The role of canonical and non-canonical Hedgehog signaling in tumor progression in a mouse model of small cell lung cancer.

Hedgehog (Hh) signaling regulates cell fate and self-renewal in development and cancer. Canonical Hh signaling is mediated by Hh ligand binding to the receptor Patched (Ptch), which in turn activates Gli-mediated transcription through Smoothened (Smo), the molecular target of the Hh pathway inhibitors used as cancer therapeutics. Small cell lung cancer (SCLC) is a common, aggressive malignancy with universally poor prognosis. Although preclinical studies have shown that Hh inhibitors block the self-renewal capacity of SCLC cells, the lack of activating pathway mutations have cast doubt over the significance of these observations. In particular, the existence of autocrine, ligand-dependent Hh signaling in SCLC has been disputed. In a conditional Tp53;Rb1 mutant mouse model of SCLC, we now demonstrate a requirement for the Hh ligand Sonic Hedgehog (Shh) for the progression of SCLC. Conversely, we show that conditional Shh overexpression activates canonical Hh signaling in SCLC cells, and markedly accelerates tumor progression. When compared to mouse SCLC tumors expressing an activating, ligand-independent Smo mutant, tumors overexpressing Shh exhibited marked chromosomal instability and Smoothened-independent upregulation of Cyclin B1, a putative non-canonical arm of the Hh pathway. In turn, we show that overexpression of Cyclin B1 induces chromosomal instability in mouse embryonic fibroblasts lacking both Tp53 and Rb1. These results provide strong support for an autocrine, ligand-dependent model of Hh signaling in SCLC pathogenesis, and reveal a novel role for non-canonical Hh signaling through the induction of chromosomal instability.

Docetaxel plus cetuximab as second-line treatment for docetaxel-refractory oesophagogastric cancer: the AGITG ATTAX2 trial.

BACKGROUND: Cetuximab can reverse chemotherapy resistance in colorectal cancer. This study evaluated the efficacy and safety of the combination of docetaxel and cetuximab as a second-line treatment in docetaxel-refractory oesophagogastric cancer. METHODS: Patients received docetaxel 30 mg m(-2) on days 1 and 8, every 3 weeks and cetuximab 400 mg m(-2) on day 1, then 250 mg m(-2) weekly. Biomarker mutation analysis was performed. RESULTS: A total of 38 patients were enrolled. Response rates were PR 6% (95% CI 2-19%), s.d. 43% (95% CI 28-59%). Main grade 3/4 toxicities were febrile neutropenia, anorexia, nausea, diarrhoea, stomatitis, and acneiform rash. Median progression-free and overall survival were 2.1 and 5.4 months, respectively. A landmark analysis showed a trend to improved survival times with increased grade of acneiform rash. No KRAS, BRAF or PIK3CA mutations were observed. CONCLUSION: Cetuximab and docetaxel achieve modest responses rates, but maintain comparable survival times to other salvage regimens with low rates of toxicity.

Bevacizumab is equally effective and no more toxic in elderly patients with advanced colorectal cancer: a subgroup analysis from the AGITG MAX trial: an international randomised controlled trial of Capecitabine, Bevacizumab and Mitomycin C.

BACKGROUND: In an ageing population, a greater proportion of geriatric patients will be considered for systemic chemotherapy. Colorectal cancer (CRC) is a common malignancy and will be a major health issue in geriatrics. We used the MAX population to investigate whether age affected the improved outcome found in CRC when bevacizumab is added to capecitabine chemotherapy. PATIENTS AND METHODS: MAX, a three arm study of Capecitabine (C) versus CBevacizumab (CB) versus CBMitomycin C (CBM), found an improvement in progression-free survival (PFS), with addition of B [+/- mitomycin C (MMC)] to C. This analysis assesses the effect of adding B (+/- MMC) to C on PFS, overall survival (OS), response rate (RR), toxicity and dose intensity in geriatric patients (age ≥ 75 years). RESULTS: Ninety-nine patients (21%) were aged 75-86 years. Baseline characteristics were well balanced. Eighty-eight per cent commenced C at the lower optional dose of 2000 mg/m(2)/day; days 1-14, q21 (61% for <75 years) and 88% were Eastern Cooperative Oncology Group 0-1. Co-morbidities were as expected in this population. The addition of B significantly improved PFS in geriatric patients(C 5.8 months versus CB 8.8 months, Hazard ratio (HR) 0.65 and C versus CBM 10.4 months HR 0.38). The interaction test for OS, RR and PFS revealed no impact of age. Dose intensity was maintained >90% in all patients. There were no major differences in toxicity patterns between age cohorts. CONCLUSIONS: Addition of B to C significantly improved PFS in this geriatric population, with similar benefits to those aged <75 years. Treatment was well tolerated with no signal of increased toxicity (including thromboembolism) when compared with those aged <75 years.

