological data. We demonstrated that miRNAs associated to Colorectal Cancer (CRC) diagnosis age (over 50s and 60s) included miR-1-3p, miR-23b-3p, miR-27b-3p, miR-143-3p, miR-145-5p and miR-193b-5p. miR-23b-3p and miR-24-3p discriminated between Lynch Syndrome and sporadic CRC. miR-10a-5p, miR-20a-5p, miR-642b and Let-7a-5p were associated to stroma abundance. miR-642b and Let-7a-5p were associated with to peritumoral inflammation abundance. miR-1-3p, miR-143-3p and miR-145-5p correlated with mucinous component. miR-326 correlated with tumour location (right or left sided). miR-1-3p associated with tumour grade. miR-20a-5p, miR-193b-5p, miR-320a, miR-326 and miR-642b-3p associated to tumour stage and progression. Remarkably, we also demonstrated that miR-1-3p and miR-326 expression significantly associated with patient overall survival (OS). Hierarchical clustering and bioinformatics analysis indicated that selected miRNAs could re-classify the patients and work cooperatively, modulating common target genes involved in colorectal cancer key signalling pathways. In conclusion, molecular characterization of CR primary tumours based on miRNAs could lead to more accurate patient reclassification and may be useful for efficient patient management.

Cetuximab is a standard-of-care treatment for RAS wild-type metastatic colorectal cancer (mCRC) but not for those harbor a KRAS mutation since MAPK pathway is constitutively activated. Nevertheless, cetuximab also exerts its effect by its immunomodulatory activity despite the presence of RAS mutation. The aim of this study was to determine the impact of polymorphism FcγRIIIa V158F and killer immunoglobulin-like receptor (KIR) genes on the outcome of mCRC patients with KRAS mutations treated with cetuximab. This multicenter Phase II clinical trial included 70 mCRC patients with KRAS mutated. We found KIR2DS4 gene was significantly associated with OS (HR 2.27; 95% CI, 1.08-4.77; P = 0.03). In non-functional receptor homozygotes the median OS was 2.6 months longer than in carriers of one copy of full receptor. Multivariate analysis confirmed KIR2DS4 as a favorable prognostic marker for OS (HR 6.71) in mCRC patients with KRAS mutation treated with cetuximab. These data support the potential therapeutic of cetuximab in KRAS mutated mCRC carrying non-functional receptor KIR2DS4 since these patients significantly prolong their OS even after heavily treatment. KIR2DS4 typing could be used as predictive marker for identifying RAS mutated patients that could benefit from combination approaches of anti-EGFR monoclonal antibodies and other immunotherapies to overcome the resistance mediated by mutation in RAS.

Purpose: Gemcitabine plus nanoparticle albumin-bound (NAB) paclitaxel (GA) significantly improved survival compared with gemcitabine alone in patients with metastatic pancreatic ductal adenocarcinoma (PDAC) and a Karnofsky performance status (PS) of 70% or greater. Because of the low number of patients with reduced PS, the efficacy of this regimen in fragile patients remains unclear. This study aimed to evaluate the efficacy and tolerability of different GA dosing regimens in patients with a poor PS., Patients and Methods: In the phase I part of this study, patients were randomly assigned to one of the following four parallel GA treatment arms (six patients per arm): a biweekly schedule of NAB-paclitaxel (150 mg/m 2 [arm A] or 125 mg/m 2 [arm C]) plus gemcitabine 1,000 mg/m 2 or a standard schedule of 3 weeks on and 1 week off of NAB-paclitaxel (100 mg/m 2 [arm B] or 125 mg/m 2 [arm D]) plus gemcitabine 1,000 mg/m 2 . The two regimens with the better tolerability profile on the basis of predefined criteria were evaluated in the phase II part of the study, the primary end point of which was 6-month actuarial survival., Results: Arms B and D were selected for the phase II part of the study. A total of 221 patients (111 patients in arm B and 110 patients in arm D) were enrolled. Baseline characteristics including median age (71 and 68 years in arms B and D, respectively), sex (51% and 55% men in arms B and D, respectively), and metastatic disease (88% and 84% in arms B and D, respectively) were comparable between arms. The most frequent grade 3 or 4 toxicities in arms B and D were anemia (12% and 7%, respectively), neutropenia (32% and 30%, respectively), thrombocytopenia (7% and 11%, respectively), asthenia (14% and 16%, respectively), and neurotoxicity (11% and 16%, respectively). In arms B and D, there were no significant differences in response rate (24% and 28%, respectively), median progression-free survival (5.7 and 6.7 months, respectively), and 6-month overall survival (63% and 69%, respectively)., Conclusion: NAB-paclitaxel administered at either 100 and 125 mg/m 2 in combination with gemcitabine on days 1, 8, and 15 every 28 days is well tolerated and results in acceptable safety and efficacy in patients with metastatic pancreatic ductal adenocarcinoma and a poor PS.

