Outcome in ulcerative colitis after switch from adalimumab/golimumab to infliximab: A multicenter retrospective study

Background

Anti-TNF therapies infliximab (IFX), adalimumab (ADA), and golimumab (GOL) are approved for treating moderate to severe ulcerative colitis (UC). In UC, only the switch from IFX to ADA has been investigated, reaching no more than 10–43% remission rates at 12 months.

Poorly differentiated small cell neuroendocrine carcinoma localized in three different endocrine glands: response to chemotherapy and octreotide LAR

Neuroendocrine tumors represent a heterogeneous category of neoplasm, with conflicting diagnostic and therapeutic demands. We here describe the case of a 72-yr-old woman with evidence of a poorly differentiated small-cell neuroendocrine carcinoma (NEC) localized in different endocrine glands and other non-endocrine organs. In particular, a large ovarian mass, multinodular thyroid goiter, right adrenal mass, cystic liver metastases and anterior mediastinum lymph node metastasis were present. The largest thyroid nodule caused tracheal restriction and dyspnea. Diagnosis of poorly differentiated metastasized NEC of unknown origin was made on the basis of histological and immunohistochemical findings, and treatment with etoposide (100 mg/m2 in days 1, 2 and 3) and cisplatinum (45 mg/m2 in days 2 and 3) was initiated. Simultaneously, im administration of octreotide LAR 20 mg every 28 days was started, according to the presence of SS receptors at 111In-octreotide scan. Rapid improvement of dyspnea and a reduction of the largest thyroid nodule, liver metastases and adrenal mass by 50% were observed after 3 months of treatment; the dimensions remained stable thereafter, while the pericardial lymph node disappeared. In conclusion, poorly differentiated NEC of unknown primary site is a well-recognized category, usually with an aggressive behavior, rapid growth rate and wide dissemination. Median survival of these patients is 6 months if left untreated. Our patient is alive 18 months after beginning the treatment, reporting good general condition and quality of life over the whole follow-up period.     

Tacrolimus plus mycophenolate mofetil vs. cyclosporine plus everolimus in deceased donor kidney transplant recipients: three‐yr results of a single‐center prospective clinical trial

We compared in kidney transplantation two immunosuppressive regimens: tacrolimus plus mycophenolate mofetil (MMF) (TAC) and everolimus plus low‐dose cyclosporine (EVE). Sixty consecutive patients received TAC (30 patients) or EVE (30 patients) as immunosuppressive regimen; all subjects also received induction with basiliximab and corticosteroids. After three‐yr follow‐up, no difference was found in patient and graft survival (PTS: TAC: 97% vs. EVE: 100%; GS: TAC: 93% vs. EVE: 93%). The incidence of acute rejection was higher in the EVE group but the difference was not statistically significant (17% vs. 23%, p = ns). Patients in EVE showed higher serum cholesterol (205 ± 41 vs. 235 ± 41 mg/dL, p = 0.0012) and lower hemoglobin concentration (13.6 ± 1.4 vs. 12.4 ± 1.9, p = 0.01). Renal function was not significantly different in the two groups (3 Y creatinine: TAC 1.4 ± 0.8 vs. EVE 1.6 ± 0.8 mg/dL, p = ns). Treatment discontinuation was higher in the EVE group (TAC 17 vs. EVE 36%, p = ns). Our data show that in the middle‐term follow‐up, an immunosuppressive regimen with tacrolimus plus MMF has a similar efficacy and safety profile in comparison with the combination of low‐exposure cyclosporine plus everolimus. Further follow up could evidence the benefits related to the anti‐proliferative effects of everolimus.     

Short-Term Outcomes of Laparoscopy Combined with Enhanced Recovery Pathway after Ileocecal Resection for Crohn’s Disease: a Case-Matched Analysis

Background

Laparoscopy combined with an enhanced recovery pathway (ERP) is widely considered to be the first-choice option for patients with colorectal cancer. However, no previous reports have focused on patients with Crohn’s disease (CD) treated by laparoscopy and ERP.

Methods

Twenty patients with CD underwent laparoscopic ileocecal resection with an ERP at two institutions. The ERP protocol included no bowel preparation nor fasting, no nasogastric tube, no abdominal drains, early removal of urinary catheter, early solid dietary intake and mobilization, opioid-sparing analgesia and restrictive fluid management. This group was compared with a matched historical control group of 70 CD patients who underwent laparoscopic ileocecal resection treated with conventional care.

Results

Compliance with the ERP was high (≥80 %) for all items except no drain placement. A significantly earlier return of bowel function (time to first flatus and stool) was observed in the ERP group. Mean postoperative and total length of stay were significantly shorter in the ERP group. Postoperative complications were similar in both groups.

Conclusions

This is the first reported experience of laparoscopy with ERP in CD patients and suggests that optimized perioperative care combined with minimally invasive techniques may lead to further improvements in surgical outcomes for CD patients.     

Do Patients Who Participate in a Clinic Experimental Protocol Have the Same Probability of Success From That Who Were Not Selected or Refused To Participate? Outcome Surveillance,Safety, and Bioethical Considerations in Kidney Transplant Clinical Research

Introduction

Safety in conducting a clinical trial is a prerequisite for patients who will be enrolled into that study. The aim of the present study was to evaluate retrospectively if patient and graft survival were similar among patients who participated in clinical trials versus those who did not.

