Final report on serial phase II trials of all-intraperitoneal chemotherapy with or without bevacizumab for women with newly diagnosed, optimally cytoreduced carcinoma of Müllerian origin.

BACKGROUND: Intraperitoneal (IP) chemotherapy can improve outcomes for women with optimally cytoreduced epithelial ovarian cancer but toxicities are a concern. We conducted 2 phase 2 trials of an IV/IP regimen using carboplatin and paclitaxel without (Trial A) and with bevacizumab (Trial B). METHODS: Both trials consisted of carboplatin AUC 6 day 1, and paclitaxel 60 mg/m2 on days 1,8, 15 of a 21-day cycle; in Trial B, patients received IV bevacizumab 15 mg/kg every cycle starting cycle 2. Chemotherapy was administered IV for cycle 1 and then IP for all subsequent cycles. Primary objectives included safety and tolerability, pathologic CR rate (Trial A), and the rate of completion of IP cycles of therapy (Trial B). Progression-free (PFS), overall survival (OS), and pharmacokinetic analysis were secondary endpoints. RESULTS: 81 patients were treated on both trials (n = 40 and 41 in trials A and B, respectively). Median age for trials A and B was 59 (range, 36-76) and 55 (range, 19-69) years, respectively. 68% and 85% of patients, respectively for A and B, completed at least 4 cycles of treatment in both trials. Treatment with bevacizumab resulted in higher rates of grade 3 fatigue (37 versus 33%) and grade 3-4 diarrhea (22 versus 8%). Median PFS was 23.5 (95%CI 16.2-35.3) and 25 (95%CI 16.4-42.7) months, respectively; median OS was 68 (95%CI 49.5-NR) and 79.7 (95%CI 59.0-79.7) months, respectively for Trial A and B. CONCLUSIONS: Weekly administered IP carboplatin and IP paclitaxel is tolerable and safe with similar activity with and without concommittant bevacizumab in these 2 trials.

Stage-for-stage comparison of definitive chemoradiotherapy, surgery alone and neoadjuvant chemotherapy for oesophageal carcinoma.

BACKGROUND: Definitive chemoradiotherapy (dCRT) has been proposed as an alternative therapy for selected patients with oesophageal cancer. The aim of this study was to determine the outcomes of dCRT, surgery alone, and neoadjuvant chemotherapy followed by surgery (CS) in patients with oesophageal cancer. METHODS: Consecutive patients diagnosed with oesophageal cancer and managed by a multidisciplinary team were staged by computed tomography and endoluminal ultrasonography. Those deemed unsuitable for surgery on the grounds of performance status, bulky local disease or personal choice received dCRT. The primary outcome measure was overall survival measured from date of diagnosis. RESULTS: Of 417 patients, 173 received dCRT, 126 underwent surgery alone and 118 received CS. The incidence of grade III/IV toxicity after dCRT and CS was 39.3 and 60.2 per cent respectively. Operative morbidity rates were 42.9 and 44.4 per cent after surgery alone and CS respectively. Thirty-day mortality rates were zero, 7.9 and 0.8 per cent after dCRT, surgery alone and CS respectively. Overall 2-year survival rates were 44.3, 56.2 and 42.4 per cent (P = 0.422). CONCLUSION: These findings support the need for a randomized trial of dCRT versus CS for resectable oesophageal cancer.

Phase II multicenter open-label study of karenitecin in previously treated epithelial ovarian and primary peritoneal cancer: a Gynecologic Oncology Group Study.

The topoisomerase I agents are established as a therapy in recurrent ovarian cancer. Karenitecin, an analog of topotecan with solubility and pharmacologic advantages, was tested in a phase II trial in previously treated patients with recurrent or persistent ovarian cancer. The drug was administered intravenously over 1 h at a dose of 1.0 mg/m(2) daily for 5 days every 21 days. Patients were treated until disease progression, intolerable toxicity, or voluntary withdrawal. Response was evaluated according to modified RECIST criteria. Twenty-seven patients were entered into the study. One patient was inevaluable for not receiving any treatment. Of the 26 evaluable patients, there were two partial responses and one complete response for a total response rate of 12%. This response rate was insufficient to justify accrual to the second stage. The most common grade 3 or 4 toxicities were neutropenia (19%) and gastrointestinal (15%). Karenitecin is a well-tolerated topoisomerase compound but has minimal activity in extensively pretreated ovarian cancer with the dose-schedule employed.

Prospective comparison of endosonography, computed tomography, and histopathological stage of junctional oesophagogastric cancer.