The growing increase in world population and generalised aging have been accompanied by an increase in the prevalence of cancer in the elderly. Aging is associated with certain physiological changes, some of which are enhanced by the neoplasm itself. Along with this, the elderly oncology patient usually has more problems than the rest of the elderly, and has a multitude of deficits. These characteristics require a special handling of the older patient with cancer, by using the main tool used in Geriatrics, the comprehensive geriatric assessment. This article analyses the importance of the comprehensive geriatric assessment in this population group, paying special attention to its ability to predict the toxicity of chemotherapy and the survival of the elderly oncology, as well as its ability to classify these patients into groups that help in the decision making process., (Copyright © 2018 SEGG. Publicado por Elsevier España, S.L.U. All rights reserved.)

Although approximately 50% of cancer patients are 70 years of age or older, cancer treatment in the elderly remains a therapeutic challenge. The elderly form a very heterogeneous group in relation to their general health state, degree of dependence, comorbidities, performance status, physical reserve and geriatric situation, for which therapeutic decisions must be made in an individualized manner. In addition, changes in pharmacokinetics and pharmacodynamics of the drugs occur with age, as well as the tolerance of the tissues, leading to a narrowing of the therapeutic margin and an increase in toxicity. In the general population, Performace Status (PS) has traditionally been used to estimate tolerance to chemotherapy, but in the elderly population it is not useful. In this review we summarize the current knowledge about the pharmacology of antineoplastic drugs in the elderly and the tools available to help us identify risk of chemotherapy toxicity in these patients., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Population aging is associated with greater numbers of older people with cancer. Thanks to treatment advances, not only are more seniors diagnosed with cancer, but there are also more and more older cancer survivors. This upward trend will continue. Given the heterogeneity of aging, managing older patients with cancer poses a significant challenge for Medical Oncology. In Spain, a Geriatric Oncology Task Force has been set up within the framework of the Spanish Society for Medical Oncology (SEOM). With the aim of generating evidence and raising awareness, as well as helping medical oncologists in their training with respect to seniors with cancer, we have put together a series of basic management recommendations for this population. Many of the patients who are assessed in routine clinical practice in Oncology are older. CGA is the basic tool by means of which to evaluate older people with cancer and to understand their needs. Training and the correct use of recommendations regarding treatment for comorbidities and geriatric syndromes, support care, and drug-drug interactions and toxicities, including those of antineoplastic agents, as detailed in this article, will ensure that this population is properly managed.

