Phase II study of maytansine in the treatment of advanced or recurrent adenocarcinoma of the ovary. A Gynecologic Oncology Group study

Twenty-nine patients with advanced or recurrent adenocarcinoma of the ovary no longer responsive to standard treatment measures were given maytansine 1.2 mg/m2 I.V. every 3 weeks. None of the 29 patients demonstrated an objective regression of disease. Eighteen (62%) demonstrated stable disease for 1 or more months, while 11 (38%) developed rapid progression of disease. Adverse effects consisted primarily of leukopenia (7/29), thrombocytopenia (9/29), and nausea and vomiting (14/29). Only one patient developed life-threatening toxicity (platelets less than 25,000 microliters), and no drug-related deaths were observed. Maytansine thus appears inactive in the treatment of adenocarcinoma of the ovary at the dose and schedule tested.     

Positionspapier zur Versorgungslage der perkutanen transluminalen Angioplastie (PTA) peripher-arteriell und renovaskul?r in Kliniken und Praxen Deutschlands

Taking into account real life patient care in Germany and by international comparison, the indication assessment and performance of peripheral angioplasty is as an integral part of comprehensive patient care substantially in the fields of cardiology and angiology. As peripheral arterial disease (PAD) is often associated with systemic atherosclerosis, which may involve the whole arterial vascular system and considering resulting points of interference in both vascular diagnostics and therapy, the establishment of an interdisciplinary vascular conference within the clinic is recommended to assure optimal patient care and patient management. In order to improve medical further training in cardiology and angiology as well as for the implementation of the actual reality of patient care, there is an urgent need for adaption of the further education catalogue for cardiology and angiology by inclusion of peripheral angioplasty.     

Raphe magnus/pallidus neurons regulate tail but not mesenteric arterial blood flow in rats

In urethane-anesthetized rats with body temperature maintained at 39-40 degrees C, electrical stimulation of raphe magnus/pallidus/parapyramidal region within 0.5 mm of the ventral medullary surface reduced arterial blood flow to the tail cutaneous bed (measured with a chronically implanted Doppler ultrasonic flowmeter) from 28+/-5 to 6+/-1 cm/s (P<0.01), without changing mesenteric arterial blood flow, and with only small, variable changes in arterial pressure. Injection of bicuculline (50 pmol in 50 nl) at the same site reduced tail flow from 19+/-2 to 3+/-1 cm/s (P<0.01), again without significantly changing mesenteric flow, but with a moderate increase in arterial pressure. When the rat was cooled to reduce basal tail blood flow, injection of muscimol (1 nmol in 100 nl) or GABA (100 nmol in 100 nl) into the raphe site restored tail blood flow to 93+/-4% of the pre-cooling level.These recordings are the first reported direct measurements of rat tail blood flow changes elicited by alteration of neuronal function in the brainstem. The rostral medullary raphe controls the tail cutaneous vascular bed in a relatively selective manner. Our findings add to evidence that raphe magnus/pallidus/parapyramidal neurons are involved in regulating cutaneous blood flow in response to changes in body temperature in the rat.     

Large colorectal polyps: colonoscopy, pathology, and management

Between 1984 and 1987, we reviewed all large (greater than or equal to 3.0 cm) colorectal polyps to determine the efficacy of colonoscopic polypectomy from both an oncologic and technical viewpoint. Forty-eight polyps greater than or equal to 3.0 cm were identified in 46 patients. Twenty polyps were entirely benign, 20 polyps contained noninvasive carcinoma, and invasive carcinoma was present in eight polyps. Four of the invasive cancers were associated with residual adenoma; the remaining four were polypoid carcinomas. Among the eight cases of invasive carcinoma, four had tumors that did not extend through the submucosa. Invasive cancer was more prevalent in left-side sessile lesions but was absent in all 10 right-sided polyps. Thirty-two polyps were removed by colonoscopic polypectomy. Four patients required colectomy after polypectomy for the following reasons: incomplete excision (N = 1), presence of invasive carcinoma at the resection margin (N = 1), and inability to define the level of carcinoma on pathologic examination (N = 2). Two polyps with cancer confined to the submucosa were successfully excised colonoscopically. Complications of polypectomy included three cases of minor hemorrhage. Sixteen polyps (the majority located in the right colon) were removed by primary surgical colectomy. We conclude that colonoscopic polypectomy is oncologically and technically successful for most large colorectal polyps. A minority of large polyps require colectomy because of incomplete removal or the presence of invasive cancer that is not curable with colonoscopic excision.     

Mitotic indices, anti-PCNA immunostaining, and AgNORs in thick cutaneous melanomas displaying paradoxical behaviour.

