Small-cell lung carcinoma: an analysis of 194 consecutive patients.

The treatment of small-cell lung carcinoma (SCLC) requires the careful combination of chemotherapy and radiation therapy. To understand the factors involved in the outcome of these patients, the authors undertook a study of patients treated for limited stage SCLC. The charts of 194 consecutive patients treated at our facilities between 1986 and 1994 were reviewed. All patients underwent thoracic radiation therapy (TRT), 50% received prophylactic cranial irradiation (PCI), and all but one received chemotherapy. The probability of survival at 5 years was 14%, and the disease-free survival (DFS) was 17%. Patients receiving a combination of platinum and etoposide (PE) and Cytoxan (Bristol-Myers, Evansville, IN, U.S.A.), Adriamycin (Adria Laboratories, Dublin, OH, U.S.A.), and Vincristine (Eli Lilly, Indianapolis, IN, U.S.A.) (CAV) experienced a DFS at 3 years of 31%, versus 14% for CAV only and 18% for PE only (p = 0.004). In a multivariate survival analysis, only PCI (p = 0.001), having received PE and CAV (p = 0.01), and response to treatment (p = 0.001) were significant. Radiation dose and field size did not influence outcome. The combination of PE and CAV chemotherapy produced the best results in our series. Unanswered questions regarding the optimal TRT dose, field size, and timing of TRT await the results of ongoing randomized trials.

The impact of Clostridium difficile on a surgical service: a prospective study of 374 patients.

OBJECTIVE: To evaluate the epidemiology of Clostridium difficile colitis (CDC) in a subset of patients admitted specifically to a surgical service. SUMMARY BACKGROUND DATA: CDC is an increasingly prevalent nosocomial infection that can prolong hospitalization and adversely affect patient outcome. Although this disease has been investigated extensively in patients admitted to medical services, the incidence and risk factors for the development of this disease in patients admitted to a surgical service have not been studied. METHODS: Over a 5-month period, 374 patients admitted to the general, vascular, thoracic, and urologic surgery services were monitored for the development of symptomatic CDC (defined as >3 bowel movements per 24 hours and a positive cytotoxin assay or culture). RESULTS: Twenty-one patients developed CDC (incidence, 5.6%). Factors that independently predisposed to infection included admission from a skilled care facility, use of the antibiotic cefoxitin, and an operative procedure for bowel obstruction. Other factors associated with CDC included colectomy, treatment with any antibiotic, nasogastric tube suction, advanced age, and prior antibiotic treatment. Abdominal pain and fever were also more common in patients with CDC. Morbidity included prolonged hospitalization in all patients and urgent colectomy in one. CONCLUSIONS: CDC frequently affects surgical patients, producing morbidity ranging from mild diarrhea to life-threatening illness. A variety of factors, many of which are associated with intestinal stasis, predispose to the development of CDC.

Formation of p27-CDK complexes during the human mitotic cell cycle.

In eukaryotic cells, the coordinated activation of different cyclin-dependent kinases regulates entry into S-phase. In vitro and in nonproliferating cells, p27 associates with and inhibits cyclin/cycin-dependent kinase (CDK) holoenzymes containing either CDK4, CDK6, or CDK2. Although many different types of proliferating cells contain p27 protein, neither the interactions of p27 with cyclin/CDK complexes nor the consequences of this interaction during the mitotic cycle have been fully explored. We report that, in MANCA cells, the amount of p27 is constant during the cell cycle. In addition, p27 associates with three different CDKs: CDK2, CDK4, and CDK6. Furthermore, the amount of p27 is significantly lower than the amount of cyclin D3 in these cells. The amount of CDK4 and CDK6 associated with p27 does not change in a cell cycle-dependent fashion; in contrast, the amount of CDK2 associated with p27 is lowest in early G1 cells and increases to a maximum in mid-G1 phase, reaching a steady-state level in late G1-phase cells. After mid-G1 phase, the amount of each p27/CDK complex remains constant through the remainder of the cell cycle. p27-immunoprecipitates contain an Rb-kinase activity. The substrate specificity, the expression pattern of this kinase, and the ability to deplete 50% of this kinase activity with a CDK6-specific antibody suggest that the CDK6 protein mediates, in part, the p27-associated Rb-kinase activity. In contrast, p27 complexes containing CDK2 are incapable of phosphorylating histone H1. These data are consistent with a model wherein cyclin D/CDK complexes sequester the CDK2-dependent kinase inhibitory activity of p27.