AIMS: To assess the strength of agreement between the perceived preoperative stage of Siewert II (oesophagogastric junction) and Siewert III (proximal gastric tumours) as determined by computed tomography (CT) and endoscopic ultrasound (EUS), both alone and in combination, with histopathological stage. METHODS: Forty-four patients with Siewert II (n=18) and III (n=26) adenocarcinomas of the oesophagogastric junction underwent preoperative CT at their local hospitals followed by specialist EUS, and the strengths of the agreement between the radiological stages and the histopathological stages were determined by the weighted Kappa statistic (Kw). RESULTS: Kw for Siewert II T and N stages was 0.491 (p=0.016) and 0.4 (p=0.087) for CT compared with 0.852 (p=0.0001) and 1 (p=0.0001) for EUS. Kw for Siewert III T and N stages was 0.181 (p=0.206) and 0.121 (p=0.376) for CT compared with 0.173 (p=0.195) and 0.263 (p=0.031) for EUS. CONCLUSION: Siewert II tumour T and N stages were more accurately predicted by EUS than CT, but Siewert III tumour T and N stages were more difficult to assess, arguably because of anatomical constraints at the oesophagogastric junction. CT and EUS are complimentary techniques, and these results highlight the importance of multidisciplinary discussion in planning treatment.

Prognostic significance of failure to cross esophageal tumors by endoluminal ultrasound.

SUMMARY: Failure to intubate and cross esophageal tumors by endosonography is reported in as many as 30% of cases and is thought to be associated with an especially poor prognosis. The aim of this study was to audit the above in a large consecutive case series of Endoscopic Ultrasound (EUS) examinations for esophageal cancer performed in a regional specialist cancer network with particular reference to outcome. A consecutive series of 411 patients underwent EUS examination by a specialist radiologist over a period of 9 years. Forty (10%) of patients required dilation, and there was total failure to cross the tumor in 12 patients (2.9%). Failure to traverse the primary tumor was associated with a diagnosis of squamous cell cancer (8 of 12 patients, 66%, rho = -0.182, P = 0.011). Limited staging information was obtained in 7 of these patients, which altered the computed tomography stage in 5 patients (71%, 3 upstaged, 2 downstaged). Six patients received definitive chemoradiotherapy, two patients surgery and four patients palliative chemotherapy. The median and 5-year survival in patients whose tumors were not crossed was 10 months and 28%, respectively, compared with 24 months and 24%, respectively in patients whose tumors were fully assessed. Failure to cross esophageal tumors in practice was far less common than the literature suggests, and esophageal tumor luminal stenosis should no longer be considered a limitation of endosonography.

Prospective cohort comparison of neoadjuvant chemoradiotherapy versus chemotherapy in patients with oesophageal cancer.

BACKGROUND: Chemotherapy and chemoradiotherapy are common neoadjuvant treatments for resectable T3 N0-1 M0 oesophageal carcinoma. The aim of this study was to compare the outcomes of these therapies in consecutive cohorts of patients. METHODS: Between January 1998 and December 2001, 88 patients received neoadjuvant chemoradiotherapy (two cycles of cisplatin and 5-fluorouracil (5-FU), prior to 45 Gy in 25 F concurrent radiotherapy with cisplatin and 5-FU). From 2002, 117 patients received neoadjuvant chemotherapy (76 patients had two cycles of cisplatin and 41 had four cycles of epirubicin, cisplatin and 5-FU). The primary outcome measure was survival, and analysis was by intention to treat. RESULTS: Postoperative morbidity and mortality rates were 56 per cent (40 patients) and 10 per cent (seven patients) respectively in the chemoradiotherapy group, compared with 47 per cent (46 patients) and 1 per cent (one patient) in the chemotherapy group (P = 0.008). The cumulative 5-year survival rate by intention to treat was 35 per cent after chemoradiotherapy versus 21 per cent after chemotherapy (P = 0.188). The cumulative corrected 5-year survival rate after completed treatment was 44 per cent for chemoradiotherapy compared with 25 per cent for chemotherapy (P = 0.032). CONCLUSION: Neoadjuvant chemoradiotherapy should remain an option for patients with satisfactory performance status.

Deletion mapping of two potential chromosome 14 tumor suppressor gene loci in ovarian carcinoma.

