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Pancreatic ductal adenocarcinoma (PDAC) harbouring germline BRCA1-2 pathogenic variants (gBRCA1-2pv) is a distinct nosological entity. Information on second-line therapy (2LT) outcome in this setting is lacking.Data of gBRCA1-2pv metastatic PDAC patients treated with chemotherapy were collected. A primary analysis of 2LT RECIST response, median progression-free survival (mPFSEighty-four gBRCA1-2pv metastatic PDAC patients were enrolled. The primary analysis, including 43 patients, highlighted a significant improvement of mPFSThis study highlighted the beneficial role of platinum agents in gBRCA1-2pv PDAC patients also in second-line treatment setting. However, our data suggest that early use of 3- and 4-drug platinum-based chemotherapy combinations provides a survival outcome advantage.

Kaplan-Meier curves of progression-free survival (A) and overall survival (B) in the discovery cohort population.

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Purpose:Pancreatic cancer is one of the most lethal solid tumors, mainly because of its intrinsic chemoresistance. We identified TAK1 as a central hub sustaining this resistance. Nanoliposomal irinotecan (nal-IRI) is a novel treatment for metastatic gemcitabine-refractory pancreatic cancer. We endeavored to identify circulating markers for TAK1 activation predicting chemoresistance in this setting.Experimental Design:In vivo activity of nal-IRI was validated in an orthotopic nude murine model expressing TAK1-specific shRNA. Plasma concentration of 20 different cytokines were measured by a multiplex xMAP/Luminex technology in patients prospectively enrolled to receive nal-IRI plus 5-fluorouracil/leucovorin (5-FU/LV). The optimal cutoff thresholds able to significantly predict patients' outcome were obtained on the basis of the maximization of the Youden's statistics.Results:Differential expression profiling revealed the gene coding for IL8 as the most significantly downregulated in shTAK1 pancreatic cancer cell lines. Mice bearing shTAK1 tumors had significantly lower plasma levels of IL8 and experienced a significant reduction in tumor growth if treated with nal-IRI, whereas those bearing TAK1-proficient tumors were resistant to this agent. In a discovery cohort of 77 patients, IL8 was the circulating factor most significantly correlated with survival (plasma levels lower vs higher than cutoff: mPFS 3.4 months vs 2.8 months; hazard ratio [HR], 2.55; 95% CI, 1.39–4.67; P = 0.0017; median overall survival 8.9 months vs 5.3 months; HR, 3.51; 95% CI, 0.84–6.68; P = 4.9e−05). These results were confirmed in a validation cohort of 50 patients.Conclusions:Our study identified IL8 as the most significant circulating factor for TAK1 pathway activation and candidates IL8 as a potential predictive biomarker of resistance to nal-IRI in gemcitabine-refractory patients with pancreatic cancer.

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Purpose: Pancreatic cancer is one of the most lethal solid tumors, mainly because of its intrinsic chemoresistance. We identified TAK1 as a central hub sustaining this resistance. Nanoliposomal irinotecan (nal-IRI) is a novel treatment for metastatic gemcitabine-refractory pancreatic cancer. We endeavored to identify circulating markers for TAK1 activation predicting chemoresistance in this setting. Experimental Design: In vivo activity of nal-IRI was validated in an orthotopic nude murine model expressing TAK1-specific shRNA. Plasma concentration of 20 different cytokines were measured by a multiplex xMAP/Luminex technology in patients prospectively enrolled to receive nal-IRI plus 5-fluorouracil/leucovorin (5-FU/LV). The optimal cutoff thresholds able to significantly predict patients' outcome were obtained on the basis of the maximization of the Youden's statistics. Results: Differential expression profiling revealed the gene coding for IL8 as the most significantly downregulated in shTAK1 pancreatic cancer cell lines. Mice bearing shTAK1 tumors had significantly lower plasma levels of IL8 and experienced a significant reduction in tumor growth if treated with nal-IRI, whereas those bearing TAK1-proficient tumors were resistant to this agent. In a discovery cohort of 77 patients, IL8 was the circulating factor most significantly correlated with survival (plasma levels lower vs higher than cutoff: mPFS 3.4 months vs 2.8 months; hazard ratio [HR], 2.55; 95% CI, 1.39–4.67; P = 0.0017; median overall survival 8.9 months vs 5.3 months; HR, 3.51; 95% CI, 0.84–6.68; P = 4.9e−05). These results were confirmed in a validation cohort of 50 patients. Conclusions: Our study identified IL8 as the most significant circulating factor for TAK1 pathway activation and candidates IL8 as a potential predictive biomarker of resistance to nal-IRI in gemcitabine-refractory patients with pancreatic cancer.

