A multicenter, open-label, randomized, phase II study of cediranib with or without lenalidomide in iodine 131-refractory differentiated thyroid cancer.

BACKGROUND: Multitargeted tyrosine kinase inhibitors (TKIs) of the vascular endothelial growth factor receptor (VEGFR) pathway have activity in differentiated thyroid cancer (DTC). Lenalidomide demonstrated preliminary efficacy in DTC, but its safety and efficacy in combination with VEGFR-targeted TKIs is unknown. We sought to determine the safety and efficacy of cediranib, a VEGFR-targeted TKI, with or without lenalidomide, in the treatment of iodine 131-refractory DTC. PATIENTS AND METHODS: In this multicenter, open-label, randomized, phase II clinical trial, 110 patients were enrolled and randomized to cediranib alone or cediranib with lenalidomide. The primary endpoint was progression-free survival (PFS). Secondary endpoints included response rate, duration of response, toxicity, and overall survival (OS). Patients (≥18 years of age) with DTC who were refractory to further surgical or radioactive iodine (RAI) therapy as reviewed at a multispecialty tumor board conference, and evidence of disease progression within the previous 12 months and no more than one prior line of systemic therapy were eligible. RESULTS: Of the 110 patients, 108 started therapy and were assessable for efficacy. The median PFS was 14.8 months [95% confidence interval (CI) 8.5-23.8 months] in the cediranib arm and 11.3 months (95% CI 8.7-18.9 months) in the cediranib with lenalidomide arm (P = 0.36). The 2-year OS was 64.8% (95% CI 43.3% to 86.4%) and 75.3% (95% CI 59.4% to 91.0%), respectively (P = 0.80). The serious adverse event rate was 41% in the cediranib arm and 46% in the cediranib with lenalidomide arm. CONCLUSIONS: Single-agent therapy with cediranib showed promising efficacy in RAI-refractory DTC similar to other VEGFR-targeted TKIs, while the addition of lenalidomide did not result in clinically meaningful improvements in outcomes.

OPTIMA: a phase II dose and volume de-escalation trial for human papillomavirus-positive oropharyngeal cancer.

BACKGROUND: Patients with HPV+ oropharyngeal squamous cell carcinoma were assigned to dose and volume de-escalated radiotherapy (RT) or chemoradiotherapy (CRT) based on response to induction chemotherapy in an effort to limit treatment-related toxicity while preserving efficacy. PATIENTS AND METHODS: Patients were classified as low-risk (≤T3, ≤N2B, ≤10 pack-year history) or high-risk (T4 or ≥N2C or >10 PYH). After three cycles of carboplatin/nab-paclitaxel, response was assessed using Response Evaluation Criteria in Solid Tumors 1.1. Low-risk patients with ≥50% response received 50 Gray (Gy) RT (RT50) while low-risk patients with 30%-50% response or high-risk patients with ≥50% response received 45 Gy CRT (CRT45). Patients with lesser response received standard-of-care 75 Gy CRT (CRT75). RT/CRT was limited to the first echelon of uninvolved nodes. The primary end point was 2-year progression-free survival compared with a historic control of 85%. Secondary end points included overall survival and toxicity. RESULTS: Sixty-two patients (28 low risk/34 high risk) were enrolled. Of low-risk patients, 71% received RT50 while 21% received CRT45. Of high-risk patients, 71% received CRT45. With a median follow-up of 29 months, 2-year PFS and OS were 95% and 100% for low-risk patients and 94% and 97% for high-risk patients, respectively. The overall 2-year PFS was 94.5% and within the 11% noninferiority margin for the historic control. Grade 3+ mucositis occurred in 30%, 63%, and 91% of the RT50, CRT45, and CRT75 groups, respectively (P = 0.004). Rates of any PEG-tube use were 0%, 31%, and 82% for RT50, CRT45, and CRT75 groups, respectively (P < 0.0001). CONCLUSIONS: Induction chemotherapy with response and risk-stratified dose and volume de-escalated RT/CRT for HPV+ OPSCC is associated with favorable oncologic outcomes and reduced acute and chronic toxicity. Further evaluation of induction-based de-escalation in large multicenter studies is justified. CLINICAL TRIAL REGISTRATION: Clinical trials.gov identifier: NCT02258659.

