Intermittent therapy with high-dose 5-aminosalicylic acid enemas maintains remission in ulcerative proctitis and proctosigmoiditis

PURPOSE: The aim of this study was to compare the efficacy of intermittent therapy with mesalazine enemas and continuous oral mesalazine to maintain remission of distal ulcerative colitis or proctitis. METHODS: Thirt-yeight patients with distal ulcerative colitis (n=17) or ulcerative proctitis (n=21) in clinical, endoscopic, and histologic remission were randomly assigned to receive either oral mesalazine (0.5 g three times/day, Eudragit L coating, n=19) or intermittent therapy with mesalazine enemas (4 g of 5-aminosalicylic acid enema every third night, n=19). Both groups were comparable in regard to sex, age, age at disease onset, extent and duration of disease, number and mode of treatment of previous attacks, and time in remission. Patients were reviewed at the beginning of the study and, subsequently, at two-month intervals for 24 months or until a relapse occurred. At each visit, diaries were reviewed and clinical and laboratory assessments were performed. Sigmoidoscopy was carried out and biopsies were obtained by a blinded observer. Histology was assessed without knowledge of the patient's clinical state or treatment category. RESULTS: At the end of the study, 6 of 19 patients on oral mesalazine (32 percent) and 14 of 19 patients on mesalazine enemas (74 percent) were still in full remission (log rank test: 15.280,P <0.001). Differences in relapse rates between groups were significant even when data were stratified by extent of disease (P <0.01). In the oral group, six and seven patients relapsed at 12 and 24 months, respectively. In the enema group, three and two relapses occurred in the first and second year of the study, respectively. All patients complied with the treatment satisfactorily and there were no dropouts. CONCLUSION: These results suggest that intermittent therapy with mesalazine enemas is more effective than continuous oral mesalazine in maintaining remission in patients with distal ulcerative colitis and proctitis.Read at the meeting of the First United European Gastroenterology Week, Athens, Greece, September 25 to 30, 1992.     

Improving Glucose Homeostasis after Parathyroidectomy for Normocalcemic Primary Hyperparathyroidism with Co-Existing Prediabetes

We have previously described increased fasting plasma glucose levels in patients with normocalcemic primary hyperparathyroidism (NPHPT) and co-existing prediabetes, compared to prediabetes per se. This study evaluated the effect of parathyroidectomy (PTx) (Group A), versus conservative follow-up (Group B), in a small cohort of patients with co-existing NPHPT and prediabetes. Sixteen patients were categorized in each group. Glycemic parameters (levels of fasting glucose (fGlu), glycosylated hemoglobin (HbA1c), and fasting insulin (fIns)), the homeostasis model assessment for estimating insulin secretion (HOMA-B) and resistance (HOMA-IR), and a 75-g oral glucose tolerance test were evaluated at baseline and after 32 weeks for both groups. Measurements at baseline were not significantly different between Groups A and B, respectively: fGlu (119.4 ± 2.8 vs. 118.2 ± 1.8 mg/dL, p = 0.451), HbA_1c (5.84 ± 0.3 %vs. 5.86 ± 0.4%, p = 0.411), HOMA-IR (3.1 ± 1.2 vs. 2.9 ± 0.2, p = 0.213), HOMA-B (112.9 ± 31.8 vs. 116.9 ± 21.0%, p = 0.312), fIns (11.0 ± 2.3 vs. 12.8 ± 1.4 μIU/mL, p = 0.731), and 2-h post-load glucose concentrations (163.2 ± 3.2 vs. 167.2 ± 3.2 mg/dL, p = 0.371). fGlu levels demonstrated a positive correlation with PTH concentrations for both groups (Group A, rho = 0.374, p = 0.005, and Group B, rho = 0.359, p = 0.008). At the end of follow-up, Group A demonstrated significant improvements after PTx compared to the baseline: fGlu ((119.4 ± 2.8 vs. 111.2 ± 1.9 mg/dL, p = 0.021) (−8.2 ± 0.6 mg/dL)), and 2-h post-load glucose concentrations ((163.2 ± 3.2 vs. 144.4 ± 3.2 mg/dL, p = 0.041), (−18.8 ± 0.3 mg/dL)). For Group B, results demonstrated non-significant differences: fGlu ((118.2 ± 1.8 vs. 117.6 ± 2.3 mg/dL, p = 0.031), (−0.6 ± 0.2 mg/dL)), and 2-h post-load glucose concentrations ((167.2 ± 2.7 vs. 176.2 ± 3.2 mg/dL, p = 0.781), (+9.0 ± 0.8 mg/dL)). We conclude that PTx for individuals with NPHPT and prediabetes may improve their glucose homeostasis when compared with conservative follow-up, after 8 months of follow-up.     