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.

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.

Background Pancreaticoduodenal cancer (PDC) is a group of malignant tumors arising in the ampullary region, which lack approved targeted therapies for their treatment. Methods This retrospective, observational study is based on Secondary Data Use (SDU) previously collected during a multicenter collaboration, which were subsequently entered into a predefined database and analyzed. FoundationOne CDx or Liquid, a next-generation DNA sequencing (NGS) service, was used to identify genomic alterations of patients who failed standard treatments. Detected alterations were described according to ESMO Scale of Clinical Actionability for molecular Targets (ESCAT). Results NGS analysis was performed in 68 patients affected by PDC. At least one alteration ranking tier I, II, III, or IV according to ESCAT classification was detected in 8, 1, 9, and 12 patients respectively (44.1%). Ten of them (33.3%) received a matched therapy. Patients with ESCAT tier I to IV were generally younger than the overall population (median = 54, range = 26–71 years), had an EGOG performance status score = 0 (83.3%), and an uncommon histological or clinical presentation. The most common mutations with clinical evidence of actionability (ESCAT tier I-III) involved genes of the RAF (10.3%), BRCA (5.9%) or FGFR pathways (5.9%). We present the activity of the RAF kinases inhibitor sorafenib in patients with RAF-mutated advanced PDC. Conclusions In advanced PDC, NGS is a feasible and valuable method for enabling precision oncology. This genomic profiling method might be considered after standard treatments failure, especially in young patients maintaining a good performance status, in order to detect potentially actionable mutations and offer molecularly targeted therapeutic approaches.

Objective Germline BRCA1-2 pathogenic variants (gBRCApv) increase the risk of pancreatic cancer and predict for response to platinating agents and poly(ADP-ribose) polymerase inhibitors. Data on worldwide gBRCApv incidence among pancreatic ductal adenocarcinoma (PDAC) patients are sparse and describe a remarkable geographic heterogeneity. The aim of this study is to analyze the epidemiology of gBRCApv in Italian patients. Materials and methods Patients of any age with pancreatic adenocarcinoma, screened within 3 months from diagnosis for gBRCApv in Italian oncologic centers systematically performing tests without any selection. For the purposes of our analysis, breast, ovarian, pancreas, and prostate cancer in a patient's family history was considered as potentially BRCA-associated. Patients or disease characteristics were examined using the χ2 test or Fisher's exact test for qualitative variables and the Student's t-test or Mann–Whitney test for continuous variables, as appropriate. Results Between June 2015 and May 2020, 939 patients were tested by 14 Italian centers; 492 (52%) males, median age 62 years (range 28-87), 569 (61%) metastatic, 273 (29%) with a family history of potentially BRCA-associated cancers. gBRCA1-2pv were found in 76 patients (8.1%; 9.1% in metastatic; 6.4% in non-metastatic). The gBRCA2/gBRCA1 ratio was 5.4 : 1. Patients with gBRCApv were younger compared with wild-type (59 versus 62 years, P = 0.01). The gBRCApv rate was 17.1% among patients 70 years old (none out of 94 patients >73 years old). gBRCApv frequency in 845 patients, Highlights • This is the largest case series of incident PDAC patients screened for germline BRCA1-2 pathologic variants (gBRCApv). • The incidence of gBRCA1-2pv was 8.1% in the whole population; 9.1% in metastatic patients; 6.4% in non-metastatic patients. • No gBRCA1-2pv was observed over the age of 73. • These data suggest screening all PDAC patients

