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Introduction: About 90% of cholangiocarcinomas are adenocarcinomas with glandular or tubular structures lined by epithelial cells, with no bile production and with a variable degree of differentiation, arising in the background of desmoplastic stroma. The remaining 10% is represented by rarer histological variants of which there is little knowledge regarding the biological behavior, molecular characterization, and sensitivity to the various possible therapies, including molecular-based treatments. Such rare tumors are described only in case reports or small retrospective series because of their exclusion from clinical trials. This national initiative, here presented, aims to address the following knowledge gap: a) how much does histological diversity translate into clinical manifestation variety? b) are those chemotherapy regimens, recommended for conventional biliary tract cancers, potentially active in rare variants?Therefore, epidemiological, pathological, and clinical characterization of series of rare biliary histotypes/variants, for which therapeutic and follow-up data are available, will be collected., Methods: An Italian task force on rare tumors of the biliary tract (IRaBiCa) has been created, whose initiative is a multicenter retrospective study involving 34 Italian cancer centers.Clinical data from approximately 100 patients will be collected and analyzed. Continuous variables will be presented as median ± standard deviation, while categorical variables will be expressed in terms of frequency. Kaplan-Maier analyses will be used to compare disease free, progression free and overall survival, according to the different histotypes., Conclusions: We expect to gather novel data on rare histotypes of biliary tract cancer that will be useful to support their molecular and immunological characterization., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: LR reports consulting fees from AstraZeneca, Basilea, Bayer, BMS, Eisai, Exelixis, Genenta, Hengrui, Incyte, Ipsen, IQVIA, Jazz Pharmaceuticals, Lilly, MSD, Nerviano Medical Sciences, Roche, Servier, Taiho Oncology, Zymeworks; lecture fees from AstraZeneca, Bayer, Eisai, Gilead, Incyte, Ipsen, Merck Serono, Roche, Sanofi, Servier; travel expenses from AstraZeneca; research grants (to Institution) from Agios, AstraZeneca, BeiGene, Eisai, Exelixis, Fibrogen, Incyte, Ipsen, Lilly, MSD, Nerviano Medical Sciences, Roche, Zymeworks.NS reports consulting fees from MSD, Bristol Myers Squibb, GSK.MN:Travel expenses from AstraZeneca, speaker honorarium from Accademia della Medicina and Incyte; honoraria from Sandoz, Medpoint SRL, Incyte and Servier for editorial collaboration. Consultant honoraria from EMD Serono, Basilea Pharmaceutica, Incyte, MSD Italia, Servier, Astrazeneca and TaihoAll other authors have nothing to declare

Background: The combination of radiotherapy (RT) and programmed death 1 inhibitors seems to increase antitumor immune responses., Objective: To assess the outcome and the role of the best combination sequence, i.e. immunotherapy given before, during, and/or after RT, in patients with non-small cell lung cancer (NSCLC)., Methods: We conducted an observational, retrospective analysis of 95 consecutive patients with advanced NSCLC who received any radiotherapy treatment and nivolumab, as clinically indicated. Median overall survival (OS) and the 95% confidence interval (CI) were estimated with the Kaplan-Meier method. Cox model was used to obtain hazard ratio (HR) and associated 95% CI with statistical inference by log-rank statistic., Results: Median OS was 11.9 months (95% CI, 6.6-17.2). Patients who received radiotherapy during an immune checkpoint inhibitor treatment started more than 60 days before showed a better outcome than patients who started immunotherapy over 60 days after RT ending (HR, 2.90 [1.37-6.12], p = 0.005; median OS, 22.4 months vs 8.6 months, p = 0.005). Median progression-free survival was 6.3 months (95% CI, 4.6-8.0)., Conclusions: This study shows that combining irradiation with nivolumab for the treatment of advanced NSCLC leads to improved OS. The optimal time window for the combination of RT and immunotherapy seems to play a critical role for therapeutic antitumor response derived by abscopal effect.

