A monoclonal antibody to human platelet glycoprotein IIIa detects a related protein in cultured human endothelial cells.

We have previously described a series of monoclonal antibodies against platelet membrane glycoproteins. Two of the antibodies, B59.2 and B2.12, recognize the glycoprotein IIb-IIIa complex. These two antibodies react specifically with glycoprotein (GP) IIIa, as shown by immunoblotting of sodium dodecyl sulfate-polyacrylamide gels of solubilized platelet membranes. Monoclonal B2.12, but not B59.2, binds to cultured human endothelial cells obtained from umbilical vein, internal iliac artery, and inferior vena cava. At saturation approximately 100,000 binding sites were detected per human umbilical vein endothelial cell. When solubilized radioiodinated cells were chromatographed on a column of agarose-bound B2.12, a single radiolabeled protein was obtained whose apparent molecular weight is slightly larger than that of platelet GP IIIa. This protein incorporated [35S]methionine when endothelial cells were labeled metabolically. These results demonstrate that human endothelial cell membranes synthesize a protein immunologically related to platelet GP IIIa.

Carcinoid tumors frequently display genetic abnormalities involving chromosome 11.

Carcinoid tumors are neuroendocrine neoplasms that are encountered either sporadically or as part of a familial syndrome, most notably-multiple endocrine neoplasia type 1 (MEN1). The MEN1 gene localizes to chromosome 11 (11q13) and presumably functions as a tumor suppressor gene. The molecular mechanisms underlying carcinoid tumor development and their clonal composition remain largely unknown. To establish whether carcinoid tumors develop via a mechanism similar to other MEN1-associated tumors, and indirectly determine their clonal composition, we analyzed 36 sporadically occurring carcinoid tumors with 16 chromosome 11 microsatellite markers, mostly from around the MEN1 region for loss of heterozygosity (LOH). Twenty one tumors (58%) displayed LOH of at least three markers, five lost almost an entire allele and the rest displayed a discontinuous pattern. Similar, but less extensive analysis was also carried out for 10 additional carcinoid tumors from Brazil, 6 of the 10 showed LOH with at least one marker. Overall, 36 of 46 tumors (78%) displayed LOH. In addition, 20 of 46 (43%) tumors exhibited a pattern of genomic instability. Thus, the majority of sporadically occurring carcinoid tumors are monoclonal whose tumorigenesis involves inactivation of a tumor suppressor gene on chromosome 11 and DNA mismatch repair genes mutations.

Patterns of remission and relapse in obsessive-compulsive disorder: a 2-year prospective study.

OBJECTIVE: This study examined the course of illness in patients with obsessive-compulsive disorder (OCD) over a 2-year period. METHOD: Sixty-six patients with a primary diagnosis of DSM-III-R OCD were followed prospectively for 2 years. Baseline information was collected on demographic characteristics, Axis I and II diagnoses, and severity of OCD symptoms. Follow-up measures obtained at 3, 6, 12, and 24 months after baseline assessment included information on symptomatic and diagnostic status as well as behavioral and somatic treatments received. RESULTS: The probability of full remission from OCD over the 2-year period was 12%. The probability of partial remission was 47%. After achieving remission from OCD, the probability of relapse was 48%. No factors were identified that significantly predicted full or partial remission. Seventy-seven percent (N = 51) of the subjects received a serotonin reuptake inhibitor (SRI) for > or =12 weeks, and 68% (N = 45) received medium-to-high doses of SRIs for > or =12 weeks. Only 18% received a full trial of behavior therapy. CONCLUSION: Despite exposure to at least 1 adequate trial of an SRI, the likelihood of full remission of OCD in this study was low. Results of this study also suggest that behavior therapy may be under-utilized.

Phase II trial of zeniplatin (CL 286,558), a new patinum compound, in patients with advanced ovarian cancer previously treated with organoplatinum-based therapy.