Insulin-like growth factors modulate the growth inhibitory effects of retinoic acid on MCF-7 breast cancer cells.

Retinoids are currently being tested for the treatment and prevention of several human cancers, including breast cancer. However, the anti-cancer and growth inhibitory mechanisms of retinoids are not well understood. All-trans retinoic acid (RA) inhibits the growth of the estrogen receptor-positive (ER+) breast cancer cell line, MCF-7, in a reversible and dose-dependent manner. In contrast, insulin-like growth factors (IGF-I, IGF-II) and insulin are potent stimulators of the proliferation of MCF-7 and several other breast cancer cell lines. Pharmacologic doses of RA (> or = 10(-6) M) completely inhibit IGF-I-stimulated MCF-7 cell growth. Published data suggest that the growth inhibitory action of RA on IGF-stimulated cell growth is linear and dose-dependent, similar to RA inhibition of unstimulated or estradiol-stimulated MCF-7 cell growth. Surprisingly, we have found that IGF-I or insulin-stimulated cell growth is increased to a maximum of 132% and 127%, respectively, by cotreatment with 10(-7) M RA, and that 10(-9) - 10(-7) M RA increase cell proliferation compared to IGF-I or insulin alone. MCF-7 cells that stably overexpress IGF-II are also resistant to the growth inhibitory effects of 10(-9) - 10(-7) M RA. Treatment with the IGF-I receptor blocking antibody, alpha IR-3, restores RA-induced growth inhibition of IGF-I-treated or IGF-II-overexpressing MCF-7 cells, indicating that the IGF-I receptor is mediating these effects. IGFs cannot reverse all RA effects since the altered cell culture morphology of RA-treated cells is similar in growth-inhibited cultures and in IGF-II expressing clones that are resistant to RA-induced growth inhibition. These results indicate that RA action on MCF-7 cells is biphasic in the presence of IGF-I or insulin with 10(-9) - 10(-7) M RA enhancing cell proliferation and > or = 10(-6) M RA causing growth inhibition. As IGF-I and IGF-II ligands are frequently detectable in breast tumor tissues, their potential for modulation of RA effects should be considered when evaluating retinoids for use in in vivo experimental studies and for clinical purposes. Additionally, the therapeutic use of inhibitors of IGF action in combination with RA is suggested by these studies.

Severe Clostridium difficile colitis.

PURPOSE: Reports of fatality related to Clostridium difficile colitis and a sharp increase in prevalence of this infection prompted a study of patients who develop a more aggressive form of this disease. METHODS: Over 38 months, 710 patients at our institution developed C. difficile colitis. Twenty-one (3 percent) of these patients either required intensive care unit admission or died as a result of their infection. A retrospective, case-controlled study was undertaken to compare these patients, who were considered to have severe C. difficile colitis, with the remaining patients with milder disease. RESULTS: Factors that predisposed to the development of severe C. difficile colitis included intercurrent malignancy, chronic obstructive pulmonary disease, immunosuppressive and antiperistaltic medications, renal failure, and administration of clindamycin (P < 0.05 for all). Patients with severe C. difficile colitis were more likely to have abdominal pain, tenderness and distention, peritonitis, hemoconcentration (> 5 points), hypoalbuminemia (< 3 mg/dl), and elevated or suppressed white blood cell count (> 25,000; < 1,500; P < 0.05 for all). These factors were used to create a scoring system that could distinguish between patients with severe C. difficile colitis and those with mild disease. Thirteen patients in the late stages of terminal illness with metastatic malignancy or age > 90 were considered poor or inappropriate surgical candidates. Only the remaining eight patients could have potentially recovered from operation with hope for long-term survival. Of these, seven were treated without colonic resection, and six of the seven survived, whereas one patient underwent colectomy and did not survive. CONCLUSIONS: Patients with severe C. difficile colitis can be readily identified. Often they have coexisting illness that precludes operation. In this series, only 1 of 21 patients with severe C. difficile might have benefited from an aggressive surgical approach.

Parastomal hernia. Is stoma relocation superior to fascial repair?