Obesity, whose prevalence is pandemic and continuing to increase, is a major preventable and modifiable risk factor for diabetes and cardiovascular diseases, as well as for cancer. Furthermore, epidemiological studies have shown that obesity is a negative independent prognostic factor for several oncological outcomes, including overall and cancer-specific survival, for several site-specific cancers as well as for all cancers combined. Yet, a recently growing body of evidence suggests that sometimes overweight and obesity may associate with better outcomes, and that immunotherapy may show improved response among obese patients compared with patients with a normal weight. The so-called 'obesity paradox' has been reported in several advanced cancer as well as in other diseases, albeit the mechanisms behind this unexpected relationship are still not clear. Aim of this review is to explore the expected as well as the paradoxical relationship between obesity and cancer prognosis, with a particular emphasis on the effects of cancer therapies in obese people., (© 2020. Springer Science+Business Media, LLC, part of Springer Nature.)

The incidence of differentiated thyroid cancer has been increasing in the last decades all over the world. Such a steady growth cannot be entirely attributable to more intensive thyroid nodule screening and more sensitive diagnostic procedures. Several environmental factors have changed with sufficient rapidity in the same time frame and may represent credible candidates for this increase. They include modified iodine intake, lifestyle-associated risk factors, exposure to various toxic compounds, pollutants and xenobiotics, nutritional deficiencies, eating habits and comorbidities. Foremost, nutritional patterns have gained high interest as possible promoters and modifiable risk factors for thyroid cancer in recent years. The aim of this narrative review is to focus on the relationship between thyroid cancer and nutritional factors, dietary habits and obesity. Low iodine intake has been associated to increased risk of thyroid cancer, favoring the development of more aggressive histotypes. Moreover, correction of iodine deficiency can shift thyroid cancer subtypes toward less aggressive forms, without affecting the overall risk for cancer. Actually, evidence regarding the association between selenium and vitamin D deficiency and thyroid cancer is very limited, despite their well-known anti-cancer potentials, and the clinical usefulness of their supplementation is still uncertain in this setting. Albeit the relationship between single foods and thyroid cancer is difficult to examine, fish and iodine-rich foods, vegetables, and fruits might exert protective effects on thyroid cancer risk. Conversely, no clear association has been found for other foods to date. Lastly, a clear association between obesity and the risk of thyroid cancer, with more aggressive behavior, seems to emerge from most studies, likely involving variations in thyroid function and chronic inflammation mediated by cytokines, insulin, leptin and adiponectins. Although no definite association between dietary factors and thyroid cancer has been firmly established so far, some nutritional patterns, together with excessive weight, seem to play a relevant role in thyroid cancer carcinogenesis as well as in its severity and aggressiveness. These effects may play an additive role to the well-established one exerted by environmental carcinogens, such as pollutants and radiation exposure.

There are demonstrations that the prognosis of patients with isolated pulmonary dissemination of pancreatic cancer is more favorable than that of patients with other patterns of disease progression. The aim of this systematic review with meta-analysis was to evaluate the oncological outcomes of pulmonary vs. non-pulmonary metastasis of patients with pancreatic cancer. A total of 11 916 patients with secondary spread of pancreatic cancer were included from 15 primary reports. In the setting of single-organ disease dissemination, the lung demonstrated a significant survival advantage over hepatic, locoregional, or peritoneal localization. In particular, patients who recurred in the lung after pancreatectomy, showed a significant survival benefit as compared to those patients with hepatic and locoregional relapse in terms of disease-free survival, survival after recurrence and overall survival., (Copyright © 2020 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Data on the association between aspirin and statin use and Pancreatic Ductal AdenoCarcinoma (PDAC) risk are conflicting. These drugs are often co-prescribed, but no studies evaluated the potential combined or confounding effect of the two at the same time. We aimed to investigate the association between aspirin and statin exclusive and combined use and PDAC occurrence. Data on environmental factors, family and medical history were screened in a case-control study. PDAC cases were matched to controls for age and gender. Power calculation performed ahead. Odds ratios (OR) and 95% confidence intervals(CI) were obtained from multivariable logistic regression analysis. In 408 PDAC patients and 816 matched controls, overall statin (OR 0.61; 95%CI,0.43-0.88), but not aspirin use was associated to reduced PDAC risk. Compared to non-users, exclusive statin (OR 0.51; 95%CI,0.32-0.80) and exclusive aspirin users (OR 0.64; 95%CI,0.40-1.01) had reduced PDAC risk. Concomitant statin and aspirin use did not further reduce the risk compared with statin use alone and no interaction was evident. Statin protective association was dose-dependent, and consistent in most subgroups, being stronger in smokers, elderly, obese and non-diabetic patients. The present study suggests that statin use is associated to reduced PDAC risk, supporting a chemopreventive action of statins on PDAC.