A carcinosarcoma/sarcomatoid carcinoma arising in a urinary bladder diverticulum

We describe an invasive polypoid carcinosarcoma/sarcomatoid carcinoma arising within a urinary bladder diverticulum in a 65-year-old patient with synchronous, moderately differentiated prostatic adenocarcinoma. Histologically, the diverticular tumor exhibits an admixture of different morphologic components, including invasive high-grade urothelial carcinoma, malignant glandular structures in a cellular background of malignant spindle cells, and areas formed exclusively by spindle and pleomorphic cells. There was full-thickness involvement of the diverticulum with extension of the tumor into the perivesical fat and ipsilateral seminal vesicle. In view of the early invasive behavior of carcinosarcoma/sarcomatoid carcinoma combined with the paucity of the muscular layer in the diverticulum wall, a graver prognosis was expected for this aggressive tumor that occurred in this unusual site.     

Pharmacokinetics of ciprofloxacin and its penetration into bronchial secretions of mechanically ventilated patients with chronic obstructive pulmonary disease

We evaluated the pharmacokinetic profile of ciprofloxacin and its penetration into bronchial secretions of critically ill patients with chronic obstructive pulmonary disease (COPD). Twenty-five mechanically ventilated patients with severe COPD who were suffering from an acute, infectious exacerbation were included in this prospective, open-label study. All subjects received a 1-hour intravenous infusion of 400 mg ciprofloxacin every 8 h. Serial blood and bronchial secretion samples were obtained at steady state, and concentrations were determined using high-performance liquid chromatography. The pharmacodynamic parameters that are associated with the efficacy of fluoroquinolones against Gram-negative pathogens were also calculated. The mean peak (maximum) concentration (C(max)) and trough (minimum) concentration in plasma were 5.37 ± 1.57 and 1 ± 0.53 mg/liter, respectively. Mean values for volume of distribution, clearance, half-life, and area under the curve from 0 to 24 h (AUC(0-24)) were 169.87 ± 84.11 liters, 26.96 ± 8.86 liters/h, 5.35 ± 2.21 h, and 47.41 ± 17.02 mg · h/liter, respectively. In bronchial secretions, a mean C(max) of 3.08 ± 1.21 mg/liter was achieved in 3.12 ± 1.01 h, and the penetration ratio was 1.16 ± 0.59. The target of AUC(0-24)/MIC of ≥125 was attained in all patients, in the majority of them (76%), and in none at MICs of 0.125, 0.25, and 1 μg/ml, respectively. Slightly better results were obtained for the ratio C(max)/MIC of ≥10. In conclusion, ciprofloxacin demonstrates excellent penetration into bronchial secretions. There is wide interindividual variability in its pharmacokinetic parameters in critically ill COPD patients and inadequate pharmacodynamic exposure against bacteria with MICs of ≥0.5 μg/ml.     

Evaluation of acute/late toxicity and local recurrence in T1–T2 glottic carcinoma treated with accelerated hypofractionated 3D-conformal external beam radiotherapy (3D-CRT)

Background

The aim of the study was to evaluate the efficacy, as well as the acute and late toxicity of an accelerated hypofractionated 3DCRT schedule as radical treatment in patients with organ confined glottic cancer cT1-2N0.

Patients and methods.

Between June of 2004 and September 2010, 47 retrospectively selected patients (29 males, 18 females) diagnosed with organ confined T1 or T2 glottic cancer, were treated with external 3DCRT in an accelerated hypofractionation schedule. The median age was 70 years. A dose of 64.4 Gy in 28 daily fractions was prescribed. The primary study endpoints were to assess the acute and late effects of radiation toxicity, according to the EORTC/ RTOG scale, as well as the therapeutic impact of this schedule in terms of local recurrence.

Results

The median follow up was 36 months. At the end of radiotherapy, grade I, II and III acute toxicity was observed in 34, 9 and4 patients, respectively. Late grade I and II toxicity was observed in 25 and in 8 patients respectively. Only two local recurrences were observed, 15 and 24 months post 3DCRT respectively.