Randomised, non-comparative phase II study of weekly docetaxel with cisplatin and 5-fluorouracil or with capecitabine in oesophagogastric cancer: the AGITG ATTAX trial.

BACKGROUND: Docetaxel administered 3-weekly with cisplatin and 5-fluorouracil leads to better survival than does standard therapy in patients with oesophagogastric cancer, but leads to high rates of haematological toxicity. Weekly docetaxel is associated with less haematological toxicity. This randomised phase II study tested weekly docetaxel-based combination chemotherapy regimens, with the aim of maintaining their activity while reducing toxicity. METHODS: Patients with histologically confirmed metastatic oesophageal or gastric carcinoma were randomised to receive weekly docetaxel (30 mg m(-2)) on days 1 and 8, cisplatin (60 mg m(-2)) on day 1, and 5-fluorouracil (200 mg m(-2) per day) continuously, every 3 weeks (weekly TCF, wTCF); or docetaxel (30 mg m(-2)) on days 1 and 8 and capecitabine (1600 mg m(-2) per day) on days 1-14, every 3 weeks (weekly TX, wTX). RESULTS: A total of 106 patients were enrolled (wTCF, n=50; wTX, n=56). Response rates, the primary end point, were 47% with wTCF and 26% with wTX. Rates of febrile neutropenia were low in each arm. Median progression-free and overall survival times were 5.9 and 11.2 months for wTCF and 4.6 and 10.1 months for wTX, respectively. CONCLUSION: Weekly TCF and TX have encouraging activity and less haematological toxicity than TCF administered 3-weekly. Weekly docetaxel-based combination regimens warrant further evaluation in this disease.

Phase II study of paclitaxel and vinorelbine (Pacl-Vin) in hormone-refractory metastatic prostate cancer: double tubulin targeting.

BACKGROUND: Androgen ablation is the standard treatment for advanced prostate cancer. However, most patients will eventually develop progressive hormone-refractory prostate cancer (HRPC). The aim of the Pacl-Vin study was to determine the efficacy and safety of paclitaxel in combination with vinorelbine in patients with HRPC, following from a phase I trial. METHODS: Thirty castrate patients with progressive, metastatic prostate cancer were enrolled. Patients were treated with paclitaxel 40 mg/m2, vinorelbine 20 mg/m2 intravenously on day 1 and day 8 of a 21-day cycle. RESULTS: Two patients demonstrated a partial response and seven patients had stable disease from a cohort of 10 patients with measurable disease. Of 30 patients assessable for prostate-specific antigen (PSA) response, 19 showed stable disease, which was maintained for at least 4 weeks, while six (20%) experienced>or=50% decline in PSA levels. Median overall survival was 7.3 months (interquartile range (IQR): 4.7-9.9 months). Median progression-free survival was 3.3 months (IQR: 2.5-7.0 months). Improvement in quality of life measures was noted after three cycles of therapy. Grade 3 and 4 toxicities were: neutropenia 8%, febrile neutropenia 4%, infection 2%, anaemia 3%, lethargy 1% and somnolescence 1%. One patient died as a result of neutropenic sepsis. CONCLUSION: In a poor prognostic cohort of patients paclitaxel and vinorelbine is a tolerable regimen, with a 20% PSA and objective response rate. The majority of patients achieved PSA stability. Furthermore, quality of life parameters, such as pain, were improved. However, the low level of activity of this regimen precludes its further testing.

A phase I trial of Capecitabine+Gemcitabine with radical radiation for locally advanced pancreatic cancer.