Phase II trial of dasatinib for recurrent or metastatic c-KIT expressing adenoid cystic carcinoma and for nonadenoid cystic malignant salivary tumors.

BACKGROUND: Adenoid cystic carcinoma (ACC) is a subtype of malignant salivary gland tumors (MSGT), in which 90% of cases express cKIT. Dasatinib is a potent and selective inhibitor of five oncogenic protein tyrosine kinases (PTKs)/kinase families including cKIT. We conducted a phase II study to determine the antitumor activity of dasatinib in ACC and non-ACC MSGT. PATIENTS AND METHODS: In a two-stage design, patients with progressive, recurrent/metastatic ACC (+cKIT) and non-ACC MSGT (separate cohort) were treated with dasatinib 70 mg p.o. b.i.d. Response was assessed every 8 weeks using RECIST. RESULTS: Of 54 patients: 40 ACC, 14 non-ACC (1, ineligible excluded); M:F = 28 : 26, median age 56 years (range 20-82 years), ECOG performance status 0 : 1 : 2 = 24 : 28 : 2, prior radiation: 44, prior chemotherapy: 21. The most frequent adverse events (AEs) (as % of patients, worst grade 2 or higher) were: fatigue (28%), nausea (19%), headache (15%), lymphopenia (7%), dyspnea (11%), alanine aminotransferase increased (7%), anorexia (7%), vomiting (7%), alkaline phosphatase increased (6%), diarrhea (6%), neutropenia (6%), and noncardiac chest pain (6%). No grade 4 AE occurred, 15 patients experienced a grade 3 AE, primarily dyspnea (5) and fatigue (4), and cardiac toxicity (1 prolonged QTc). Among ACC patients, best response to dasatinib: 1 patient (2.5%) had partial response, 20 patients (50%) had stable disease (SD) (3-14 months), 12 patients (30%) had PD, 2 withdrew, 3 discontinued therapy due to AE, and 2 died before cycle 2. Median progression-free survival was 4.8 months. Median overall survival was 14.5 months. For 14 assessable non-ACC patients, none had objective response, triggering early stopping rule. Seven had SD (range 1-7 months), 4 PD, 2 discontinued therapy due to AE, and 1 died before cycle 2. CONCLUSION: Although there was only one objective response, dasatinib is well tolerated, with tumor stabilization achieved by 50% of ACC patients. Dasatinib demonstrated no activity in non-ACC MSGT.

Response-adapted volume de-escalation (RAVD) in locally advanced head and neck cancer.

BACKGROUND: Efforts to reduce the late toxicity associated with chemoradiation (CRT) for locally advanced head and neck squamous cell cancer (LA-HNSCC) have focused on radiotherapy (RT) dose de-escalation. In this phase I/II protocol investigating the addition of everolimus to induction chemotherapy (IC), we incorporated a novel response-adapted volume de-escalation (RAVD) approach using IC response to guide the extent of RT volume reduction. PATIENTS AND METHODS: Patients with measurable LA-HNSCC received two cycles of IC (cisplatin, paclitaxel, cetuximab ± everolimus). Patients with ≥50% reduction in the sum of tumor diameters [good response (GR)] received TFHX (paclitaxel, fluorouracil, hydroxyurea, and 1.5 Gy twice daily RT every other week) to a dose of 75 Gy with the single planning target volume (PTV1) encompassing exclusively gross disease. Patients with <50% response [non-response (NR)] were treated with TFHX encompassing PTV1 and the next nodal station at risk (PTV2) to a dose of 45 Gy followed by a sequential boost to PTV1 to a dose of 75 Gy. RESULTS: Ninety-four patients were enrolled. Randomization to everolimus was discontinued on interim analysis after 50 patients due to futility. IC response was evaluable in 89 patients. Thirty-seven patients (41.6%) had GR and 52 (58.4%) had NR. There was a trend for improved progression-free (P = 0.086) but not overall survival (P = 0.94) for GR versus NR. The 2-year PFS and OS were 86.0% and 83.5% for GR and 68.7% and 85.4% for NR, respectively. NR were significantly more likely to undergo G-tube placement during treatment (50.0% GR versus 73.5% NR, P = 0.040) and be G-tube dependent at 6-month follow-up (5.7% GR versus 32.6% NR, P = 0.005). CONCLUSIONS: The addition of everolimus to IC was not beneficial. The elimination of elective nodal coverage in patients with GR to IC did not appear to compromise outcomes and resulted in significantly decreased late toxicity. Further investigation of RAVD is warranted. CLINICALTRIALSGOV: NCT01133678.