Background: Up-front surgery followed by postoperative chemotherapy remains the standard paradigm for the treatment of patients with resectable pancreatic cancer. However, the risk for positive surgical margins, the poor recovery after surgery that often impairs postoperative treatment, and the common metastatic relapse limit the overall clinical outcomes achieved with this strategy. Polychemotherapeutic combinations are valid options for postoperative treatment in patients with good performance status. liposomal irinotecan (Nal-IRI) is a novel nanoliposome formulation of irinotecan that accumulates in tumor-associated macrophages improving the therapeutic index of irinotecan and has been approved for the treatment of patients with metastatic pancreatic cancer after progression under gemcitabine-based therapy. Thus, it remains of the outmost urgency to investigate introduction of the most novel agents, such as nal-IRI, in perioperative approaches aimed at increasing the long-term effectiveness of surgery. Methods: The nITRO trial is a phase II, single-arm, open-label study to assess the safety and the activity of nal-IRI with fluorouracil/leucovorin (5-FU/LV) and oxaliplatin in the perioperative treatment of patients with resectable pancreatic cancer. The primary tumor must be resectable with no involvement of the major arteries and no involvement or 2, oxaliplatin 60 mg/m2, leucovorin 200 mg/m2, and 5-fluorouracil 2400 mg/m2, days 1 and 15 of a 28-day cycle. The primary objective is to improve from 40% to 55% the proportion of patients achieving R0 resection after preoperative treatment. Discussion: The nITRO trial will contribute to strengthen the clinical evidence supporting perioperative strategies in resectable pancreatic cancer patients. Moreover, this study represents a unique opportunity for translational analyses aimed to identify novel immune-related prognostic and predictive factors in this setting. Trial registration Clinicaltrial.gov : NCT03528785. Trial registration data: 1 January 2018 Protocol number: CRC 2017_01 EudraCT Number: 2017-000345-46

Background: On February 23rd the first case of SARS-CoV-2 infection was diagnosed at the University Hospital Trust of Verona, Italy On March 13th, the Oncology Section was converted into a 22 inpatient beds COVID unit and we had to reshape our organization and personnel to face the SARS-CoV-2 epidemic, while maintaining our oncological activity Methods: We tracked down oncological activity from January 1st to March 31st, 2020, in relationship to the organizational changes implemented and in comparison to the same period of 2019 We also recorded cases of SARS-CoV-2 infections observed in oncology health professionals and hospital admissions of active oncology patients for SARS-CoV-2 infection Results: Progressive restrictions in patients', visitors', and caregivers' access to the inpatient and outpatient facilities of the Oncology section and organizational changes were adopted early on during the epidemic peak Since March 13th, segregated personnel teams were created, one dedicated to the COVID unit and a "clean" one dedicated to oncological patients, resulting in an overall 40% and 43% reduction in oncology-dedicated medical and nursing/auxiliary staff, respectively As compared with the same trimester in 2019, the overall reduction in total numbers of inpatient admissions, chemotherapy administrations, and specialty visits in the period January-March 2020 was 8%, 6%, and 3%, respectively;based on the weekly average of daily accesses, reduction in some of the oncological activities became statistically significant from week 11 Patient's acceptance of adopted measures was very high (see abstract by Tregnago D) Overall, 8/85 (9%) health professionals tested positive for SARS-CoV-2 (no hospital admissions and no treatment required) and 7/525 (1 3%) active oncology patients were admitted for SARS-CoV-2 infection (of whom, 2 died of infection-related complications) Conclusions: A minimal (