There is a critical need to find new chemotherapeutic agents that are active in platinum-refractory ovarian cancer. A phase II trial of zeniplatin (CL 286,558), a third-generation platinum compound, was conducted in 31 patients with advanced ovarian cancer to examine the safety and activity of the agent when used as a salvage treatment in individuals previously exposed to organoplatinum-based therapy. In general the drug was well tolerated, with moderate emesis and bone marrow suppression being observed in most patients. An unexpected side-effect was significant fever, of unknown etiology, which was noted in 16% of patients. Out of 20 patients, 2 (10%; 95% confidence intervals: 1%-32%) with clinically defined platinum-refractory disease achieved a partial response. Unfortunately, although we have defined definite but modest activity for zeniplatin in platinum-refractory ovarian cancer, further development of this drug has been discontinued because of the severe renal toxicity observed in other clinical trials of this cytotoxic agent.

Pharmacokinetic evaluation of zeniplatin in humans.

Zeniplatin, a more water-soluble organoplatinum than cisplatin, was evaluated for clinical pharmacology in the context of a phase II trial in previously treated patients with ovarian carcinoma. A total of 12 patients were given zeniplatin at 120 mg/m2 by rapid intravenous infusion over 90 min, with both blood and urine being sampled. All platinum moieties were analyzed in whole blood, plasma, plasma ultrafiltrate, and urine by atomic absorption, and free zeniplatin was analyzed in plasma ultrafiltrate by specific high-performance liquid chromatography (HPLC). In a comparison of the platinum-time concentration curve, AUC (area under the curve) values indicated that approximately 90% of platinum moieties were bound to circulating plasma proteins. There was no evidence of drug accumulation after repetitive dosing. The terminal half-life (t1/2) of this drug in plasma ultrafiltrate (3.7-7.2 h.) as measured by HPLC was slightly longer than that of carboplatin, whereas total platinum moieties in plasma displayed a long t1/2 (124-154 h). Approximately 60% of platinum moieties could be recovered in the urine within 24 h. These findings suggest that zeniplatin has a pharmacokinetic profile similar to that of carboplatin.

Therapy of refractory/relapsed acute myeloid leukemia and blast crisis of chronic myeloid leukemia with the combination of cytosine arabinoside, tetrahydrouridine, and carboplatin.

Eight patients, of whom four had acute myeloid leukemia (AML) and four had chronic myeloid leukemia (CML) blast crisis, were treated with a combination of cytosine arabinoside (ARA-C: 1,600 mg/m2 in three patients, 1,200 mg/m2 in five patients), tetrahydrouridine (THU: 2,800 mg/m2 in two patients, 2,646 mg/m2 in one patient, 2,100 mg/m2 in five patients), and carboplatin (900 mg/m2 in four patients, 720 mg/m2 in one patient, 450 mg/m2 in three patients). As a result of this treatment, five of the eight patients became aplastic. Two of the four patients with CML blast crisis reverted to the chronic phase and two of the four patients with acute nonlymphocytic leukemia (ANLL) attained a remission (one partial remission and one complete remission). The major toxicities included myelosuppression, unacceptable hepatotoxicity, and diarrhea. Pharmacokinetics studies revealed that the addition of carboplatin did not significantly change the disposition of ARA-C. ARA-C levels were not significantly changed in comparison with those obtained in a prior study of ARA-C with THU (ARA-C plasma levels at 3 h, 2630 +/- 1170 ng/ml).

Catheter fracture and embolization in a totally implanted venous access catheter.

A totally implanted venous access system was placed in a 24-year-old male patient with Hodgkins disease for chemotherapy. Twelve months after implantation it was noted on chest x-ray that the catheter had fractured and the distal fragment embolized to the right ventricle. Catheter separation and embolization is a recognized but uncommon complication of Hickman catheters. It is an even rarer complication of implanted central venous catheters. With the increasing use of these new venous access systems this complication may become a more prevalent, but an avoidable complication.

Reproductive health services for men: is there a need?

PIP: There are many problems inherent in trying to provide reproductive health services for men. An example of a San Francisco male clinic is presented. In February, 1976, a pilot program for men was opened at a satellite clinic of the San Francisco District Health Center Number 4. The clinic was open for 2 hours a week, did not require an appointment and served an average of about 6 walk-in patients per session. A grant proposal was then submitted to the US Department of Health, Education, and Welfare (DHEW--now Department of Health and Human Services). In July, 1976, DHEW awarded a 1-year renewable grant of $43,000 to the family planning program. The clinic opened in October, 1976. The program consisted of 2 parts: 1) an evening clinic, and 2) an education and outreach program. Between 1977 and 1981, the total number of visits to the clinic averaged about 1200 a year. However, it is difficult to assess whether the programs broader health goals were really attained. Clinic evaluation records showed satisfaction with the services offered. There was always some conflict between the 2 separate program components. There was lack of clarity as to who felt the need for the program. What men wanted were primarily job physicals and free condoms. There is debate about whether men should be offered separate reproductive services or whether these services should be incorporated into primary health care. Emphasis in the original proposal was on training male staff. There was much turnover. The funding history of the clinic was "checkered." The general conclusions to be drawn from this example are discouraging.^ieng