Different inflammation-based scores such as the neutrophil/lymphocyte ratio (NLR), the Odonera Prognostic Nutritional Index (PNI), the Glasgow Prognostic Score, the platelet/lymphocyte ratio, and the C-reactive protein/albumin ratio have been found to be significantly associated with pancreatic cancer (PDAC) prognosis. However, most studies have investigated patients undergoing surgery, and few of them have compared these scores. We aimed at evaluating the association between inflammatory-based scores and PDAC prognosis. In a single center cohort study, inflammatory-based scores were assessed at diagnosis and their prognostic relevance as well as that of clinic-pathological variables were evaluated through multiple logistic regression and survival probability analysis. In 206 patients, age, male sex, tumor size, presence of distant metastasis, access to chemotherapy, and an NLR > 5 but not other scores were associated with overall survival (OS) at multivariate analysis. Patients with an NLR < 5 had a median survival of 12 months compared to 4 months in those with an NLR > 5. In the 81 patients with distant metastasis at diagnosis, an NLR > 5 resulted in the only variable significantly associated with survival. Among patients with metastatic disease who received chemotherapy, the median survival was 3 months in patients with an NLR > 5 and 7 months in those with an NLR < 5. The NLR might drive therapeutic options in PDAC patients, especially in the setting of metastatic disease.

Low doses of drugs delivered at close, regular intervals are increasingly being used to manage patients with different neoplasms. Despite the good tolerability, treatment-related adverse events still occur following metronomic protocols. The aim of this study was to retrospectively investigate whether polymorphisms of different genes involved in fluoropyrimidine metabolism and 5-fluorouracil (5-FU) degradation rate were associated with the outcome of a low-dose capecitabine schedule. Genotyping of DPYD IVS14+1 G>A, MTHFR C677T, and A1298C single-nucleotide polymorphisms was performed by pyrosequencing technology. A PCR technique was used for genotyping TYMS-TSER. Using peripheral blood mononuclear cells, we also evaluated the 5-FU degradation rate, which determines the net result of all the enzymatic transformation of 5-FU, in terms of the amount of drug consumed by the cells in a time unit. The association of these variables with clinical outcome was evaluated using multivariate logistic regression analysis. Eighty-four patients with metastatic gastrointestinal cancer, who had been treated with a low-dose fluoropyrimidine schedule, as a rescue therapy were included in the study. The TSER 2R/2R genotype was significantly associated with both hematologic (odds ratio=7.90, P=0.002) and gastrointestinal toxicity (odds ratio=3.24, P=0.009). Because DPYD IVS14 G>A single-nucleotide polymorphism was not observed in the cohort, it was excluded from the statistical analysis. No significant association was detected between clinical outcome and both MTHFR polymorphisms and the 5-FU degradation rate. In the advanced setting of cancer care, high attention should be paid toward avoiding toxicity and worsening of quality of life. Although metronomic chemotherapy is generally well tolerated, treatment toxicity nonetheless does occur. Our data suggest a possible role of the TSER 2R/2R polymorphism as a predictive marker of toxicity in patients treated with low-dose capecitabine.