Background: The health emergency caused by the SarS-Cov-2 pandemic has a strong impact on oncological patients' (pts) life. The purpose of this study is to explore the emotional impact and pts' perception experienced who accessed to our Oncology section at University Hospital and Trust of Verona (Italy) regarding these rules. Method(s): An questionnaire was designed by our Psycho-Oncology service and administered to all pts accessing to our outpatient facilities during a 21-days period (April 9th - April 30th, 2020). Two main areas were investigated: i) organizational aspects and ii) awareness about infection risks, protective strategies, and new rules adopted (14 items, plus demographic data). Percentage of relevant answers to questionnaire items are reported with 95% confidence intervals (95% CI). Result(s): Among 241 respondents, fear of accessing hospital facilities and that chemotherapy treatment could increase the infection risk was reported to be quite high or high in 34% (95% CI: 29-41%) and 27% (95% CI: 21-33%), respectively. Awareness of disease-related risks of infection and strategies to reduce them was "very clear" or "fairly clear" [83% (95% CI: 78-88%) and 93% (95% CI: 90-96%), respectively]. Availability of medical personnel to be contacted while not in hospital was perceived as "very high". Almost all pts felt that organizational measures were clearly expressed (98%, 95% CI: 96-100%) and mainly obtained through the information received at the triage (73%, 95% CI: 67-79%). Overall acceptance of these measures was very high (>70%). Of note, the acceptance of phone-based follow-up and visits were perceived as "not very adequate" or "absolutely not adequate" by 17% (95% CI: 12-22 %) and 18% (95% CI: 13-23%) of respondents, respectively. Conclusion(s): Herein, we report among the first real-life experiences about oncological pts' perception of infection risks and their level of acceptance of protective measures during SarS-Cov-2 pandemic. A timely and thoughtful measures adoption, the coordinated efforts of all figures involved in cancer care and an effective communication strategy to share the necessary risks and sacrifices with pts/caregivers, can lead to effective protection of oncological pts. Legal entity responsible for the study: The authors. Funding(s): Has not received any funding. Disclosure: All authors have declared no conflicts of interest.Copyright © 2020

Background:Prognosis of patients affected by metastatic esophageal–gastric junction (EGJ) or gastric cancer (GC) remains dismal. Trastuzumab, an anti-HER2 monoclonal antibody, is the only targeted agent approved for the first-line treatment of patients with HER2-overexpressing advanced EGJ or GC in combination with chemotherapy. However, patients invariably become resistant during this treatment. We recently identified the overexpression of fibroblast growth factor (FGF) receptor 3 (FGFR3) as a molecular mechanism responsible for trastuzumab resistance in GC models, providing the rationale for the inhibition of this receptor as a potential second-line strategy in this disease. Pemigatinib is a selective, potent, oral inhibitor of FGFR1, 2, and 3.Methods:The FiGhTeR trial is a phase II, single-arm, open-label study to assess safety and activity of the FGFR inhibitor pemigatinib as second-line treatment strategy in metastatic EGJ/GC patients progressing under trastuzumab-containing therapies. The primary endpoint is the 12-week progression-free survival rate. Plasma and tumor tissue samples will be collected for translational research analyses at baseline, during treatment, and at progression on pemigatinib.Discussion:Co-alterations in genes coding for different tyrosine-kinase receptors are emerging as relevant mechanisms of acquired resistance to anti-HER2 therapeutic strategies in GC. In particular, our group has recently identified that in GC models the overexpression of FGFR3 sustains the acquired resistance to trastuzumab. This trial aims to assess the safety, tolerability and activity of the FGFR inhibitor pemigatinib as a second-line treatment in metastatic EGJ/GC patients refractory to first-line trastuzumab-containing therapies. Furthermore, this study offers the opportunity to prospectively study mechanisms and pathways involved in trastuzumab resistance.Protocol number:CRC2017_02EudraCT Number:2017-004522-14

Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease, whose main molecular trait is the MAPK pathway activation due toKRASmutation, which is present in 90% of cases.The genetic landscape ofKRASwild type PDAC can be divided into three categories. The first is represented by tumors with an activated MAPK pathway due toBRAFmutation that occur in up to 4% of cases. The second includes tumors with microsatellite instability (MSI) due to defective DNA mismatch repair (dMMR), which occurs in about 2% of cases, also featuring a high tumor mutational burden. The third category is represented by tumors with kinase fusion genes, which marks about 4% of cases. While therapeutic molecular targeting ofKRASis an unresolved challenge,KRAS-wild type PDACs have potential options for tailored treatments, includingBRAFantagonists and MAPK inhibitors for the first group, immunotherapy with anti-PD-1/PD-L1 agents for the MSI/dMMR group, and kinase inhibitors for the third group.This calls for a complementation of the histological diagnosis of PDAC with a routine determination ofKRASfollowed by a comprehensive molecular profiling ofKRAS-negative cases.