Background: This multicentre, randomised, and phase II study evaluated mFOLFOX+cetuximab followed by maintenance mFOLFOX+cetuximab or single-agent cetuximab in metastatic colorectal cancer (mCRC) patients (NCT01161316)., Patients and Methods: Previously, untreated mCRC patients (wild-type KRAS) were randomised to receive cetuximab+mFOLFOX-6 (8 cycles for 2 weeks) followed by maintenance therapy: single-agent cetuximab (Arm-A) or mFOLFOX-6 + cetuximab (Arm-B) until progression. Primary endpoint was progression-free survival (PFS) at 9 months., Results: One hundred ninety-three patients (median [range] age 60 [33-74] years) were randomised (2:1): 129 Arm-A versus 64 Arm-B. PFS at 9 months (95% confidence interval) showed non-inferiority between arms (Arm-A/Arm-B: 60 [52, 69]%/72 [61, 83]%, p [non-inferiority]<0.1). There were no statistically significant differences in the PFS (Arm-A/Arm-B: 9 [95% CI 7, 10] months/10 [7,13] months, hazard ratio [HR] = 1.19 [0.80, 1.79]) or overall survival (23 [19, 28] months/27 [18, 36] months, HR = 1.24 [0.85, 1.79]) between arms. The objective response rate was also similar (48 [39, 57]%/39 [27, 52]%). The safety profile was similar between arms, and all patients experienced at least one adverse event (AE) (Arm-A/Arm-B grade ≥III AEs: 70%/68%). The most common grade ≥III AEs were as follows: neutropenia (Arm-A/Arm-B: 28%/26%), rash acneiform (15%/24%) and sensory neuropathy (2%/15%) in any group. Arm-A was associated with less grade ≥III rash and sensory neuropathy and a lower rate of serious AEs (20%/27%)., Conclusion(s): This phase II exploratory trial with a non-inferiority design suggests that maintenance therapy with single-agent cetuximab following mFOLFOX+cetuximab induction could be a valuable option compared with mFOLFOX+cetuximab treatment continuation. We await phase III trials to confirm single-agent cetuximab as maintenance therapy in mCRC patients., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objectives: The aim of this work was to reach a national consensus in Spain regarding the Comprehensive Geriatric Assessment (CGA) domains in older oncological patients and the CGA scales to be used as a foundation for widespread use., Material and Methods: The Delphi method was implemented to attain consensus. Representatives of the panel were chosen from among the members of the Oncogeriatric Working Group of the Spanish Society of Medical Oncology (SEOM). Consensus was defined as ≥66.7% coincidence in responses and by the stability of said coincidence (changes ≤15% between rounds). The study was conducted between July and December 2016., Results: Of the 17 people invited to participate, 16 agreed. The panel concluded by consensus that the following domains should be included in the CGA:(and the scales to evaluate them): functional (Barthel Index, Lawton-Brody scale, gait speed), cognitive (Pfeiffer questionnaire), nutritional (Mini Nutritional Assessment - MNA), psychological/mood (Yesavage scale), social-familial (Gijon scale), comorbidity (Charlson index), medications, and geriatric syndromes (urinary and/or fecal incontinence, low auditory and/or visual acuity, presence of falls, pressure sores, insomnia, and abuse). Also by consensus, the CGA should be administered to older patients with cancer for whom there is a subsequent therapeutic intent and who scored positive on a previous frailty-screening questionnaire., Conclusion: After 3 rounds, consensus was reached regarding CGA domains to be used in older patients with cancer, the scales to be administered for each of these domains, as well as the timeline to be followed during consultation., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objective: Patients' psychological reactions to multigene cancer panel testing might differ compared with the single-gene testing reactions because of the complexity and uncertainty associated with the different possible results. Understanding patients' preferences and psychological impact of multigene panel testing is important to adapt the genetic counselling model., Methods: One hundred eighty-seven unrelated patients with clinical suspicion of hereditary cancer undergoing a 25-gene panel test completed questionnaires after pretest genetic counselling and at 1 week, 3 months, and 12 months after results to elicit their preferences regarding results disclosure and to measure their cancer worry and testing-specific distress and uncertainty., Results: A pathogenic variant was identified in 38 patients (34 high penetrance and 4 moderate penetrance variants), and 54 patients had at least one variant of uncertain significance. Overall, cancer panel testing was not associated with an increase in cancer worry after results disclosure (P value = .87). Twelve months after results, carriers of a moderate penetrance variant had higher distress and uncertainty scores compared with carriers of high penetrance variants. Cancer worry prior to genetic testing predicted genetic testing specific distress after results, especially at long term (P value <.001). Most of the patients reported the wish to know all genetic results., Conclusions: Our results suggest that patients can psychologically cope with cancer panel testing, but distress and uncertainty observed in carriers of moderate penetrance cancer variants in this cohort warrant further research., (Copyright © 2018 John Wiley & Sons, Ltd.)

The management of pancreatic ductal adenocarcinoma (PDAC) is a major public health concern worldwide. Currently, most PDAC patients are diagnosed in advanced stages. The signs and symptoms of the disease, except for jaundice, are non-specific. Thus, the current challenge is to identify earlier those individuals for whom specific screening tools and specific treatments would be beneficial. On the basis of the recommendations of the group of experts of multiple medical specialties of the GALLgo Project, the patients with PDAC should be managed by a multidisciplinary team to assess the personal and family history, the best diagnostic and staging procedures and consider all important aspects for treatment decisions. In this article, the group of experts proposes strategies to shorten the diagnosis times in PDAC patients.