Comparison of outcomes of locoregionally advanced oropharyngeal and non-oropharyngeal squamous cell carcinoma over two decades.

BACKGROUND: Human papillomavirus (HPV) has emerged as a causative agent and positive prognostic factor for oropharyngeal (OP) head and neck squamous cell cancer (HNSCC). This prompts inquiry into whether therapy improvements or increasing incidence of HPV drives the apparent improvements in HNSCC outcomes observed in non-randomized clinical trials. PATIENTS AND METHODS: We reviewed all locoregionally advanced HNSCC patients treated with chemotherapy and radiation in prospective institutional trials at a single institution. Patients were divided into three groups (1, 2, 3) according to treatment time period (1993-1998, 1999-2003, 2004-2010, respectively). We reasoned that if a favorable trend was observed over time in OP but not non-OP patients, HPV status may be confounding treatment effects, whereas this would be unlikely if both subgroups improved over time. RESULTS: Four hundred and twenty-two patients were identified with OP (55.7%) and non-OP (44.3%) HNSCC. Five-year OP overall survival (OS) improved from 42.3% (group 1) to 72.5% (group 2), and 78.4% (group 3), adjusted P = 0.0084. Non-OP 5-year OS was 51.0% (group 1), 58.8% (group 2), and 66.3% (group 3), adjusted P = 0.51. Five-year recurrence-free survival (RFS) improved for OP groups from 42.3% to 68.4% to 75.8% (adjusted P = 0.017). Non-OP 5-year RFS was 42.9%, 53.6%, and 61.7% for sequential groups (adjusted P = 0.30). Five-year OP distant failure-free survival (DFFS) improved from 42.3% to 71.1% to 77.8% (adjusted P = 0.011). Five-year non-OP DFFS was 46.9%, 57.1%, and 66.0% for sequential groups (adjusted P = 0.38). CONCLUSIONS: Over the past two decades, OP HNSCC outcomes improved significantly, while non-OP outcomes only trended toward improvement. Although our patients are not stratified by HPV status, improving OP outcomes are likely at least partly due to the increasing HPV incidence. These data further justify trial stratification by HPV status, investigations of novel approaches for carcinogen-related HNSCC, and current de-intensification for HPV-related HNSCC.

Use of biosynthetic human C-peptide in the measurement of insulin secretion rates in normal volunteers and type I diabetic patients.