In recent years, metronomic chemotherapy, consisting of continuous administration of low doses of cytotoxic agents, has being used as rescue therapy for different tumours. The aim of this study was to retrospectively assess the efficacy and safety of low-dose metronomic, oral capecitabine in pretreated or frail patients with recurrent upper gastrointestinal tract cancer. Patients with pretreated upper gastrointestinal tract cancer or who were not candidates for standard chemotherapy because of toxicity concerns received capecitabine at 1500 mg per day continuously until disease progression or occurrence of toxicity. Forty-seven patients (25 oesophagogastric cancer, 22 pancreatobiliary cancer; 25 men, 22 women; median age 69 years, range 42-90) were included in the study. Forty-five percent of the patients had received at least two previous lines of treatment and the median number of previous treatments was 1 (range 0-5). Twelve (31.6%) patients achieved clinical benefit (one partial response, 11 stable disease), whereas nine (23.7%) patients were progression free for at least 6 months. In an exploratory analysis, there was a significant relationship between performance status and clinical benefit (hazard ratio=8.25; P=0.01). The median overall survival was 5 months. A good performance status was associated with a longer survival (hazard ratio=0.26; P<0.01). No severe toxicity or treatment-related death was reported. Metronomic capecitabine showed good safety and moderate activity in frail or pretreated patients with advanced, upper gastrointestinal tract cancer.

The aim of the study was to retrospectively assess the efficacy and safety of low-dose metronomic oral capecitabine in pretreated or frail patients with recurrent colorectal cancer. Patients with recurrent colorectal cancer and prior treatment with fluoropyrimidines, oxaliplatin, and irinotecan or unable to receive standard chemotherapy because of toxicity concerns were included. Treatment consisted of oral capecitabine 1,500 mg daily until disease progression or unacceptable toxicity. Response rates were determined according to RECIST criteria. The end points were disease control rate [(DCR) consisting of complete response, partial response (PR), and stable disease (SD)], overall survival (OS), and safety. Sixty-eight patients, median age 72.5 years, were treated. The median number of previous treatments was 2 (range 0-5). Sixty-two percent of patients had received ≥2 previous lines of treatment. The overall DCR was 26%, PR in 2 (3%) and SD in 14 (23%). Nineteen percent of patients were progression free for at least 6 months. In an exploratory analysis, there was a significant relation of performance status with DCR (HR = 3.3; P = 0.05). The median OS was 8 months. DCR was associated with a longer survival (HR = 0.4; P < 0.01). Grade 3 toxicities included anemia (1), diarrhea (1), and hand-foot syndrome (1). There were no cases of grade 4 toxicity or treatment-related deaths. Metronomic capecitabine was moderately active and well-tolerated in pretreated or frail patients with recurrent colorectal cancer.

Background: About 10% of pancreatic cancer patients are aged ≤50 at diagnosis and defined as Early Onset Pancreatic Cancer (EOPC). There is limited information regarding risk factors for EOPC occurrence and their outcome., Aim: To investigate risk factors, presentation features and outcome of EOPC patients., Methods: Consecutive, histologically confirmed, pancreatic cancer patients enrolled. Data regarding environmental and genetic risk factors, clinical and pathological information, treatment and survival were recorded. EOPC patients (aged ≤50 at diagnosis) were compared to older subjects., Results: Twenty-five of 293 patients (8.5%) had EOPC. There was no difference regarding sex distribution, medical conditions and alcohol intake between EOPC and older subjects. EOPC patients were more frequently current smokers (56% vs 28% p = 0.001) and started smoking at a significantly lower mean age (19.8 years, 95%CI 16.7-22.9) as compared to older patients (26.1, 95%CI 24.2-28) (p = 0.001). Current smoking (OR 7.5; 95%CI 1.8-30; p = 0.004) and age at smoking initiation (OR 0.8 for every increasing year; 95%CI 0.7-0.9; p = 0.01) were significant and independent risk factors for diagnosis of EOPC. There were no differences regarding genetic syndromes and pancreatic cancer family history. EOCP presented less frequently with jaundice (16% vs 44%, p = 0.006) and had a higher rate of unresectable disease, albeit not significantly (84% vs 68%, p = 0.1). EOPC patients were more frequently fit for surgery or chemotherapy than their counterpart, resulting in similar stage-specific survival probability., Conclusion: EOPC seems related to active and early smoking but not to familial syndromes. Young patients display aggressive disease but not worse outcome., (Copyright © 2015 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Data on the potential of circulating tumor cells (CTC) count in predicting overall survival (OS) in patients with colorectal cancer are timely and worthy of interest. This study aimed to evaluate the prognostic role of CTC count in both localized and metastatic colorectal cancer patients., Methods: Consecutive patients with histological diagnosis of colorectal cancer were enrolled. CTC count was performed, by using a quantitative immunofluorescence method, at baseline (T0) and 1 month following start of chemotherapy (T1). A CTC count <2 was considered negative, whilst a CTC level >/= 2 was positive. Overall survival was calculated accordingly., Results: A total of 75 colorectal cancer patients were enrolled, including 54 stages I-III and 21 stage IV patients. Overall, 21 (28%) patients had a positive CTC count at baseline, and it was significantly associated with a worse prognosis as compared to a negative status (OS: 36.2 vs. 61.6 months; P = 0.002). CTC count remained positive after chemotherapy in 22.4% of the patients and it was an independent prognostic factor of OS (P = 0.03; Hazard Ratio: 3.55; 95% CI: 1.1-11.5)., Conclusions: This study found that the presence of CTCs is associated with a reduced survival in colorectal cancer patients. Further studies aimed at testing such a predictive value in early stage colorectal cancer are awaited.

