Large periampullary villous tumor of the duodenum

A 67-year-old woman, who had symptoms of epigastric pain and abdominal distension, was found, on endoscopy, to have a large sessile villous adenoma of the periampullary duodenum. Despite the lack of evidence of malignancy, a pancreaticoduodenectomy procedure was performed, mainly because of the tumor size and site, involving the ampulla of Vater. The presence of the carcinoma was diagnosed only in the resected specimen by definitive histology. Because there is no general consensus on the optimal surgical procedure for the treatment of villous tumors of the duodenum, especially for the early stages, the indications for the operative procedure are discussed, based on a review of the literature.     

Complex variant Philadelphia translocations involving the short arm of chromosome 6 in chronic myeloid leukemia

BACKGROUND AND OBJECTIVES: Around 5% of chronic myeloid leukemias (CML) are characterized by complex variant Philadelphia (Ph) translocations involving one or more chromosomal regions in addition to 9 and 22. The BCR/ABL1 fusion gene is usually found on der(22). The additional gene(s) involved in complex variant Ph rearrangements have not been characterized. DESIGN AND METHODS: We performed fluorescent in situ hybridization (FISH) in three complex variant Ph translocations involving the short arm of chromosome 6 in addition to 9 and 22. The BCR/ABL1 D-FISH probe was applied to localize the BCR/ABL1 fusion gene as well as the 5'ABL1 and the 3'BCR. Locus-specific probes were used to narrow the 6p breakpoint. RESULTS: In all cases the BCR/ABL1 fusion gene was located on the Ph chromosome whereas the reciprocal ABL1/BCR gene was detected only in patient #2. On 6p, breakpoints were narrowed to three different regions: centromeric to the human major histocompatibility complex (MHC), between PAC 524E15 and PAC162J16, in the first patient, and telomeric to the MHC, between PAC 329A5 and PAC 145H9, and between PAC 136B1 and PAC 206F19, in the second and third patients, respectively. In patients #2 and 3 a chromosomal rearrangement different from a true complex variant was discovered. In both cases, a classical t(9;22) was associated with an additional translocation involving the der(9)t(9;22). INTERPRETATION AND CONCLUSIONS: Rearrangements at 6p in complex Ph aberrations involve more than one gene/locus. Classical t(9;22), masked by additional chromosomal rearrangements, can resemble complex variant Ph translocations, and can be detected only using appropriate FISH probes.     

IL-1 is required for tumor invasiveness and angiogenesis

Here, we describe that microenvironmental IL-1 beta and, to a lesser extent, IL-1 alpha are required for in vivo angiogenesis and invasiveness of different tumor cells. In IL-1 beta knockout (KO) mice, local tumor or lung metastases of B16 melanoma cells were not observed compared with WT mice. Angiogenesis was assessed by the recruitment of blood vessel networks into Matrigel plugs containing B16 melanoma cells; vascularization of the plugs was present in WT mice, but was absent in IL-1 beta KO mice. The addition of exogenous IL-1 into B16-containing Matrigel plugs in IL-1 beta KO mice partially restored the angiogenic response. Moreover, the incorporation of IL-1 receptor antagonist to B16-containing plugs in WT mice inhibited the ingrowth of blood vessel networks into Matrigel plugs. In IL-1 alpha KO mice, local tumor development and induction of an angiogenic response in Matrigel plugs was less pronounced than in WT mice, but significantly higher than in IL-1 beta KO mice. These effects of host-derived IL-1 alpha and IL-1 beta were not restricted to the melanoma model, but were also observed in DA/3 mammary and prostate cancer cell models. In addition to the in vivo findings, IL-1 contributed to the production of vascular endothelial cell growth factor and tumor necrosis factor in cocultures of peritoneal macrophages and tumor cells. Host-derived IL-1 seems to control tumor angiogenesis and invasiveness. Furthermore, the anti-angiogenic effects of IL-1 receptor antagonist, shown here, suggest a possible therapeutic role in cancer, in addition to its current use in rheumatoid arthritis.     

Investigational therapies currently in Phase II clinical trials for the treatment of pelvic serous carcinomas

Introduction: Pelvic serous carcinomas (PSCs) are a controversial entity, which mostly comprise fallopian tube carcinoma (FTC), primary peritoneal carcinoma (PPC) and serous ovarian carcinoma (OC). Despite incremental attention towards understanding pelvic serous carcinogenesis, the gold standard treatment and survival rates have not substantially changed in these last decades.