Standard chemoradiotherapy with infusional 5FU for locally advanced pancreatic cancer (LAPC) has limited efficacy in this disease. The combination of Capecitabine (Cap) and Gemcitabine (Gem) are synergistic and are potent radiosensitisers. The aim of this phase I trial was thus to determine the highest administered dose of the Cap plus Gem combination with radical radiotherapy (RT) for LAPC. Patients had LAPC, adequate organ function, ECOG PS 0-1. During RT, Gem was escalated from 20-50 mg m(-2) day(-1) (twice per week), and Cap 800-2000 mg m(-2) day(-1) (b.i.d, days 1-5 of each week). Radiotherapy 50.4 Gy/28 fractions/5.5 weeks, using 3D-conformal techniques. Three patients were entered to each dose level (DL). Dose-limiting toxicity(s) (DLTs) were based on treatment-related toxicities. Twenty patients were accrued. Dose level (DL) 1: Cap/Gem; 800/20 mg m(-2) day(-1) (3 patients), DL2: 1000/20 (12 patients), DL3: 1300/30 (5 patients). Dose-limiting toxicities were observed in DL3; grade 3 dehydration (1 patient) and grade 3 diarrhoea and dehydration (1 patient). Dose level 2 was the recommend phase 2 dose. Disease control rate was 75%: PR=15%, SD=60%. Median overall survival was 11.2 months. The addition of Cap and Gem to radical RT was feasible and active and achieved at relatively low doses.

Policy implications for implementing evidence-based practices.

The authors describe the policy and administrative-practice implications of implementing evidence-based services, particularly in public-sector settings. They review the observations of the contributors to the evidence-based practices series published throughout 2001 in Psychiatric Services. Quality and accountability have become the watchwords of health and mental health services; evidence-based practices are a means to both ends. If the objective of accountable, high-quality services is to be achieved by implementing evidence-based practices, the right incentives must be put in place, and systemic barriers must be overcome. The authors use the framework from the U.S. Surgeon General's 1999 report on mental health to describe eight courses of action for addressing the gap between science and practice: continue to build the science base; overcome stigma; improve public awareness of effective treatments; ensure the supply of mental health services and providers; ensure delivery of state-of-the-art treatments; tailor treatment to age, sex, race, and culture; facilitate entry into treatment; and reduce financial barriers to treatment.

A phase I and pharmacokinetic study of paclitaxel and epirubicin in advanced cancer.

The objectives of this phase I trial were to determine the maximally tolerated doses of the combination of epirubicin and paclitaxel with and without G-CSF (granulocyte colony stimulating factor) support and to investigate whether epirubicin pharmacokinetics are altered by paclitaxel. Patients with advanced cancer, performance status 0-2, and a normal left ventricular ejection fraction who had received up to 1 prior chemotherapy regimen were treated with epirubicin followed by a 3-hour infusion of paclitaxel repeated every 3 weeks. Dose levels studied were (paclitaxel/epirubicin) 155/75, 175/75, 175/90, 200/90 mg/m2 without G-CSF and 175/90 mg/m2 with G-CSF. Thirty-five patients were entered and all were assessable for toxicity. The dose-limiting dose level was 175 mg/m2 paclitaxel and 90 mg/m2 epirubicin with limiting toxicities of febrile neutropenia, diarrhea and esophagitis. The addition of G-CSF did not allow escalation of epirubicin. No significant cardiac toxicity was observed. Epirubicin pharmacokinetics were studied during the first 2 cycles in 6 patients, who were randomized to receive 1 cycle with no interval between the completion of the epirubicin and the commencement of the paclitaxel infusion and the other cycle with a 72-hour interval between the drugs. There was no substantial effect of paclitaxel on epirubicin or epirubicinol pharmacokinetics, although there was a marginal increase in glucoronidation. In conclusion, paclitaxel 175 mg/m2 and epirubicin 75 mg/m2 is recommended for phase II and III studies.

The MHSIP mental health report card. A consumer-oriented approach to monitoring the quality of mental health plans. Mental Health Statistics Improvement Program.

Health care report cards have been endorsed as a mechanism for efficiently comparing key quantifiable aspects of performance across a range of health systems or plans. There are challenges in determining what to measure; how to gather and analyze data; and how to report, interpret, and use findings. Mental health has received little attention, and a consumer perspective is typically not included. The proposed MHSIP mental health report card (MMHRC) addresses these concerns. General issues for report cards are discussed, and the MMHRC is described in terms of content, data sources and quality, and analysis and reporting.

Activity and toxicity of docetaxel (Taxotere) in women with previously treated metastatic breast cancer.