Pancreatic cancer is one of the most lethal solid tumors. In many European countries gemcitabine plus nab-paclitaxel is the preferred first-line treatment. An increasing number of patients are eligible for second-line therapy, but the best regimen is still controversial. This study aimed to evaluate the efficacy of oxaliplatin-based compared to irinotecan-based therapies in this setting. 181 advanced pancreatic cancer patients consecutively treated in three centers with a second-line therapy progressed on gemcitabine plus nab-paclitaxel were retrospectively enrolled. OS and PFS were calculated using the Kaplan-Meier method and survival of the two groups was compared using the log-rank test. The median PFS and OS were respectively 3.5 (95%CI 3.2&ndash, 3.8) and 8.8 months (95%CI 7.9&ndash, 9.8) from second-line therapy in the overall population. The median PFS and OS were respectively 3.3 (95%CI 3.1&ndash, 3.5) and 8.2 months (95%CI 7.24&ndash, 9.34) with an irinotecan-based combination compared to 4.0 (95%CI 2.4&ndash, 5.7) and 10.3 months (95%CI 8.62&ndash, 12.02) in patients receiving an oxaliplatin-based combination. We observed a clear trend for longer survival outcomes with platinum-based doublet compared to regimens including irinotecan or nal-IRI. Head-to-head trials are still lacking. The neutrophil-to-lymphocyte ratio and the presence of liver metastases could drive physicians in tailoring the treatment strategy.

Background PC remains one of the most lethal solid tumors, mainly because of its intrinsic chemoresistance. We recently identified TAK1 as a central hub integrating the most relevant signals sustaining PC chemoresistance. nal-IRI is a novel standard of care for metastatic PC patients who had beenpreviously treated with a gemcitabine-based therapy.We endeavoured to identify circulating markers for TAK1 activation predicting chemoresistance in this clinical setting. Methods In vivo activity of nal-IRI was validated in an orthotopic nude mouse model of PC cells expressing TAK1- specific shRNA or a scramble sequence as control. Using multiplex xMAP/Luminex technology,the samples from 77 metastatic PC patients progressing after gemcitabine and prospectively enrolled to receive nal-IRI + 5FU/LV were analysed for the plasma concentration of 20 different TH1and TH2cytokines.The optimal cut-off thresholds able to significantly predict patient outcome were obtained based on the maximization of the Youden index. Results A significant tumour volume reduction in mice bearing shTAK1 PCtreated with nal-IRIwas detected, whereas controls were resistant to this agent. Differential gene expression profiling revealed CXCL8 as the most significantly downregulated gene coding for secreted proteins in[Office1] shTAK1 PC cell lines. After a 27 month median follow-up, in the overall population the median progression-free survival (PFS) was 3.3 months (95% CI = 3.039-3.561) and the median overall survival (OS) was 7.3 months (95% CI = 5.487-9.113). Cox proportional hazard regression multivariate analysis confirmed CXCL8 as the circulating factor most significantly correlated with survival outcomes. Patients with CXCL8 higher than 16.68 pg/mL cut-off value had a PFS of 2.8 vs 3.4 months (HR = 2.61, 95% CI = 1.42-4.79, p = 0.0014), and an OS of 5.3 vs 8.9 months (HR = 3.7, 95% CI = 1.93-7.11, p = 2.6e-05), respectively. Conclusions We identified CXCL8 as the most significant circulating marker of TAK1 activation. Our study candidates CXCL8 as a potential predictive biomarker of resistance to nal-IRI in gemcitabine-refractory PC patients. Legal entity responsible for the study The authors. Funding Associazione Italiana per la Ricerca sul Cancro (AIRC). Disclosure D. Melisi: Advisory / Consultancy, Research grant / Funding (institution): Shire. All other authors have declared no conflicts of interest.