Patients and Methods

We evaluated pretransplant and posttransplant characteristics of 245 kidney transplant (KT) patients who were selected to participate in at least one Phase II/Phase III clinical trial. We compared them with 361 KT patients who were not enrolled or refused to participate in those clinical trials; all studies were conducted at a single transplant center. Inclusion/exclusion criteria were as noted for each individual protocol. Only studies with enrollment at time of graft implant were considered.

Results

Selection of patients participating in clinical trials in general exclude high-risk patients. In our experience, only 36% of transplanted patients were selected for a multicenter, prospective, randomized, international study that included changes to the strategies in the administration of immunosuppressive drugs already on the market or development of a new immunosuppressant. After 5 years, graft and patient survival rates were similar between those who participated and those who did not participate in a clinical study. Although our data were collected retrospectively, an alternative design to achieve these conclusions would be a noninferiority study.

Conclusions

Our results demonstrated similar rates of graft and patient survival among enrolled patients versus nonenrolled patients. Outcome surveillance offers safety in participating in clinical trials that involve changes in standard immunosuppression therapy and are part of the research necessary to develop patient-centered medical interventions.     

Narrow-band imaging endoscopy to assess mucosal angiogenesis in inflammatory bowel disease: A pilot study

AIM: To investigate whether narrow band imaging (NBI) is a useful tool for the in vivo detection of angiogenesis in inflammatory bowel disease (IBD) patients. METHODS: Conventional and NBI colonoscopy was performed in 14 patients with colonic inflammation (8 ulcerative colitis and 6 Crohn’s disease). Biopsy samples were taken and CD31 expression was assayed immuno- histochemically; microvascular density was assessed by vessel count. RESULTS: In areas that were endoscopically normal but positive on NBI, ther...     

TNF-alpha suppresses the expression of clock genes by interfering with E-box-mediated transcription

Production of TNF-alpha and IL-1 in infectious and autoimmune diseases is associated with fever, fatigue, and sleep disturbances, which are collectively referred to as sickness behavior syndrome. In mice TNF-alpha and IL-1 increase nonrapid eye movement sleep. Because clock genes regulate the circadian rhythm and thereby locomotor activity and may alter sleep architecture we assessed the influence of TNF-alpha on the circadian timing system. TNF-alpha is shown here to suppress the expression of the PAR bZip clock-controlled genes Dbp, Tef, and Hlf and of the period genes Per1, Per2, and Per3 in fibroblasts in vitro and in vivo in the liver of mice infused with the cytokine. The effect of TNF-alpha on clock genes is shared by IL-1beta, but not by IFN-alpha, and IL-6. Furthermore, TNF-alpha interferes with the expression of Dbp in the suprachiasmatic nucleus and causes prolonged rest periods in the dark when mice show spontaneous locomotor activity. Using clock reporter genes TNF-alpha is found here to inhibit CLOCK-BMAL1-induced activation of E-box regulatory elements-dependent clock gene promoters. We suggest that the increase of TNF-alpha and IL-1beta, as seen in infectious and autoimmune diseases, impairs clock gene functions and causes fatigue.     

Acute severe colitis: infliximab and/or cyclosporine?

Acute severe ulcerative colitis is a serious condition that requires early hospitalization, with intensive monitoring and treatment. Despite the recent progress in the medical approach of Inflammatory Bowel Diseases acute severe ulcerative colitis remains a clinical challenge, with a mortality rate of nearly 1%. As of today, I.V. corticosteroids remain the 1(st)-line therapy for this complication. For non-responders (up to one-third of patients) possible options are surgery - whose timing is a critical point in the overall management of the disease - or rescue therapy with 2(nd)- line agents such as Cyclosporine and Infliximab. Here we will review the published studies dealing with the use of these medications in acute severe ulcerative colitis.     

Triplet repeat instability correlates with dinucleotide instability in primary breast cancer

The expansion of triplet repeat microsatellite sequences is the molecular correlate of anticipation in a number of rare Mendelian neurodegenerative disorders. This finding prompted us to study these sequences in primary breast cancer in which there is evidence of genetic anticipation. We used a PCR/silver stain method to determine whether triplet-repeat instability (TRI) was present in DNA from malignant breast tumors, and analyzed microsatellite instability (MSI) in triplets SCA1, SCA2, SCA3, SCA6, HD, DRPLA and X25-GAA. We studied 54 consecutive primary breast cancers previously analyzed for dinucleotide instability (DI) at 9 loci. Microsatellite instability (TRI and/or DI) was found in 28/54 (52%) cases, ranging from 0 to 56% in each patient. Dinucleotide instability occurred at > or =2 loci in 19/54 (35%) cases and TRI in 6/54 (11%). Considering single locus instability, we found DI in 26/54 (48%) tumors and TRI in 13/54 (24%). Triplets DRPLA and X25-GAA were most frequently unstable (14% of cases); SCA2 instability was not detected. Interestingly, most tumors with TRI had DI (11/13, 85%). There was a correlation between TRI and DI in the same tumor (42 vs 7% in DI+ and DI- tumors respectively, p=0.0028). Furthermore, TRI appears more frequently associated with lymph node metastases and more advanced clinical stages and more frequent in patients <50 years old, with positive steroidal hormone receptor status, positive p185 and negative p53. These findings are of interest because they demonstrate a relationship between TRI and the clinicopathological characteristics of cancer aggressiveness. Triplet repeat alterations can interfere with gene expression and proteomic functions, which suggests they can play a role in the neoplastic progression of mammary cells. Furthermore, the association of TRI and DI in the same tumor suggests that alterations in the DNA repair gene could culminate in selective phenotypes and breast cancer progression in a considerable number of patients.