Purpose: Over the past few years, more and more new selective molecules directed against specific cellular targets have become available for cancer therapy, leading to impressive improvements. In this evolving scenario, a new way of delivering older cytotoxic drugs has also been developing. Many studies demonstrated that several cytotoxic drugs have antiangiogenic properties if administered frequently and at lower doses compared with standard schedules containing maximal tolerated doses (MTD). Such a new strategy, named metronomic chemotherapy, focuses on a different target: the slowly proliferating tumour endothelial cells. About 10 years ago, metronomic chemotherapy was firstly enunciated and hereafter many clinical experiences were published related to almost any cancer disease. This review analyses available studies dealing with metronomic chemotherapy and its combination with several targeted agents in solid tumours., Methods: A computerized literature search of MEDLINE was performed using the following search terms: metronomic OR "continuous low dose" AND chemotherapy AND cancer OR solid tumours., Results: Satisfactory results have been achieved in diverse tumour types, such as breast and prostate cancer or paediatric sarcomas. Moreover, many studies have reported that metronomic chemotherapy determined minimal toxicity compared to MTD chemotherapy. Overall, published series on metronomic schedules are very heterogeneous often reporting on retrospective data, while only very few studies were randomized trials. These limitations still prevent to draw definitive conclusions in diverse tumour types., Conclusions: Large well-designed studies are eagerly awaited for confirming the promises of metronomic schedules and their combinations with targeted molecules.

Background: Current international guidelines on colorectal cancer (CRC) treatment suggest performing adjuvant chemotherapy only in Stage II patients presenting with high-risk prognostic factors. Aim of the study was to a the impact of these parameters on the survival of Stage IIa CRC patients, focusing on the prognostic value of the number of harvested lymph nodes (NHLN)., Patients and Methods: Out of 651 CRC patients undergoing surgical resection, 204 T3-N0-M0 were selected and reviewed. Univariate and multivariate survival analyses were adapted for the evaluation of the prognostic factors., Results: The 5 years actuarial DFS, DSS, and OS rates of patients with a NHLN >12 were significantly better compared to those of patients with a NHLN <12 (respectively: 72.8% vs. 50.4% P=0.001; 82% vs. 56% P=0.001; 78.5% vs. 53.1% P=0.001). Multivariate analysis revealed that a NHLN >12 was the only independent parameter of statistical significance influencing DFS, DSS, and OS., Conclusions: According to our findings, the NHLN is the main predictor of survival in Stage IIa CRC patients. This would appear to suggest the need of a better stratification of Stage IIa CRC patients, sub-dividing patients with more or less than 12 NHLN., (Copyright © 2012 Wiley Periodicals, Inc.)