Effect of fibrin on endothelial cell production of prostacyclin and tissue plasminogen activator.

Fibrin formed on endothelial cells has previously been shown to have deleterious effects on the cells. Additionally, substances that cause endothelial cell damage have been reported to induce cultured endothelial cells to synthesize prostacyclin and tissue plasminogen activator (t-PA). The present studies were undertaken to determine whether fibrin formed on cultured human umbilical vein endothelial cells would alter synthesis of prostacyclin and t-PA by the cells. Fibrin was found to increase synthesis of both prostacyclin and t-PA in a dose and time dependent manner. Stimulation of prostacyclin synthesis was completely inhibited by indomethacin; partially inhibited by actinomycin D, cycloheximide, and trifluoperazine; and not affected by cytochalasin D or vinblastine. In contrast, stimulation of t-PA synthesis was completely inhibited by actinomycin D and cycloheximide; partially inhibited by cytochalasin D, vinblastine, and trifluoperazine; and not affected by indomethacin. Fibrin I, formed with Reptilase, caused only slight stimulation of t-PA production, but virtually no stimulation of prostacyclin synthesis. Neither collagen polymerization on the cells nor thrombin added in concentrations that did not induce fibrin polymer formation stimulated production of either substance. Furthermore, soluble fibrin II generated in the presence of the fibrin polymerization inhibitor gly-pro-arg-pro also failed to stimulate either prostacyclin or t-PA production. The presence of platelets in the plasma from which the fibrin was formed did not affect the amount of stimulation of the cells. Fibrin-induced stimulation of endothelial cell production of prostacyclin and t-PA could act to limit vascular occlusion in vivo by inhibiting platelet function and by stimulating fibrinolysis via t-PA.

Cognitive motivations for drinking among alcoholics: factor structure and correlates.

The aims of this study were to: a) Identify factors reflecting reasons for drinking and expectancies regarding the effects of drinking among inpatient alcoholics; b) Examine the relationship between these cognitive "motivations" for drinking and both patterns of alcohol consumption and various personal and social consequences of consumption. The factors which emerged relate to negative mood reduction, positive mood enhancement, and social functioning. Although the factors identified in this investigation were not associated with quantity of alcohol consumed, small to moderate associations were found between scores on three of four factors and a variety of adverse physical and occupational consequences of alcohol abuse.

Comprehensive management including interstitial brachytherapy for locally advanced or recurrent gynecologic malignancies.

Radical therapy for locally advanced or recurrent gynecologic malignancies (LARGM) may include interstitial brachytherapy (IB) when intracavitary brachytherapy is impossible or inadequate and external beam teletherapy would be limited by surrounding normal tissue tolerance. Sixteen women received IB as all or part of their treatment at North Shore University Hospital for the treatment of locally advanced primary or recurrent tumors of gynecologic origin from May 1988 through September 1990. Primary sites included the vulva (3), vagina (2), cervix (7), and endometrium (4). Radiosensitizing chemotherapy was used in 8 patients. With a median follow-up of 23 months (range, 12-44 months), 11 patients (69%) have experienced continuous local control of their tumor and 4 patients (25%) have experienced severe complications. While significant risks may attend the use of IB, IB is an integral part of management for select patients with LARGM.

Maximal cytoreductive surgery as a reasonable therapeutic alternative for recurrent endometrial carcinoma.