Previous allelotyping studies of epithelial ovarian carcinoma suggest that loss of heterozygosity on chromosome 14q may be a common genetic alteration in this tumor type. The purpose of this study was to determine a precise frequency of chromosome 14q allelic loss in ovarian carcinomas and to define a minimal region(s) of deletion. Seventy-six ovarian carcinomas representative of the complete spectrum of grade, stage, and histological subtype were selected for PCR-based deletion mapping analysis using 15 highly polymorphic microsatellite markers spanning the length of this chromosome arm. Loss of heterozygosity was observed in 49% of the tumors studied, placing 14q among the most frequently affected chromosomal regions in ovarian cancer. Deletions were observed in all tumor grades and stages and in all histological subtypes except tumors of low malignant potential. Deletion of the entire chromosome arm was rare; the majority of tumors displayed partial losses, providing an informative basis for detailed deletion mapping. Two distinct minimal regions of deletion were delineated. One region was defined by markers D14S80 and D14S75 at 14q12-13, and the other region was defined by markers D14S65 and D14S267 at 14q32. These data implicate the involvement of two tumor suppressor genes on chromosome 14q in a substantial fraction of ovarian carcinomas.

Mutations of the BRCA2 gene in ovarian carcinomas.

Inherited mutations in the recently discovered BRCA2 gene are believed to be responsible for a significant fraction of early-onset hereditary breast cancers. Unlike BRCA1, however, which confers a high risk to both breast and ovarian cancer, the incidence of ovarian cancer appears to be much lower In BRCA2-linked families, causing uncertainty as to the relevance of BRCA2 to hereditary ovarian cancer. Numerous allelotype studies indicate that allelic deletions Including the BRCA2 locus on chromosome 13q are common in ovarian cancers in general, suggesting that somatic mutations of this gene may be involved in sporadic ovarian tumorigenesis. The purpose of this study was to test the hypothesis that germline or somatic mutations of BRCA2 are associated with hereditary and/or sporadic ovarian cancers, respectively. The entire 10.2-kb coding region of BRCA2 was screened for mutations in 130 consecutive ovarian tumors, the only selection criterion being a pathological diagnosis of epithelial ovarian carcinoma. Loss of heterozygosity at markers flanking BRCA2 was observed in 56% of the tumors. Four germline mutations and two somatic mutations were identified; two of the germline mutations are recurrent, having been previously described. Remarkably, the patients with germline mutations were late-onset cases with no medical or family histories suggestive of hereditary cancer. These data suggest that mutations of BRCA2 are rare in sporadic ovarian cancers, and that the proportion of ovarian cancers resulting from hereditary predisposition may be higher than previously suspected based on estimates derived from studies of highly penetrant genetic loci.

Therapeutic efficacy of prenylation inhibitors in the treatment of myeloid leukemia.

Farnesyltransferase inhibitors (FTIs) represent a new class of anticancer agents that specifically target post-translational farnesylation of various proteins that mediate several cellular processes such as signal transduction, growth, differentiation, angiogenesis and apoptosis. These compounds were originally designed to block oncogenic RAS-induced tumor growth by impeding RAS localization to the membrane, but it is now evident that FTIs also affect processing of several other proteins. The need for novel therapies in myeloid leukemia is underscored by the high rate of treatment failure due to high incidences of relapse- and treatment-related toxicities. As RAS deregulation is important in the pathogenesis of myeloid leukemias, targeting of RAS signaling may provide a new therapeutic strategy. Several FTIs (eg BMS-214662, L-778,123, R-115777 and SCH66336) have entered phase I and phase II clinical trials in myeloid leukemias. This review discusses recent clinical results, potential combination therapies, mechanisms of resistance and the clinical challenges of toxicities associated with prenylation inhibitors.

Synergistic cytotoxic effects in myeloid leukemia cells upon cotreatment with farnesyltransferase and geranylgeranyl transferase-I inhibitors.

As deregulation of RAS signaling is important in the pathogenesis of myeloid leukemias, molecular targeting of RAS signaling may be a promising therapeutic strategy. Farnesyl transferase inhibitors (FTIs) are the most promising class of these new cancer therapeutics. Several FTIs have entered phase II clinical trials in acute myeloid leukemia (AML). Since geranylgeranylation of K-RAS and N-RAS in the presence of FTIs may represent an important mechanism of FTI resistance, 6 geranylgeranyl transferase-I inhibitors (GGTIs) were screened alone and in combination with FTI for growth inhibition of myeloid leukemia cells. Significant growth inhibition (>70%) in myeloid cell lines was observed for GGTI-286 (9/19), GGTI-298 (14/19), GGTI-2147 (16/19) and FTI L-744,832 (17/17). GGTI treatment of NB-4 cells resulted in an accumulation of cells in G(0)/G(1), whereas FTI L-744,832 primarily caused an increase in G(2)/M. FTI and GGTIs both induced apoptosis. In all cases, FTI/GGTI cotreatment led to synergistic cytotoxic effects in both myeloid cell lines (5/5) and primary AML cells (6/6). This synergy coincided with increased apoptosis. FTI/GGTI cotreatment caused an accumulation of unprocessed N-RAS and inactive N-RAS-RAF complexes. Our results suggest that alternative geranylgeranylation of N-RAS may represent an important mechanism of resistance to FTI monotherapy in myeloid leukemia cells.