Those melanomas which fail to behave as expected from their Breslow thickness provide interesting material for study. In an attempt to explain differences in behaviour, we have evaluated three distinct proliferative markers in 23 thick melanomas which failed to metastasize and in 20 well-matched control tumours with documented metastasis. The test group demonstrated significantly greater numbers of mitoses when expressed as an index (mitoses per 1000 cells), whilst no difference was found when the results were expressed in terms of mitoses per unit area. Tumours showing epidermal ulceration possessed higher mitotic indices than those of non-ulcerated lesions. High fractions of PCNA immunolabelling combined with low mitotic indices were observed frequently in the non-metastasizing group. This result and its possible relation to survival advantage are discussed in detail. Both AgNOR numbers and patterns failed to act as prognostic variables--indeed, AgNORs failed to correlate with the other proliferative indices, suggesting that their value as a marker of tumour growth is severely limited.     

Rab14 Regulates Maturation of Macrophage Phagosomes Containing the Fungal Pathogen Candida albicans and Outcome of the Host-Pathogen Interaction

Avoidance of innate immune defense is an important mechanism contributing to the pathogenicity of microorganisms. The fungal pathogen Candida albicans undergoes morphogenetic switching from the yeast to the filamentous hyphal form following phagocytosis by macrophages, facilitating its escape from the phagosome, which can result in host cell lysis. We show that the intracellular host trafficking GTPase Rab14 plays an important role in protecting macrophages from lysis mediated by C. albicans hyphae. Live-cell imaging of macrophages expressing green fluorescent protein (GFP)-tagged Rab14 or dominant negative Rab14, or with small interfering RNA (siRNA)-mediated knockdown of Rab14, revealed the temporal dynamics of this protein and its influence on the maturation of macrophage phagosomes following the engulfment of C. albicans cells. Phagosomes containing live C. albicans cells became transiently Rab14 positive within 2 min following engulfment. The duration of Rab14 retention on phagosomes was prolonged for hyphal cargo and was directly proportional to hyphal length. Interference with endogenous Rab14 did not affect the migration of macrophages toward C. albicans cells, the rate of engulfment, the overall uptake of fungal cells, or early phagosome processing. However, Rab14 depletion delayed the acquisition of the late phagosome maturation markers LAMP1 and lysosomal cathepsin, indicating delayed formation of a fully bioactive lysosome. This was associated with a significant increase in the level of macrophage killing by C. albicans. Therefore, Rab14 activity promotes phagosome maturation during C. albicans infection but is dysregulated on the phagosome in the presence of the invasive hyphal form, which favors fungal survival and escape.     

Phase II clinical trial of capecitabine in ovarian carcinoma recurrent 6-12 months after completion of primary chemotherapy, with exploratory TS, DPD, and TP correlates: a Gynecologic Oncology Group study

PURPOSE: A phase II trial was conducted to evaluate the anti-tumor activity and adverse effects of capecitabine in women with measurable platinum-sensitive ovarian cancer or platinum-sensitive primary peritoneal cancer and to explore the ability of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), and thymidine phosphorylase (TP) to predict response and toxicities. EXPERIMENTAL DESIGN: Patients were treated with a daily starting dose of 2500 mg/m2/day (divided in two doses given every 12 h) for 14 days of each 21-day cycle. Genotyping in the 5' and 3' ends of TS was performed in DNA from 23/23 pre-treatment blood specimens. Relative gene expression of TS, DPD, and TP was quantified in 18/21 paraffin-embedded tumor specimens. RESULTS: Of the 27 patients enrolled on study, 2 were never treated leaving 25 patients evaluable. Two patients (8.0%) achieved a partial response, 13 (52%) exhibited stable disease, 5 (20%) displayed increasing disease, and response could not be assessed in 5 (20%). The median time to progression and survival was 3.9 and 21.2 months, respectively. The most common serious toxicities were nausea/vomiting, gastrointestinal, and dermatological. There was one treatment-related death. TS expression was associated with severe nausea/vomiting (P = 0.039), but not with other severe toxicities. TS genotype or expression of DPD or TP was not associated with any of the severe toxicities. CONCLUSIONS: Based on the low response rate, this trial was closed after the first stage of accrual, the drug was not selected for further study in this patient population, and biomarker associations with response could not be assessed.     

Headache with Aura: A case report of ocular melanoma

Background

Headaches and visual complaints are common conditions encountered in the emergency department. While a patient's age, risk factors, and comorbidities often aid in risk stratification and guide emergency department evaluation, atypical presentations of serious disease may still occur in young otherwise healthy patients