OBJECTIVE: The objective was to determine if maximal cytoreductive surgery could carry any benefit in pelvic and abdominal recurrent endometrial carcinoma. METHODS: Twenty women at their first large pelvic or abdominal recurrence from endometrial carcinoma were treated with maximal cytoreductive surgery. Women were classified as R1 (residual tumor) or R0 (no residual tumor) by tumor left at the end of surgery. Adjuvant postoperative therapy was undertaken upon clinical judgement. Progression-free, overall, and cancer-related survivals were analyzed with the product-limit method and compared with the log-rank test. The Cox regression model was used to study the variables involved in progression-free and overall survival. RESULTS: Complete macroscopic resection of tumor was feasible in 13 women (65%). R0 group women had a significant both progression-free (median reached at 9.1 months) and overall survival (median reached at 11.8 months) compared to R1 group women. There were 2 (10%) perioperative deaths. Eight women died of cancer, 5 in the R1 group and 3 in the R0 group. There were four intercurrent deaths in women still free from the disease. Local control of neoplasia was achieved in 84.6% of R0 women and their survival was affected mostly by distant recurrences or intercurrent deaths. Residual tumor at the end of surgery was the only significant variable to affect both progression-free and overall survival. CONCLUSION: Intensive surgery is a valid treatment option in women with large pelvic or abdominal recurrence from endometrial carcinoma. Tumor can be completely resected and local control of the disease can be achieved in most of the patients, although survival could be affected by distant recurrence and intercurrent deaths.

A portrait of the nest-leaving process in early adulthood.

This paper provides an in-depth portrait of the nest-leaving process in early adulthood as it emerged in the 1980s. Event histories are used to describe transitions in and out of the parental home during the years from age 15 through age 23. We focus on the role of the "new" forms of living arrangements in the leaving-home process, namely nonfamily living and cohabitation. The results show that the transition to full residential independence is more gradual, with more intermediate steps, than previous studies suggested. Cohabitation is rare as a route out of the parental home, and both nonfamily living and cohabitation lead to much higher return rates than does marriage.

Different patterns of chromosome and molecular breakage in classic Ph1 chronic myelogenous leukemia (CML) and variant Ph1 CML.

Variant translocations involving either chromosome 9, chromosome 22, or both with other chromosomes have been reported in about 8% of chronic myelogenous leukemia (CML) patients. In the 22 Ph+ patients studied in our laboratory, two showed variant translocations: t(9;22;11) (q34;q11;q13), and t(9;11) (q34;q11). We compared the pattern of involvement of different chromosomes (and bands) in secondary structural changes in CMLs carrying the t(9;22) (q34;q11) and in the variant translocations. Analysis showed significant differences in the pattern of involvement of different chromosomes and chromosome sites in the secondary structural changes in classic CMLs. This study, thus identifies nonrandomly involved chromosome sites that may be targeted for detailed molecular analysis to obtain an understanding of their role in disease progression. In the variant translocations chromosomes and chromosome bands were nonrandomly involved. Breakpoint cluster region (bcr) of the BCR gene was found to be rearranged in our two cases. We compared the location of molecular breaks within the bcr in classic and variant translocations. We found that translocation breaks occurred more frequently in the 5' region, and less frequently in the 3' region of bcr in variant translocations as compared with classic translocations. The significance of these findings in the etiology of CML is discussed.

Decreased expression of Ras GTPase activating protein in human trophoblastic tumors.

The normally developing placenta undergoes extensive but regulated noninvasive cellular proliferation. Various proto-oncogenes and growth factors have been associated with the regulation of trophoblastic placental growth. Activation of some oncogenes and altered expression of growth factors have been demonstrated in trophoblastic tumors (hydatidiform mole and choriocarcinoma). The ras proto-oncogene plays a key role in the signal transduction cascade of activated growth factors, and is known to be activated or overexpressed in multiple tumor types. Ras GTPase activating protein (RasGAP), a major down-regulator of ras activity, is present at high levels in placenta. To assess the role that Ras-GAP plays in the development of trophoblastic tumors, we performed immunohistochemical analyses with anti RasGAP antibodies of normal placentas, hydatidiform moles, invasive moles, and malignant choriocarcinomas. Normal placentas and noninvasive hydatidiform mole displayed intense positive staining confined to trophoblasts, whereas no staining was observed in the trophoblasts of invasive moles or choriocarcinomas. Thus, there was an inverse correlation between expression levels of RasGAP protein and the invasive potential and malignant phenotype in human trophoblastic tumors. The data indicate that RasGAP may play a regulatory role in trophoblast proliferation and that abolishing its activity may be associated with malignant transformation of these cells.