Preoperative chemo- and radiotherapeutic strategies followed by surgery are currently a standard approach for treating locally advanced gastric and esophagogastric junction cancer in Western countries. However, in a large number of cases, the tumor is extremely resistant to these treatments and the patients are exposed to unnecessary toxicity and delayed surgical therapy. The current clinical trials evaluating the combination of preoperative systemic therapies with modern targeted and immunotherapeutic agents represent a unique opportunity for identifying predictive biomarkers of response to select patients that would benefit the most from these treatments. However, it is of utmost importance that these potential biomarkers are corroborated by extensive preclinical and translational research. The aim of this review article is to present the most promising biomarkers of response to classic chemotherapeutic, anti-HER2, antiangiogenic, and immunotherapeutic agents that can be potentially useful for personalized preoperative systemic therapies in gastric cancer patients.

Cancer and obesity are the two major epidemics of the 21st century. Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of death, with a five-year overall survival rate of only 8%. Its incidence and mortality have increased in recent years, and this cancer type is expected to be among the top five leading causes of cancer-related death by 2030 in the United States (US). In the last three decades, the prevalence of overweight people has boosted with a consequent increase in obesity-related diseases. Considerable epidemiologic evidence correlates overweight and obese conditions to an increased risk of several types of cancer, including PDAC. Besides being a risk factor for multiple metabolic disorders, the tumor-promoting effects of obesity occur at the local level via inflammatory mediators that are associated with adipose inflammation and metabolic or hormones mediators and microbiota dysbiosis. Although an excess of body mass index (BMI) represents the second most modifiable risk factor for PDAC with an increased cancer related-death of more than 20–40%, still little is known about the molecular mechanisms that underlie this strong association. In this review, we focused on the role of obesity as a preventable risk factor of PDAC, discussing the molecular mechanisms linking obesity to cancer initiation and progression. Moreover, we highlighted the role of obesity in defining chemoresistance, showing how a high BMI can actually reduce response to chemotherapy.

To compare fetal biometric measurements with standard growth charts for ultrasound parameters existing from the last 30 years.A preliminary prospective study.Artemisia Mean Centre of Perinatal Diagnosis, Rome,Italy.A cross sectional study involving 1000 pregnant women with uncomplicated singleton pregnancy between 14(th) and 41(th) weeks of gestation from 1 January to 30 June 2008. All recruited pregnant women enrolled had an abdominal ultrasonography for fetal biometry. For each measurement, regression models were fitted to estimate the mean and SD. The results were compared with existing references from the last 30 years using Student's T distribution. Moreover, neonatal weights were obtained from 1977 to 2008 by ISTAT.One thousand normal fetuses from pregnant women, between 22(th) and 23(th) weeks, between 32(th) and 33(th) weeks and at 38(th) week, were thoroughly measured. THERE WERE SIGNIFICANT DIFFERENCES FROM THE COMPARISON WITH OUR DATA FOR EACH GESTATIONAL AGE: femur length and homer length, abdominal circumference, head circumference and occipitofrontal diameter were longer than all parameters of existing references from the last 30 years. The analysis of neonatal weights on ISTAT data from 1977 to 2007 demonstrated a significant increment through the years.Fetus is grown up across the years. It is necessary to modify the standard growth charts for ultrasound parameters existing from the last 30 years with actually fetal biometric measurements. It is helpful for a correct clinical approach and for an appropriate management mother-fetus.

Gestational Trophoblastic Disease (GTD) originates from placental tissue and is among the rare human tumors that can be cured even in the presence of widespread metastases. GTD include a spectrum of interrelated tumors including complete and partial hydatidiform mole, invasive mole, choriocarcinoma, and placental site trophoblastic tumor, that have different propensities for local invasion and spread. Although most GTD develop after a mole, they can follow any antecedent pregnancy.Transvaginal ultrasound, routinary dosage of beta-hCG and current approaches to chemotherapy, let most women with malignant gestational trophoblastic disease to be cured and their reproductive function preserved.