Areas covered: This review summarizes and gives a critical overview of the ongoing Phase II trials investigating therapies for PSC.

Expert opinion: Several novel molecules have been developed and are currently under investigation for the treatment of PSC, including FTC, PPC and serous OC. The trend of novel targeted agents is one towards individualized, tailored therapy, based on the molecular and biological differences that characterize tumors that seem similar based solely on histological analysis. The task of developing new molecules is particularly difficult for PSC, given the recurrent development of new patterns of drug resistance. However, even if current research is focused towards identifying the best treatments for each woman with a molecularly defined disease, a deeper knowledge of the molecular biology and genetics underlying FTC and its relation as a precursor of PSC is needed.     

Effects of metformin on clinical outcome in diabetic patients with advanced HCC receiving sorafenib

Background and objective: Several studies have reported an association between type 2 diabetes mellitus and hepatocellular carcinoma (HCC). Data from several retrospective studies and meta-analyses have highlighted a reduction of about 50% in the risk of developing HCC in cirrhotic patients treated with metformin for diabetes. The aim of this study was to evaluate the different outcomes of patients who received or did not receive metformin during treatment with sorafenib.

Methods: We analyzed 93 patients consecutively treated with sorafenib. Forty-two (45.2%) patients were diabetic, of whom 31 were on metformin. Progression-free survival (PFS) and overall survival (OS) were estimated with the Kaplan-Meier method and compared with the log-rank test.

Results: The concomitant use of sorafenib and metformin was associated with a median PFS of 2.6 months (95% CI 1.9–3.3) compared to 5.0 months (95% CI 2.5–8.2) for patients receiving sorafenib alone (p = 0.029). The median OS of patients treated with the combination was 10.4 months (95% CI 3.9–14.4) compared to 15.1 months (95% CI 11.7–17.8) for those who were not given metformin (p = 0.014).

Conclusions: Our findings could be the result of increased tumor aggressiveness and resistance to sorafenib in metformin-treated patients.     

Asunaprevir for hepatitis C: a safety evaluation

Introduction: The introduction of direct-acting antiviral (DAA) agents has revolutionized the treatment of hepatitis C virus (HCV) chronic infection. Non-structural 3 protease inhibitors are currently the most numerous class of DAAs on the market.

Areas covered: This review mainly focuses on the tolerability and safety profile of asunaprevir (ASV)-containing DAA regimens. ASV is a second-wave protease inhibitor currently in Phase III clinical development in most countries and already available in Japan.

Expert opinion: ASV shows potent antiviral effect and clinical efficacy on HCV genotypes 1 and 4. The all-oral combination daclatasvir/ASV reached high eradication rates in HCV genotype 1b and 4 infection, and a lower efficacy in genotype 1a infection. ASV presents a low potential for drug–drug interaction and a good tolerability as part of multiple, including all-oral, regimens. ASV is associated with a transient and usually mild increase in aminotransferase levels in a low percentage of cases. Due to the impaired pharmacokinetic profile observed in advanced liver disease, ASV use in patients with moderate or severe hepatic impairment is not allowed. In conclusion, ASV represents a powerful weapon against HCV infection and has to be considered an optimal option as a component of genotype tailored interferon-free combinations.     

Novel de novo heterozygous loss-of-function variants in MED13L and further delineation of the MED13L haploinsufficiency syndrome

MED13L haploinsufficiency has recently been described as responsible for syndromic intellectual disability. We planned a search for causative gene variants in seven subjects with intellectual disability and overlapping dysmorphic facial features such as bulbous nasal tip, short mouth and straight eyebrows. We found two de novo frameshift variants in MED13L, consisting in single-nucleotide deletion (c.3765delC) and duplication (c.607dupT). A de novo nonsense variant (c.4420A>T) in MED13L was detected in a further subject in the course of routine whole-exome sequencing. By analyzing the clinical data of our patients along with those recently described in the literature, we confirm that there is a common, recognizable phenotype associated with MED13L haploinsufficiency, which includes intellectual disability and a distinctive facial appearance. Congenital heart diseases are found in some subjects with various degree of severity. Our observation of cleft palate, ataxia, epilepsy and childhood leukemia observed in single cases broadens the known clinical spectrum. Haploinsufficiency for MED13L should be considered in the differential diagnosis of the 1p36 microdeletion syndrome, due to overlapping dysmorphic facial features in some patients. The introduction of massive parallel-sequencing techniques into clinical practice is expected to allow for detection of other causative point variants in MED13L. Analysis of genomic data in connection with deep clinical evaluation of patients could elucidate genetic heterogeneity of the MED13L haploinsufficiency phenotype.     