Aim: The effect of KRAS status on response to bevacizumab plus chemotherapy in metastatic colorectal cancer is still unclear. We aimed to evaluate the overall clinical response to such a therapy in clinical practice and assess the role of KRAS status on therapy response., Patients & Methods: This was a retrospective study enrolling 108 metastatic colorectal cancer patients. KRAS mutation analysis was performed by PCR., Results: Overall, 41.7% of patients had stable disease, 39.8% a partial response, 3.7% a complete response and 14.8% disease progression. Both clinical benefit and objective response rate tended to be higher in patients with only hepatic metastases than those with extrahepatic or multiple metastases. Response to therapy would appear to be independent of KRAS status, but larger studies are needed., Conclusion: Bevacizumab plus chemotherapy provides clinical benefit and objective response rate in patients with metastatic colorectal cancer independently of KRAS expression, especially in those patients with only liver metastases.

Background: The biliary tract carcinomas rank fifth in incidence among all gastrointestinal tumours. This group of tumours includes both cholangiocarcinoma and gallbladder carcinoma. Although surgery represents the main therapeutic option for these patients, both radiotherapy and chemotherapy could be used in a multidisciplinary approach. Several studies are currently available on the use of chemotherapy, including 5-fluorouracil, mitomycin C, methotrexate, doxorubicin and cisplatin or newer anticancer molecules, such as gemcitabine, capecitabine, oxaliplatin and irinotecan. However, the small sample size of most of these studies prevents generalization., Discussion: We reviewed the available data on both chemotherapy and targeted therapies for biliary carcinoma. By using conventional chemotherapy, a response rate ranging from 10% to 40% has been reported. Although encouraging data emerged with the use of targeted therapies, further efforts are needed to improve treatment options for patients with biliary tract cancer.

Carcinomas of the Ampulla of Vater are rare tumors, accounting for 0.2% of gastrointestinal cancers. Compared with other biliary tract neoplasms, these tumors have a relatively favorable prognosis after surgical resection. Based on their epithelium of origin, two subtypes of ampullary carcinoma have been recently distinguished: intestinal and pancreatobiliary. This study evaluates histopathological features and outcomes of ampullary carcinoma and to compares the survival of these tumors to that of other biliary tract tumors. The chemotherapic options available for ampullary cancer are also reviewed. We analyzed data from 20 consecutive patients with ampullary carcinomas and 26 patients with other biliary tract carcinomas, observed in our Institution. Statistical analysis was performed by using either Fisher's exact test or χ(2) test for categorical variables. Median time of survival was calculated and compared using the Log-Rank test. Similar distribution of demographic characteristics and stage between ampullary and other biliary tract cancers was observed. Patients with ampullary cancer underwent surgery more frequently than other biliary cancers while chemotherapy and radiotherapy were used equally. In accordance with the literature, a longer median survival was observed in the group of ampullary carcinomas.

Some authors have suggested that intraductal papillary mucinous neoplasms of the bile duct (IPMN-B) could be the the biliary counterpart of IPMN of the pancreas (IPMN-P) since they share several clinical-pathological features. These include prominent intraductal papillary proliferation pattern, a gastrointestinal phenotype, frequent mucin hyper-secretion and progression to mucinous carcinoma. To date there are just four reported cases of patients with synchronous IPMN-B and IPMN-P all of which were treated surgically. We hereby report the case of a 76-year-old woman who was incidentally diagnosed with both an asymptomatic 3 cm bulky fluid lesion obstructing the bile duct lumen, diagnosed as a malignant IPMN-B, and synchronous multiple pancreatic cystic lesions (10-13 mm) communicating with an irregular Wirsung, diagnosed as branch duct IPMN-P. Since surgery was ruled-out because of the patient's age and preferences, she underwent a conservative management regimen comprising both chemotherapy and radiotherapy. This was effective in decreasing the mass size and in resolving subsequent jaundice. This is also the first reported case of IPMN-B successfully treated with chemoradiotherapy. Clinicians should consider medical treatment as an option in this clinical scenario, in patients who may be unfit for surgery.