Estrogens and non-reproductive behaviors related to activity and fear.

Estrogens affect a variety of behaviors in addition to sexual responses, some of them related to motor activity and emotional reactivity. This is true in experimental animals and in humans. The literatures on these subjects are confusing because not all of the experimental results point in the same direction. Here we propose the following theoretical suggestion, hoping to account for the variety of reports extant: following the generally arousing effects of estrogens, their hormonal actions on motor activity and fear depend on context. In a safe environment, estrogen treatment causes increased activity. But in a novel environment or in contexts otherwise perceived as threatening, activity is reduced by estrogen, due to the hormone's arousing action, which heightens fear. Many hormone-dependent neural circuits involving several neuropeptides could provide mechanisms for this dynamic. We suggest a causal route could involve the activation of corticotropin releasing hormone gene expression in the brain. In sum, estrogenic effects on arousal states, as manifest differently according to details of the environmental context during behavioral test, could account for some of the discrepancies in the literature.

Paranoid schizophrenia may be caused by dopamine hyperactivity of CA1 hippocampus.

Explicit consolidation of memory, or fixation of declarative belief, appears to be physically represented in changes of synaptic conductances of neurons in the parietal-temporal-occipital association cortex (PTO) of the mammalian forebrain. This fixation of belief in PTO is postulated to be critically dependent on a diffuse reinforcement signal via the inferior temporal cortex (ITC) ultimately caused by an increased output of the CA1 pyramidal cells of hippocampus. Analogous to the reinforcing mechanisms of other forebrain systems, this updating of the connection weights of the neural nets in PTO by the output of the critical neurons in CA1 is directly related to concentrations of dopamine (DA). We propose that the delusions (i.e., unreasonable beliefs) of paranoid schizophrenia are caused by a hyperactivity of the same DA-sensitive CA1 neurons that are responsible for the fixation of normal beliefs. The dramatic reduction in delusions with administration of neuroleptics, as DA D2 blockers, in schizophrenics may thus be explained by their acting to ameliorate the hyperactivity of these CA1 DA D2 receptors.

Complete amino acid sequence of the nucleic acid-binding protein of bovine leukemia virus.

The complete amino acid sequence of the nucleic acid-binding protein p12 of bovine leukemia virus (BLV) has been determined. Peptides were generated by enzymatic digestion and formic acid cleavage, purified by reversed-phase liquid chromatography and subjected to automated Edman degradation. BLV p12 is a proline-rich linear polypeptide composed of 69 amino acids with Mr 7558. A comparison of the p12 structure to that of the avian and murine type C retroviral nucleic acid-binding proteins shows significant homology only in the putative binding domain. This conserved region is duplicated BLV p12 as in the avian homolog.

Lung tumor induction in strain A mice with benzotrichloride.

Benzotrichloride (BTC) is used in the synthesis of benzoyl chloride and benzoyl peroxide. Epidemiological data suggest that BTC is a human lung carcinogen. In the present study, BTC was evaluated for its ability to induce lung adenomas in strain A/J mice. Four groups of 15 male and 15 female A/J mice were injected i.p. with either tricaprylin or BTC in tricaprylin three times a week for 8 weeks. BTC groups received doses totaling 1440 mg/kg, 719 mg/kg or 287 mg/kg. The mean number of lung tumors per mouse was 127 87 +/- 5.81, 43 +/- 2.44, and 17.73 +/- 1.09 in the groups treated with either 1440 mg/kg, 719 mg/kg, or 287 mg/kg, respectively. Tricaprylin-vehicle controls had a mean number of 0.46 +/- 0.15 lung tumors per mouse. Therefore, BTC produced a significant (P less than 0.001) and dose-related increase in the lung tumor response when compared to tricaprylin controls and is a potent carcinogen in the strain A mouse lung tumor bioassay.

Application of backpropagation neural networks to diagnosis of breast and ovarian cancer.