BACKGROUND: Metastatic breast cancer is a major cause of cancer death in Australian women. Docetaxel is a new cytotoxic drug that has shown promise in the treatment of metastatic breast cancer in patients who have previously received other chemotherapy, particularly an anthracycline, and has recently been approved for marketing in Australia. AIM: To report the first Australian experience with docetaxel in a group of women with metastatic breast cancer. METHODS: Patients with progressive metastatic breast cancer who had previously received other chemotherapy were treated with docetaxel 75 mg/m2 or 100 mg/m2 given as a one hour infusion every three weeks. All patients received oral dexamethasone for five days starting 24 hours prior to docetaxel as prophylaxis against fluid retention. The patients' response to docetaxel and toxicity were assessed by standard criteria. RESULTS: Twenty-six patients were treated. The major toxicity was neutropenia with 92% of patients experiencing at least one episode of grade 4 (absolute neutrophil count < 0.5 x 10(9)/L) neutropenia. Hospital admission for febrile neutropenia occurred in 44% of patients with one death from sepsis. Cumulative fluid retention was observed but in only one patient was it dose-limiting. Apart from alopecia, other toxicities were infrequent and rarely serious. In 23 patients assessable for response, there were 11 partial responses (48%). Three other patients whose disease could not be assessed for response had clinical improvement. The median survival of all patients treated was eight months. CONCLUSIONS: The response rate observed with docetaxel is comparable to that seen in trials in the United States and Europe and confirms the high activity of this new cytotoxic agent. Neutropenia is the major toxicity, and consideration should be given to the use of prophylactic oral antibiotics or colony stimulating factors to try and prevent febrile episodes. Clinicians will need to balance the benefits, toxicities, and cost of docetaxel in determining the appropriateness of its use in their patients.

Region-specific loss of heterozygosity on chromosome 19 is related to the morphologic type of human glioma.

Allelic mutation on chromosome 19 has previously been reported as a frequent genetic event in human glial tumors. In an effort to localize specific regions of importance on this chromosome better, 13 highly polymorphic genetic markers distributed along the length of chromosome 19 were used for evaluation of loss of heterozygosity (LOH) and microsatellite instability in a total of 100 brain tumors, including 75 astrocytomas (55 grade 4; 7 grade 3; 5 grade 2; 6 grade 1; and 2 other), 17 oligodendrogliomas (1 grade 4; 5 grade 3; 10 grade 2; and 1 grade 1), and 8 mixed oligoastrocytomas (MOA) (3 grade 4; 2 grade 3; and 3 grade 2). No microsatellite expansion was observed in these glial tumors for any of the chromosome 19 loci examined. LOH for loci on chromosome 19 was detected in 23/74 informative astrocytomas (31%), 11/17 oligodendrogliomas (65%), and 3/8 MOA (38%). Partial deletion of chromosome 19 occurred more frequently (31/37 cases) than did loss of one whole copy of the chromosome, and a morphology-specific pattern of LOH was observed. In 12/14 (86%) instances of chromosome 19 deletion in oligodendrogliomas and MOA, the 19q arm showed LOH, whereas the 19p arm showed no loss for all informative loci. Conversely, in 17/23 (74%) instances of chromosome 19 deletion in astrocytomas, the 19p arm showed LOH, whereas the 19q arm showed no loss for one or more loci. Thus, loss of 19q and retention of 19p are strongly associated with oligodendroglioma and MOA, whereas loss of 19p and retention of distal 19q is associated with astrocytoma.(ABSTRACT TRUNCATED AT 250 WORDS)

Prognostic factors in gliomas. A multivariate analysis of clinical, pathologic, flow cytometric, cytogenetic, and molecular markers.

BACKGROUND: The ability to divide subsets of patients with glial neoplasms into prognostic groups currently is limited because only a few clinical and pathologic variables are available. The goal of this investigation was to identify biologic factors of potential prognostic value in patients with cerebral gliomas. METHODS: This prospective investigation used clinical, pathologic, flow cytometric, cytogenetic, and molecular genetic variables as potential prognostic factors in 207 patients with newly diagnosed gliomas (153 astrocytic tumors of the fibrillary type, 31 oligodendrogliomas, and 23 pilocytic astrocytomas). Classification and regression tree (CART) analysis was performed as part of the multivariate statistical analysis. RESULTS: The age of the patient and the grade of the tumor were confirmed as strong prognostic factors. Cytogenetic or molecular genetic abnormalities of chromosomes 7 and 10 were associated with poor survival in univariate analysis (P < 0.0001). CART multivariate analysis identified several subsets of patients with different prognoses. In the subset of patients younger than 66.5 years with Grade 4 tumors, the survival time was longer for those with aneuploid tumors than for those with nonaneuploid tumors. In the subset of patients with Grades 1-3 tumors, the survival time was longer for those whose tumors had a %G2M of less than 6.9 than for those whose tumors had a %G2M of 6.9 or greater. CONCLUSION: This investigation provides further evidence that flow cytometry, cytogenetic, and molecular genetic factors that may have prognostic value in patients with gliomas can be identified.