To consider all the historical reasons for the slow growth of colposcopy through a brief biography of Hinselmann. The history of colposcopy is beginning in March 1924. In the first experiments, colposcopic examination was almost impossible to perform because of the distance from the focus, that was no more than 80 mm. Hinselmann tried to solve this problem by pulling out the uterine cervix. The examined part is anemised by this procedure, which can prejudice the final result and a small amount of blood might leak as well. Beside that, a patient can feel pain if the portio is held by a thin forceps. The colposcopy, established in Germany, had spread throughout slowly its motherland, probably thanks to the many mistakes caused by Hinselmann himself: a technique proposed and almost exclusively intended for early discovery of cervical carcinoma;very authoritative imposition of terms, especially histological, which caused resistance by hystopathologists possibly induced by the fear of loosing their prestige who considered them too complex;his stubbornness in considering leukoplakia as precancerous lesion imposed him a lot of opponents;until the 1950's there had not yet been any adequate didactic material at the disposal of numerous gynaecologists;Hinselmann's temper, described by Wespi as a mixture of innocence and missionary eagerness, had not prepared him for dialogue and compromise.It might seem surprising that colposcopy, accurate in detecting all benign lesions and initial atypical transformations, and perfectly capable of pointing safe biopsy in cases of suspicious lesions, did not develop as it should have a method whose function is of great importance in the prevention and treatment of CIN. Despite the role and the importance of cytology in the realization of the population programme of cervical cancer detection, the colposcopy allows the precise diagnosis among women with abnormal pap smears.

Intracranial cysts are central nervous system malformations involving different brain regions, and commonly diagnosed during prenatal period by ultrasound scan (US). A malformative cyst is a nontumoral fluid-filled collection exerting a mass effect on the brain parenchyma and/or on the ventricles, regardless of its location within subarachnoid spaces, brain or ventricles, and of the nature of its limiting membrane, which is always unknown prenatally. Although a large number of case reports have been published, many uncertainties remain concerning their epidemiology, pathogenesis, and outcome. Most of these lesions, if not associated with other fetal anomalies, are benign in nature, remain clinically silent, do not evolve or even frequently regress spontaneously and do not impair physiologic neurodevelopment. The normality of the adjacent brain is the major argument in favour of a malformative lesion. The correct diagnosis is of crucial importance to exclude the presence of other rare lesions (e.g. cystic neoplasms or intracranial hemorrhage) that could negatively affect neurodevelopmental outcome of the child. To establish a correct prognosis all efforts must aim to precisely interpret the US images accurately analyzing the brain anatomy.

Pelvic dilatation is the alteration of the urinary tractmost frequently detected by maternal-fetalultra-sound. Hydronephrosis is not a diagnosis; it is an imagefinding. The diagnosis is the cause that produces it. Since pelvic dilatation is relatively frequent in thenormal fetus, and the definition and diagnosis of hy-dronephrosis are difficult, once it is detected, adequate follow-up is required. Therefore, it is important for the urologist and obstetrician to understanddifferential diagnosis and clinical implications in order to offer an accurate counselling to the parents.

Fetal ultrasonografy is the most important tool to provide prenatal diagnosis of fetal anomalies. The detection of limb abnormalities may be a complex problem if the correct diagnostic approch is not established. A careful description of the abnormality using the rigth nomenclature is the first step. Looking for other associated abnormalities is the threshold to suspect chromosomal abnormalities or single gene disorder. According to the patogenic point of view, limb abnormalities may be the result of malformation, deformation, or disruption. The prenatal diagnosis and the management of limb abnormalities involve a multidisciplinary team of ostetrician, radiologist/sonologist, clinical geneticist, neonatologist, and orthopedic surgeons to provide the parents with the information regarding etiology of the disorder, prognosis, option related to the pregnancy and recurrence risk for future pregnancies.The aim of this review is to describe the importance of detailed fetal ultrasonography in prenatal diagnosis of limb abnormalities.