Background: Pancreatic ductal adenocarcinoma (PDAC) is usually diagnosed in late adulthood; therefore, many patients suffer or have suffered from other diseases. Identifying disease patterns associated with PDAC risk may enable a better characterization of high-risk patients., Methods: Multimorbidity patterns (MPs) were assessed from 17 self-reported conditions using hierarchical clustering, principal component, and factor analyses in 1705 PDAC cases and 1084 controls from a European population. Their association with PDAC was evaluated using adjusted logistic regression models. Time since diagnosis of morbidities to PDAC diagnosis/recruitment was stratified into recent (<3 years) and long term (≥3 years). The MPs and PDAC genetic networks were explored with DisGeNET bioinformatics-tool which focuses on gene-diseases associations available in curated databases., Results: Three MPs were observed: gastric (heartburn, acid regurgitation, Helicobacter pylori infection, and ulcer), metabolic syndrome (obesity, type-2 diabetes, hypercholesterolemia, and hypertension), and atopic (nasal allergies, skin allergies, and asthma). Strong associations with PDAC were observed for ≥2 recently diagnosed gastric conditions [odds ratio (OR), 6.13; 95% confidence interval CI 3.01-12.5)] and for ≥3 recently diagnosed metabolic syndrome conditions (OR, 1.61; 95% CI 1.11-2.35). Atopic conditions were negatively associated with PDAC (high adherence score OR for tertile III, 0.45; 95% CI, 0.36-0.55). Combining type-2 diabetes with gastric MP resulted in higher PDAC risk for recent (OR, 7.89; 95% CI 3.9-16.1) and long-term diagnosed conditions (OR, 1.86; 95% CI 1.29-2.67). A common genetic basis between MPs and PDAC was observed in the bioinformatics analysis., Conclusions: Specific multimorbidities aggregate and associate with PDAC in a time-dependent manner. A better characterization of a high-risk population for PDAC may help in the early diagnosis of this cancer. The common genetic basis between MP and PDAC points to a mechanistic link between these conditions., (© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The management of prostate cancer in the elderly is a major public health concern in most countries. Currently, most prostate cancers are diagnosed in elderly males. The elderly population is very heterogeneous. Thus, the current challenge is to identify better those individuals for whom specific screening tools and a Comprehensive Geriatric Assessment (CGA) would be beneficial. On the basis of the recommendations of the Prostate Cancer Working Group in the International Society of Geriatric Oncology, older patients with prostate cancer should be managed according to their individual health status and not by their age. CGA is the best tool for determining the health status of an older patient. In this article, we sought to assemble all available evidence on the models of CGA and the prevalence of geriatric conditions in older patients with prostate cancer. We also discuss the feasibility of the most used screening tools in elderly patients, that is, the Vulnerable Elders Survey-13 (VES-13) and G-8 as screening tools in this group of patients.

The management of patients with pancreatic cancer has advanced over the last few years. We convey a multidisciplinary group of experts in an attempt to stablish practical guidelines for the diagnoses, staging and management of these patients. This paper summarizes the main conclusions of the working group. Patients with suspected pancreatic ductal adenocarcinoma should be rapidly evaluated and referred to high-volume centers. Multidisciplinary supervision is critical for proper diagnoses, staging and to frame a treatment plan. Surgical resection together with chemotherapy offers the highest chance for cure in early stage disease. Patients with advanced disease should be classified in treatment groups to guide systemic treatment. New chemotherapeutic regimens have resulted in improved survival. Symptomatic management is critical in this disease. Enrollment in a clinical trial is, in general, recommended.

Objectives: To develop a predictive model of toxicity to chemotherapy in elderly patients with cancer, using the variables associated with sarcopenia, and to identify which of these parameters, sarcopenia or frailty, is the best predictor of toxicity to chemotherapy in the elderly., Material and Methods: A prospective observational study with patients ≥70 years treated with chemotherapy in the Cancer Unit for the Elderly, in the Medical Oncology Section of the Hospital Virgen de la Luz de Cuenca. The following tests will be performed by each patient before chemotherapy: muscle strength (handgrip, cylindrical handgrip, pinch gauge, hip flexion, knee extension), muscle mass (skeletal muscle mass index), and physical function (gait speed and 5STS test). The occurrence of severe toxicity will be recorded over a period of 4 months of chemotherapy treatment. It will be evaluated, using logistic regression analysis, whether sarcopenia (defined by the European Working Group on Sarcopenia in Older People) or frailty (defined by the phenotype of frailty) is the best predictor of chemotherapy toxicity. Using a multinomial logistic regression analysis, we will try to create the first model to predict toxicity to chemotherapy in elderly patients with diagnosis of cancer, based on the definition of sarcopenia., Conclusions: It is expected that the final analysis of this project will be useful to detect predictive factors of toxicity to chemotherapy in elderly patients with cancer., (Copyright © 2016 SEGG. Publicado por Elsevier España, S.L.U. All rights reserved.)