Phase I study of combined alpha interferon, alpha difluoromethylornithine (DFMO), and doxorubicin in advanced malignancy.

Interferon (IFN) and conventional cytotoxic chemotherapeutic agents have been successfully combined in various studies. Alpha difluoromethylornithine (DFMO) is a novel antitumor agent which is an inhibitor of polyamine metabolism. A phase I study of IFN 24 x 10(6) U/m2/day IM (days 3-7), DFMO 9 gm/m2 p.o. daily (days 1-7), and a variable dose of doxorubicin starting at 20 mg/m2 (day 6), of each 28 day cycle was performed. The aim of the study was to determine the maximally tolerable dose of doxorubicin in this combination. Three patients were treated with doxorubicin at 20 mg/m2 and six patients at 40 mg/m2. The dose limiting toxicities were neutropenia, fatigue and fever. All other toxicities were mild and there was no grade IV toxicity. A doxorubicin dose of 40 mg/m2 produced tolerable toxicity and is recommended for phase II studies. No major antitumor effects were seen.

Hispanic Americans and the state mental hospitals in Texas: ethnic parity as a latent function of a fiscal incentive policy.

This paper examines patterns of utilization of the state mental hospitals in Texas by Hispanics compared to Anglos over a 5-year period from FY 1984 to FY 1988. Historically, Hispanics have been underrepresented in public mental health client populations in the United States. In the mid-1980s in Texas, the ethnic gap in use of psychiatric facilities was expected to widen as Hispanic population growth outpaced the capacity of the public system to provide accessible mental health services for persons with serious and persistent psychiatric illnesses. But in the inpatient sector, the gap narrowed significantly in the second half of the decade, due to a policy-driven sharp reduction in the overall census of the state mental hospitals. A fiscal incentive program to stimulate the development of community-based mental health services had a markedly different effect on subsequent inpatient utilization by Anglos compared to Hispanics, most notably in counties that were less urban and less affluent and counties with a relatively high proportion of Hispanic residents. The context and mixed implications of these developments are explored.

Molecular genetics of neuroendocrine tumors.

Neuroendocrine tumors are a group of malignancies that arise from primitive neuroectodermal cells. There is, however, considerable variation in the location and clinical behavior of these tumors. They are often difficult to distinguish from other malignancies and difficult to classify. Recent advances in molecular genetics have attempted to resolve some issues regarding accurate diagnosis, classification into prognostic subgroups, and understanding of basic common mechanisms underlying the development of these tumors. Correlation of morphologic changes with molecular changes induced by some potential therapeutic differentiating agents may lead to more rational therapy for these malignancies.

Current status of adjuvant chemotherapy for colorectal cancer. Can molecular markers play a role in predicting prognosis?

BACKGROUND: Recent clinical trials establish a beneficial effect for adjuvant chemotherapy after surgical resection of the primary tumor (1) as single treatment for patients with colonic cancer and (2) combined with radiation therapy for patients with rectal cancer. Because adjuvant chemotherapy is not universally effective and is associated with toxicity and some degree of risk, it would be desirable to supplement standard pathologic staging criteria to define more precisely the subset of patients at high risk for tumor recurrence who would benefit most from adjuvant therapy. Tumor cell DNA content and cell proliferation measured by flow cytometry were identified as important and independent prognostic factors for patients undergoing curative resection of colorectal cancer. Basic laboratory investigations show a series of more specific molecular and genetic abnormalities that might provide better prognostic discrimination. Recent molecular studies suggest that the process of tumorigenesis in colorectal cancer proceeds through a series of genetic alterations that include both dominant and recessive protooncogenes. Characterization of these molecular genetic abnormalities may provide valuable prognostic information for use in patient management. METHODS: Allelic loss was studied for chromosomes 5, 17, and 18, and immunohistochemical analysis was done of the p53 protein product in tumors from 91 patients with colorectal cancer. RESULTS: Preliminary analysis of disease-free survival after surgical resection in 60 patients with Dukes' B or C tumors suggests a poorer prognosis associated with allelic loss on chromosome 18q (P = 0.08). CONCLUSIONS: Additional studies involving a much larger population of patients with Dukes' B and C colorectal cancer are needed to define the true prognostic significance of these molecular markers.