Background: A possible anticancer role for somatostatin has been suggested. This study assessed the presence of somatostatin receptor subtype 2A (SSTR2A) in gastric cancer, correlating its expression with histological type, grade, human epidermal growth factor receptor 2 (HER2) expression, and disease outcome., Materials and Methods: Gastric cancer tissues of 51 consecutive patients were collected for immunohistochemical assessment of both SSTR2A and HER2 expression., Results: SSTR2A expression was observed in 38 (74.5%) cases. Prevalence of SSTR2A expression was significantly higher in well to moderately (G1-2) differentiated gastric cancer as compared to poorly (G3) differentiated tumors (96% vs. 52%; p<0.01), as well as in intestinal- than in diffuse-type cancer (97% vs. 20%; p<0.001). HER2 expression was positive in 18 (35%) patients, and it was associated with SSTR2A expression (r=0.50, p<0.001), being co-expressed in 17 (95%) out of 18 positive cases. RFS was significantly lower in patients with diffuse HER2 expression., Conclusion: This study demonstrated a co-localization between SSTR2A and HER2, potentially opening new therapeutic strategies for patients with gastric cancer.

Although the remarkable efficacy of biological therapy has resulted in significant success in inflammatory bowel disease (IBD) management, susceptibility to infections remains a concern. The biological agents include the tumor necrosis factor-alpha (TNF-alpha) inhibitors, for instance infliximab, and other immunomodulating agents, such as natalizumab. Progressive multifocal leukoencephalopathy (PML), a rare but mostly fatal opportunistic brain infection caused by reactivation of the human polyomavirus JC virus (JCV), has been found in two patients with multiple sclerosis and one patient with Crohn's disease (CD), linked to treatment with natalizumab. After these cases of PML, the commercial and investigational use of natalizumab was suspended in February 2005 but was subsequently resumed for multiple sclerosis and for CD, only through a special restricted distribution program. This review, starting from an extensive literature search by the PubMed database, resumes the clinical aspects and pathophysiology of CD and focuses on the biologics in current use in CD (infliximab, adalimumab, and natalizumab), in order to provide a reference and gateway to prevention, recognition, and management of JCV, in the early years of biological agents therapy. It also proposed to provide an overview on the hypothetical mechanism of reactivation of JC virus related to the use of these drugs.

Hemorrhagic cystitis is characterized by hematuria due to inflammation of the bladder. In bone marrow transplants, this disease is linked to the infection by human polyomavirus BK, whereas the role of the human polyomavirus JC is unclear. The transcriptional control regions of both viruses contain important cellular transcription factor binding sites that undergo rearrangement process generating suitable variants that could be more active for viral replication and for the onset of hemorrhagic cystitis. In this study urine obtained from seven patients with bone marrow transplant were examined. Polyomavirus genomes were quantified by PCR and viral loads were compared. The transcriptional regions of both viruses were amplified and sequenced to determine the presence of variants. Subtypes of polyomaviruses were determined by amplification and sequencing of the viral protein 1 region. The results showed that four of seven patients were positive for BK DNA, two of seven patients had BK and JC DNA and one of seven had JC DNA. Positive samples were amplified and sequenced successively for transcriptional regions. The viral archetype was always found in both viruses. Finally, typing showed that BK virus subtype I infected patients with BK, whereas JC virus genotype IA and genotype 1B were found in patients infected with JC. The data suggest that new and different approaches are required to improve the morbidity and mortality caused by polyoma-associated hemorrhagic cystitis, since it known that BK virus is involved in the onset of hemorrhagic cystitis, whereas the role of JC virus should be investigated further., ((c) 2009 Wiley-Liss, Inc.)

Herpes simplex virus (HSV) infection is one of the most common viral sexually transmitted diseases worldwide. The first time infection of the mother may lead to severe illness in pregnancy and may be associated with virus transmission from mother to foetus/newborn. Since the incidence of this sexually transmitted infection continues to rise and because the greatest incidence of herpes simplex virus infections occur in women of reproductive age, the risk of maternal transmission of the virus to the foetus or neonate has become a major health concern. On these purposes the Authors of this review looked for the medical literature and pertinent publications to define the status of art regarding the epidemiology, the diagnosis, the therapy and the prevention of HSV in pregnant women and neonate. Special emphasis is placed upon the importance of genital herpes simplex virus infection in pregnancy and on the its prevention to avoid neonatal HSV infections.