Ghrelin does not mediate the somatotroph and corticotroph responses to the stimulatory effect of glucagon or insulin-induced hypoglycaemia in humans

OBJECTIVE: Acylated ghrelin, a gastric peptide, possesses a potent GH- but also significant ACTH/cortisol-releasing activity mediated by the activation of GH secretagogue receptors (GHS-R) at the hypothalamus-pituitary level. The physiological role of ghrelin in the control of somatotroph and corticotroph function is, however, largely unclear. Glucagon is known to induce a clear increase of GH, ACTH and cortisol levels in humans, at least after intramuscular administration. In fact, glucagon is considered to be a classical alternative to insulin-induced hypoglycaemia (ITT) for the combined evaluation of the function of GH and the hypothalamus-pituitary-adrenal (HPA) axis. We aimed to clarify whether ghrelin mediate the GH and corticotroph responses to intramuscular glucagon or ITT, which has recently been reported able to induce a surprising ghrelin decrease. SUBJECTS: To this aim we enrolled six normal young male subjects [age (mean +/- SD): 29.0 +/- 8.0 years, body mass index (BMI) 21.9 +/- 2.5 kg/m(2)]. DESIGN AND MEASUREMENTS: In all the subjects we studied ghrelin, GH, ACTH, cortisol and glucose levels after glucagon (GLU; 0.017 mg/kg intramuscularly), ITT (0.1 IU/kg insulin intravenously) or saline administration. RESULTS: Saline infusion was not followed by any significant variation in ghrelin, GH and glucose levels while ACTH and cortisol showed the expected spontaneous morning trend toward a decrease. GLU administration increased (P < 0.01) circulating GH, ACTH and cortisol as well as insulin and glucose levels. ITT induced an obvious increase (P < 0.01) of GH, ACTH and cortisol levels. The ITT-induced increases in GH and ACTH, but not cortisol, levels were higher (P < 0.01) than those after GLU. Circulating ghrelin levels were not modified by GLU. On the other hand, ghrelin levels underwent a transient reduction (P < 0.01) after insulin-induced hypoglycaemia. CONCLUSIONS: Ghrelin does not mediate the GH and ACTH responses to glucagon or to the ITT. In fact, ghrelin levels are not modified at all by glucagon and transiently decrease during the ITT. These findings support the assumption that ghrelin does not play a major role in the physiological control of somatotroph and corticotroph function.     

Weekly docetaxel versus CMF as adjuvant chemotherapy for elderly breast cancer patients: safety data from the multicentre phase 3 randomised ELDA trial

Within an ongoing multicentre phase 3 randomised trial (ELDA, cancertrials.gov ID: NCT00331097), early breast cancer patients, 65-79 years old, with average to high risk of recurrence, are randomly assigned to receive CMF (cyclophosphamide 600 mg/m2, methotrexate 40 mg/m2, fluorouracil 600 mg/m2, days 1-8) or docetaxel (35 mg/m2 days 1-8-15), every 4 weeks. Here we report an unplanned safety analysis prompted by an amendment introducing creatinine clearance as a tool to adjust methotrexate dose. Before such change, 101 patients with a median age of 70 were randomly assigned CMF (53 patients) or docetaxel (48 patients). At least one grades 3-4 toxic event of any type was reported in 40 (75.5%) and 19 (39.6%) patients with CMF and docetaxel, respectively (p=0.0002). Grades 3-4 hematological events were observed in 37 (69.8%) vs. 4 (8.3%) cases (p<0.0001) and grades 3-4 non-hematological toxicity in 12 (22.6%) vs. 15 (31.2%) patients (p=0.11), with CMF and docetaxel, respectively. A higher incidence of anemia, neutropenia, thrombocytopenia and febrile neutropenia was reported with CMF. Constipation, mucositis, nausea and vomiting were more common with CMF; diarrhoea, abdominal pain, dysgeusia, neuropathy and liver toxicity were more frequent with docetaxel. No significant interaction was found between the occurrence of severe toxicity and baseline variables, including creatinine clearance and geriatric activity scales. In conclusion, weekly docetaxel appears to be less toxic than CMF in terms of hematological toxicity.