Conclusions

Our radiotherapy schedule achieves a high locoregional control rate with the advantage of voice preservation. The proposed hypofractionated schedule can be recommended as a standard radiotherapy treatment, since these results are comparable with those of conventional fractionation schedules.     

Favorable outcome of Ewing sarcoma family tumors to multiagent intensive preoperative chemotherapy: a single institution experience

BACKGROUND: Aim of our study was to evaluate the efficacy of multiagent intensive preoperative chemotherapy in patients with Ewing sarcoma family tumors (ESFT), in order to succeed a better percentage of necrosis before surgical resection. PROCEDURE: Eighteen patients with ESFT were treated with the same multiagent intensive preoperative protocol. 5/18 patients had bone Ewings sarcoma (EWS) and 13/18 had peripheral primitive neuroectodermal tumor (PNET). None had metastases at diagnosis. Chemotherapy consisted of 5 or 6 cycles with vincristine, cisplatin, cyclophosphamide, and Adriamycin, followed by 12 cycles of vincristine, cyclophosphamide, and actinomycin-D. Five patients with EWS underwent total resection after 5-6 cycles of preoperative chemotherapy and prosthetic replacement was performed in two of them. In 3/13 patients with PNET the tumor was resected at diagnosis and in 1/13 after 5 cycles of chemotherapy, while 9/13 patients received chemotherapy only and/or radiotherapy. RESULTS: In patients with EWS, the histologic specimens of the resected tumors showed that tissue necrosis was 100% in four patients and 95% in one patient. The good histologic response reflects the effectiveness of this regimen in all ESFT. No patient had topical recurrence or developed metastatic disease during follow-up period (2-13 years, mean time 7.4 years). All patients had the scheduled cycles without delays or dose reductions. There were no major side effects of chemotherapy. CONCLUSIONS: The intensive chemotherapy schedule, comprising of 5-6 cycles preoperatively, seems to maximize the percentage of tumor necrosis, thus improving outcome. Our study implies that this combined therapy may improve the prognosis of ESFT.     

Mutually exclusive lymphangiogenesis or perineural infiltration in human skin squamous-cell carcinoma

Although tumor-associated lymphangiogenesis correlates with metastasis and poor prognosis in several cancers, it also supports T cell infiltration into the tumor and predicts favorable outcome to immunotherapy. The role of lymphatic vessels in skin squamous-cell carcinoma (sSCC), the second most common form of skin cancer, remains mostly unknown. Although anti-PD-1 therapy is beneficial for some patients with advanced sSCC, a greater understanding of disease mechanisms is still needed to develop better therapies.Using quantitative multiplex immunohistochemistry, we analyzed sSCC sections from 36 patients. CD8+ T cell infiltration showed great differences between patients, whereby these cells were mainly excluded from the tumor mass. Similar to our data in melanoma, sSCC with high density of lymphatic endothelial cells showed increased CD8+ T cell density in tumor areas. An entirely new observation is that sSCC with perineural infiltration but without metastasis was characterized by low lymphatic endothelial cell density. Since both, metastasis and perineural infiltration are known to affect tumor progression and patients’ prognosis, it is important to identify the molecular drivers, opening future options for therapeutic targeting. Our data suggest that the mechanisms underlying perineural infiltration may be linked with the biology of lymphatic vessels and thus stroma.     

Solid extraintestinal malignancies in patients with inflammatory bowel disease

Malignancies constitute the second cause of death in patients with inflammatory bowel diseases (IBD), after cardiovascular diseases. Although it has been postulated that IBD patients are at greater risk of colorectal cancer compared to the general population, lately there has been evidence supporting that this risk is diminishing over time as a result of better surveillance, while the incidence of extraintestinal cancers (EICs) is increasing. This could be attributed either to systemic inflammation caused by IBD or to long-lasting immunosuppression due to IBD treatments. It seems that the overall risk of EICs is higher for Crohn’s disease patients and it is mainly driven by skin cancers, and liver-biliary cancers in patients with IBD and primary sclerosing cholangitis. The aims of this review were first to evaluate the prevalence, characteristics, and risk factors of EICs in patients with IBD and second to raise awareness regarding a proper surveillance program resulting in early diagnosis, better prognosis and survival, especially in the era of new IBD treatments that are on the way.