We undertook this study to examine the accuracy of plasma C-peptide as a marker of insulin secretion. The peripheral kinetics of biosynthetic human C-peptide (BHCP) were studied in 10 normal volunteers and 7 insulin-dependent diabetic patients. Each subject received intravenous bolus injections of BHCP as well as constant and variable rate infusions. After intravenous bolus injections the metabolic clearance rate of BHCP (3.8 +/- 0.1 ml/kg per min, mean +/- SEM) was not significantly different from the value obtained during its constant intravenous infusion (3.9 +/- 0.1 ml/kg per min). The metabolic clearance rate of C-peptide measured during steady state intravenous infusions was constant over a wide concentration range. During experiments in which BHCP was infused at a variable rate, the peripheral concentration of C-peptide did not change in proportion to the infusion rate. Thus, the infusion rate of BHCP could not be calculated accurately as the product of the C-peptide concentration and metabolic clearance rate. However, the non-steady infusion rate of BHCP could be accurately calculated from peripheral C-peptide concentrations using a two-compartment mathematical model when model parameters were derived from the C-peptide decay curve in each subject. Application of this model to predict constant infusions of C-peptide from peripheral C-peptide concentrations resulted in model generated estimates of the C-peptide infusion rate that were 101.5 +/- 3.4% and 100.4 +/- 2.8% of low and high dose rates, respectively. Estimates of the total quantity of C-peptide infused at a variable rate over 240 min based on the two-compartment model represented 104.6 +/- 2.4% of the amount actually infused. Application of this approach to clinical studies will allow the secretion rate of insulin to be estimated with considerable accuracy. The insulin secretion rate in normal subjects after an overnight fast was 89.1 pmol/min, which corresponds with a basal 24-h secretion of 18.6 U.

Insulin secretory defects in polycystic ovary syndrome. Relationship to insulin sensitivity and family history of non-insulin-dependent diabetes mellitus.

The increased prevalence of non-insulin-dependent diabetes mellitus (NIDDM) among women with polycystic ovary syndrome (PCOS) has been ascribed to the insulin resistance characteristic of PCOS. This study was undertaken to determine the role of defects in insulin secretion as well as familial factors to the predisposition to NIDDM seen in PCOS. We studied three groups of women: PCOS with a family history of NIDDM (PCOS FHx POS; n = 11), PCOS without a family history of NIDDM (PCOS FHx NEG; n = 13), and women without PCOS who have a family history of NIDDM (NON-PCOS FHx POS; n = 8). Beta cell function was evaluated during a frequently sampled intravenous glucose tolerance test, by a low dose graded glucose infusion, and by the ability of the beta cell to be entrained by an oscillatory glucose infusion. PCOS FHx POS women were significantly less likely to demonstrate appropriate beta cell compensation for the degree of insulin resistance. The ability of the beta cell to entrain, as judged by the spectral power for insulin secretion rate, was significantly reduced in PCOS FHx POS subjects. In conclusion, a history of NIDDM in a first-degree relative appears to define a subset of PCOS subjects with a greater prevalence of insulin secretory defects. The risk of developing NIDDM imparted by insulin resistance in PCOS may be enhanced by these defects in insulin secretion.

C-peptide and insulin secretion. Relationship between peripheral concentrations of C-peptide and insulin and their secretion rates in the dog.

Estimation of the insulin secretory rate from peripheral C-peptide concentrations depends upon the following characteristics of C-peptide kinetics: (a) equimolar secretion of insulin and C-peptide by pancreatic beta cells; (b) negligible hepatic extraction of C-peptide; (c) constant metabolic clearance rate (MCR) of C-peptide over a physiological and pathophysiological range of plasma levels; and (d) proportional changes in the secretion rate of C-peptide and its peripheral concentrations under varying physiological conditions. In the present experiments, the relationship between a variable intraportal infusion of C-peptide and its concentration in the femoral artery was explored in 12 pancreatectomized dogs. As the infusion of C-peptide was rapidly increased, the magnitude of its peripheral concentration initially increased less than the infusion rate by 20-30%. After an equilibration period of approximately 30 min, however, further increases and decreases in the intraportal infusion were accompanied by nearly proportional changes in its peripheral concentration. Estimates of the amount of C-peptide infused during the experiment based on the steady state C-peptide MCR and its peripheral concentration were within 20% of the amount of C-peptide actually infused. These experiments demonstrate that the portal delivery rate of C-peptide can be calculated from its MCR and peripheral concentration in the dog. They also provide a basis for testing the validity of more complicated models of insulin secretion based on peripheral C-peptide concentrations in the dog as well as other species, including man. Finally, we have shown that the hepatic extraction of endogenously secreted C-peptide is negligible in the basal state (3.1 +/- 6.1%), and does not change after oral glucose ingestion. The MCR of exogenous dog C-peptide was similar whether measured by constant peripheral intravenous infusion (12.3 +/- 0.7 ml/kg per min), constant intraportal infusion (13.4 +/- 0.6 ml/kg per min), or analysis of the decay curve after a bolus injection (13.5 +/- 0.7 ml/kg per min).