OBJECTIVE: To evaluate methods of parastomal hernia repair. DESIGN: Retrospective analysis. SETTING: Two tertiary care institutions. PATIENTS: Eighty patients undergoing 94 parastomal hernia repairs between 1983 and 1991. INTERVENTIONS: Three methods of repair were examined: fascial repair, stoma relocation, and fascial repair with prosthetic material. MAIN OUTCOME MEASURE: Parastomal hernia recurrence and short- and long-term complications. RESULTS: Fifty-five (93%) of 59 living patients were available and examined at a median of 31.5 months following repair, providing 68 repairs for consideration. Fascial repair was used in 36 cases, stoma relocation in 25 cases, and fascial repair with prosthetic material in seven cases. Overall, 63% of patients developed a recurrent parastomal hernia and 63% had at least one postoperative complication. Following first-time repair, parastomal hernia recurrence developed in 22 (76%) of 29 patients who had fascial repair but in only six (33%) of 18 patients who had stoma relocation (P < .01). When repair was undertaken for recurrent parastomal hernia, fascial repair failed in all seven cases, stoma relocation failed in five (71%) of seven cases, and fascial repair with prosthetic material failed in one (33%) of three cases. The only factor that significantly affected the recurrence rate was the technique of repair. Complications were more common following stoma relocation (88%) than following fascial repair (50%) (P < .05). In particular, incisional hernias developed in 52% of patients following stoma relocation but in only 3% of patients following fascial repair. When postoperative occurrence of all abdominal-wall hernias was compared, there was no significant difference between the fascial repair group (29 [81%] of 36 repairs) and the stoma relocation group (17 [68%] of 25 repairs). Furthermore, the reoperation rate for hernia repair was nearly identical (31% vs 28%) between these two groups. CONCLUSIONS: Parastomal hernia repair is often unsuccessful and rarely without complication. For first-time parastomal hernia repairs, stoma relocation is superior to fascial repair. For recurrent parastomal hernias, repair with prosthetic material is the most promising of a group of poor alternatives.

Isolation and characterization of granules of the toad bladder.

The electron-dense granules that lie just below the apical plasma membrane of granular epithelial cells of toad urinary bladder contribute glycoproteins to that apical membrane. Also, exocytosis of granules (and tubules) elicited by antidiuretic hormone potentially doubles that apical surface, during the same period the transport changes characteristic of the hormonal response occur. Granules separated from other membrane systems of the cells provide the material to assess the importance of the granules as glycocalyx precursors and in hormone action. We used isosmotic media to effect preliminary separations by differential centrifugation. Then granules were isolated by centrifugation on self-forming gradients of Percoll of decreasing hypertonicity. We find qualitative and quantitative changes in protein composition and enzymic activities in the isolated fractions. The primary criterion for granule purification was electron microscopic morphology. In addition, polypeptide species found in the granule fraction are limited in number and quantity. The granules are enzymically and morphologically not lysosomal in nature. Granules may provide the glycoproteins of the apical glycocalyx but they differ from the isolated plasma membrane fraction enzymically, in protein composition and in proportion of esterified cholesterol. We conclude that the granules are not "average" plasma membrane precursors. Their role in the membrane properties of the toad urinary bladder may now be evaluated by characterizing permeability and other properties of the isolated organelles.

Membrane transport during erythroid differentiation.

Transport, unidirectional flux, of a monosaccharide, a nucleoside and three amino acids, all of which enter cells by independent, discrete carriers, was compared at three stages of erythroid maturation, the normal (anucleate) mouse erythrocyte, and in differentiated and undifferentiated Friend erythroleukemia cells. We found specific transport alterations during this developmental program. Transport of 3-O-methylglucose increased with each successive developmental stage. Aminoisobutyrate transport was maintained during Friend cell differentiation, but fell slightly in erythrocytes. Leucine, lysine and uridine transport began to fall two days after dimethylsulfoxide exposure, and diminished further in red cells. These studies of transport are not directly comparable to uptake studies reported by others. Median cell volume and thus surface area decreased more during differentiation than amino acid transport declined, so flux, transport past a unit area of membrane, actually increased. Monosaccharide flux also increased. Only uridine transport fell in parallel to surface area. Perhaps sites for nutrient transport required for energy production are preferentially maintained.