Background: Gemcitabine and erlotinib have shown a survival benefit in the first-line setting in metastatic pancreatic cancer (mPC). The aim of this study was to assess whether combining capecitabine (C) with gemcitabine + erlotinib (GE) was safe and effective versus GE in patients with mPC., Patients and Methods: Previously untreated mPC patients were randomised to receive G (1000 mg/m 2 , days 1, 8, 15) + E (100 mg/day, days 1-28) + C (1660 mg/m 2 , days 1-21) or GE, q4 weeks, until progression or unacceptable toxicity. Primary end-point: progression-free survival (PFS); secondary end-points: overall survival (OS), response rate, relationship of rash with PFS/OS and safety., Results: 120 patients were randomised, median age 63 years, ECOG status 0/1/2 33%/58%/8%; median follow-up 16.5 months. Median PFS in the gemcitabine-erlotinib-capecitabine (GEC) and GE arms was 4.3 and 3.8 months, respectively (hazard ratio [HR]: 0.88, 95% confidence interval [CI]: 0.58-1.31; p = 0.52). Median OS in the GEC and GE arms was 6.8 and 7.7 months, respectively (HR: 1.09, 95% CI: 0.72-1.63; p = 0.69). Grade 3/4 neutropenia (GEC 43% versus GE 15%; p = 0.0008) and mucositis (GEC 9% versus GE 0%; p = 0.03) were the only statistically significant differences in grade 3/4 adverse events. PFS and OS were significantly longer in patients with rash (grade ≥1) versus no rash (grade = 0): PFS 5.5 versus 2.0 months (HR = 0.39, 95% CI: 0.26-0.6; p < 0.0001) and OS: 9.5 versus 4.0 months (HR = 0.51, 95% CI: 0.33-0.77; p = 0.0014)., Conclusion: PFS with GEC was not significantly different to that with GE in patients with mPC. Skin rash strongly predicted erlotinib efficacy. The study was registered with ClinicalTrials.gov: NCT01303029., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objective: Studies indicate an inverse association between ductal adenocarcinoma of the pancreas (PDAC) and nasal allergies. However, controversial findings are reported for the association with asthma. Understanding PDAC risk factors will help us to implement appropriate strategies to prevent, treat and diagnose this cancer. This study assessed and characterised the association between PDAC and asthma and corroborated existing reports regarding the association between allergies and PDAC risk., Design: Information about asthma and allergies was collated from 1297 PDAC cases and 1024 controls included in the PanGenEU case-control study. Associations between PDAC and atopic diseases were studied using multilevel logistic regression analysis. Meta-analyses of association studies on these diseases and PDAC risk were performed applying random-effects model., Results: Asthma was associated with lower risk of PDAC (OR 0.64, 95% CI 0.47 to 0.88), particularly long-standing asthma (>=17 years, OR 0.39, 95% CI 0.24 to 0.65). Meta-analysis of 10 case-control studies sustained our results (metaOR 0.73, 95% CI 0.59 to 0.89). Nasal allergies and related symptoms were associated with lower risk of PDAC (OR 0.66, 95% CI 0.52 to 0.83 and OR 0.59, 95% CI 0.46 to 0.77, respectively). These results were supported by a meta-analysis of nasal allergy studies (metaOR 0.6, 95% CI 0.5 to 0.72). Skin allergies were not associated with PDAC risk., Conclusions: This study shows a consistent inverse association between PDAC and asthma and nasal allergies, supporting the notion that atopic diseases are associated with reduced cancer risk. These results point to the involvement of immune and/or inflammatory factors that may either foster or restrain pancreas carcinogenesis warranting further research to understand the molecular mechanisms driving this association., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)