Neural network programs have been developed in an attempt to improve the diagnosis of breast and ovarian cancer using a group of laboratory tests and the age of the patient. The laboratory tests employed in this study include albumin, cholesterol, HDL-cholesterol, triglyceride, apolipoproteins A1 and B, NMR linewidth (the Fossel Index) and a tumor marker (i.e., CA 15-3 or CA 125). The breast cancer study involved 104 patients (45 malignant and 59 benign subjects). The ovarian cancer study involved 98 individuals (35 malignant, 36 benign and 27 control subjects). Methods are outlined for identification of the most influential input parameters and optimization of network structure and training. Network characteristics were contrasted with the test results of the appropriate serum tumor marker assay. For the breast cancer study, the best neural network program, using six input parameters, had a sensitivity of only 55.6% and a specificity of 72.9%. The tumor marker CA 15-3 alone gave results of 61.3% and 64.4%, respectively. For the ovarian cancer study, the best neural network program, using six input parameters, had a sensitivity of 80.6% and a specificity of 85.5%. The tumor marker CA 125 alone gave results of 77.8% and 82.3%, respectively. These methods provide an objective approach to neural network optimization and parameter selection applicable to other data bases of clinical and laboratory data.

Levels of alpha-melanotrophin in the plasma and pituitary glands of fetal and juvenile rats, and in the plasma of adult female rats during pregnancy and lactation.

alpha-Melanotrophin was detected by radioimmunoassay in the pituitary glands of fetal rats from day 17 of gestation. The pituitary content of alpha-melanotrophin increased regularly, at a gradually decreasing rate, throughout gestation and in the postnatal period. Concentrations of alpha-melanotrophin in the plasma of fetal and newborn rats were below the detection limit of the radioimmunoassay (10 pmol/l). Detectable concentrations were first found in young rats on day 3 after birth and did not differ significantly from those in their mothers throughout the period of suckling. Plasma concentrations of alpha-melanotrophin were raised in pregnant rats during the last 4 days of gestation and after parturition. They returned to basal levels in the 2 weeks after delivery. After weaning at 3 weeks of age, a large increase in the plasma concentration of alpha-melanotrophin was detected in juvenile rats. Plasma levels had returned to the normal adult range by 6 weeks of age. The increases in alpha-melanotrophin in the blood were thought to be the result of non-specific stress effects. The data did not provide evidence for a role of alpha-melanotrophin in reproductive processes in the rat.

Cyclical changes in concentrations of alpha-melanotrophin in the plasma of male and female rats.

Radioimmunoassay measurements of alpha-melanotrophin in plasma have identified a diurnal rhythm in male rats. Animals maintained on a 12 h light : 12 h darkness photoperiod had raised levels of plasma alpha-melanotrophin during the dark phase. Time-series analysis gave a fitted mean level of alpha-melanotrophin of 52.4 pmol/l, an amplitude of 12.1 pmol/l and peak levels 2.2 h before dawn. Measurements throughout the oestrous cycle in female rats showed that similar variations between the dark and light phases occurred on the 2 days of dioestrus. The raised levels during the dark period were, however, absent on the nights of pro-oestrus and oestrus. During this pro-oestrous/oestrous period, plasma alpha-melanotrophin levels were below average but higher than the normal minimum levels found during the light period.

Tetrasomy of the short arm of chromosome 9: prenatal diagnosis and further delineation of the phenotype.

A fetus with multiple malformations was identified by prenatal ultrasound investigation. Cordocentesis and fetal lymphocyte chromosome analysis demonstrated a model number of 47 chromosomes. The extra chromosome material was identified as an isochromosome of the entire short arm of chromosome 9 with no involvement of the heterochromatic region of the long arm [47,XY, + i(9p)]. This represents the first report of prenatal diagnosis of tetrasomy 9p. Further delineation of the phenotype is discussed.

Fungal sinusitis in healthy and immunocompromised individuals.

Clinical and microbiologic aspects of fungal sinusitis occurring in six patients are presented. Three of the six patients were immunosuppressed. Fatal disseminated fungal disease developed in two of those immunosuppressed. The three patients with normal immune function had fungal infections confined to the nasal sinuses. Aspergillus fumigatus and Aspergillus flavus were recovered from the immunosuppressed patients and Sporothrix schenckii, Alternaria species, and Pseudallescheria boydii were recovered from the immunocompetent patients. Surgical debridement was performed on all patients; however, anti-fungal therapy only was prescribed in patients who were at risk of progressive fungal disease. The microbiology laboratory aids in the diagnosis of fungal sinusitis by examining surgical biopsy material for fungal organisms and by culturing the material for recovery of the fungal pathogen.