Use of cisplatin for elderly patients.

The ageing of the population has resulted in a greater emphasis on cancer treatment effects in elderly patients. This population has often had arbitrary dose modification of chemotherapy owing to fear of excessive side-effects. A review was undertaken to evaluate cisplatin toxicity in patients of 70 years of age or older. Thirty-four patients were evaluated. Their mean age was 72.8 years and 85.3% were women. Fourteen of 34 (41%) patients completed the planned therapy. Treatment was terminated because of disease progression (35%), renal toxicity (9%) and non-renal toxicity (15%). Our conclusion is that cisplatin can safely be administered to elderly patients. Arbitrary dose modification or elimination of cisplatin from a treatment programme on the grounds of patient age alone is not justified.

The life history calendar: a technique for collecting retrospective data.

"This paper details the authors' selection, design, and use of a life history calendar (LHC) to collect retrospective life course data. A sample of nine hundred [U.S.] 23-year-olds, originally interviewed in 1980, were asked about the incidence and timing of various life events in the nine years since their 15th birthday.... The following aspects of the LHC are described: (a) the concept, uses, and advantages of the LHC, (b) the time units and domains used, (c) the mode of recording the responses and the decisions and problems involved, (d) interviewer training, and (e) coding. The following results attest to the accuracy of the LHC retrospective data: (a) only four of the calendars had missing data in any month; (b) the data obtained in 1980 about current work, school attendance, marriage, and children showed a remarkable correspondence to the retrospective 1985 LHC reports of these events; (c) the interviewers were positive about the LHC's ability to increase respondent recall."

Somatic mutation analysis of the APP and Presenilin 1 and 2 genes in Alzheimer's disease brains.

The molecular basis for sporadic Alzheimer disease (AD) remains largely unknown. We hypothesized that in some cases of sporadic AD, a somatic mutation in an embryonic cell committed to neuronal development within the amyloid precursor protein (APP), the presenilin 1 (PS-1) or the presenilin 2 (PS-2) genes (genes known to be involved in familial AD) may result in AD phenotype. Using PCR, denaturing gradient gel electrophoresis (DGGE), restriction enzyme digest and direct DNA sequencing, we analyzed these genes in 99 brain tissues from patients with histopathologically proven AD. One brain sample showed a mutation within the PS-1 gene, His163 Arg, later shown to be a germline mutation. No other migration abnormalities were demonstrated in any sample in exon 16 or 17 of the APP gene or the coding exons of the PS-1 gene. Restriction digest pattern was normal with regard to the predominant PS-2 gene mutation (N141I). A known mutation in the APP gene, as well as novel mutations within the PS-1 gene were easily detected by DGGE (Reznick Wolf et al. manuscript submitted). We conclude that the genes that are involved in familial AD do not display somatic mutations in the brains of sporadic AD patients, and that other molecular mechanisms are probably involved in the pathogenesis of sporadic AD.

Sporadic cardiac myxomas and tumors from patients with Carney complex are not associated with activating mutations of the Gs alpha gene.

Cardiac myxomas are rare tumors that may be encountered sporadically or in the context of the Carney complex. The molecular basis for the development of cardiac myxomas and Carney complex tumors is unclear. Pathological myocardial function and myocardial hypertrophy have been associated with alterations in the heterotrimeric GTP-binding proteins. The postulated proto-oncogenic character of the gene encoding the alpha sub-unit of the stimulatory GTP-binding protein Gs alpha (gsp) in pituitary and thyroid tumors, the finding of identical somatic gsp mutations in the myocardium of patients with McCune-Albright syndrome, and the associated endocrine anomalies of the Carney complex prompted us to investigate the occurrence of activating missense mutations in the Gs alpha gene in 10 sporadically occurring atrial myxomas and in 8 tumors from 7 patients with Carney complex. No gsp mutations could be demonstrated by using the polymerase chain reaction and denaturing gradient gel electrophoresis complemented by direct DNA sequencing. Thus, activating Gs alpha mutations neither are associated with the development of atrial myxomas, nor can be demonstrated in other tumors from patients with Carney complex. The significance of these mutations in the myocardium of asymptomatic patients with McCune-Albright syndrome remains to be determined.