Quantitative study of insulin secretion and clearance in normal and obese subjects.

The secretion and hepatic extraction of insulin were compared in 14 normal volunteers and 15 obese subjects using a previously validated mathematical model of insulin secretion and rate constants for C-peptide derived from analysis of individual decay curves after intravenous bolus injections of biosynthetic human C-peptide. Insulin secretion rates were substantially higher than normal in the obese subjects after an overnight fast (86.7 +/- 7.1 vs. 50.9 +/- 4.8 pmol/m2 per min, P less than 0.001, mean +/- SEM), over a 24-h period on a mixed diet (279.6 +/- 24.2 vs. 145.8 +/- 8.8 nmol/m2 per 24 h, P less than 0.001), and during a hyperglycemic intravenous glucose infusion (102.2 +/- 10.8 vs. 57.2 +/- 2.8 nmol/m2 per 180 min, P less than 0.001). Linear regression analysis revealed a highly significant relationship between insulin secretion and body mass index. Basal hepatic insulin extraction was not significantly different in the normal and obese subjects (53.1 +/- 3.8 vs. 51.6 +/- 4.0%). In the normal subjects, fasting insulin did not correlate with basal hepatic insulin extraction, but a significant negative correlation between fasting insulin and hepatic insulin extraction was seen in obesity (r = -0.63, P less than 0.02). This finding reflected a higher extraction in the six obese subjects with fasting insulin levels within the range of the normal subjects than in the nine subjects with elevated fasting insulin concentrations (61 +/- 3 vs. 45 +/- 6%, P less than 0.05). During the hyperglycemic clamp, the insulin secretion rate increased to an average maximum of 6.2-fold over baseline in the normal subjects and 5.8-fold in the obese subjects. Over the same time, the peripheral insulin concentration increased 14.1-fold over baseline in the normals and 16.6-fold over baseline in the obese, indicating a reduction in the clearance of endogenously secreted insulin. Although the fall in insulin clearance tended to be greater in the obese subjects, the differences between the two groups were not statistically significant. Thus, under basal, fasting conditions and during ingestion of a mixed diet, the hyperinsulinemia of obesity results predominantly from increased insulin secretion. In patients with more marked basal hyperinsulinemia and during intense stimulation of insulin secretion, a reduction in insulin clearance may contribute to the greater increase in peripheral insulin concentrations that are characteristic of the obese state.+

Dormancy of mammary carcinoma after mastectomy.

BACKGROUND: The longest interval between primary treatment of breast cancer and tumor recurrence, i.e., the limit of breast cancer dormancy, defines the appropriate length of follow-up, the effectiveness of treatment, and curability (no excess mortality risk for patients relative to the general population) for the disease. To determine this limit, we analyzed long-term follow-up data from patients who underwent a radical mastectomy during a four-decade period at the University of Chicago Hospitals. METHODS: For 1547 patients operated on during the period from 1945 through mid-1987, the number of recurrences and deaths occurring within each postoperative year were tabulated, and the hazard rate for first recurrence or death from breast cancer was estimated by use of the actuarial method. The excess mortality rate was calculated for successive 5-year intervals, beginning at the time of mastectomy, by use of U.S. life tables and matching on the basis of age, race, and sex. RESULTS: Most recurrences occurred within the first 10 years after mastectomy. Recurrences were rare after 20 years; only one recurrence was reported among 192 patients followed for 26-45 years. Patients who had a recurrence within 5 years following mastectomy had shorter subsequent survival times than those whose recurrence appeared after 5 years (two-sided P = .0001). The excess death rate increased with pathologic stage of the primary tumor. Overall, there was evidence of excess mortality up to 20 years postsurgery (two-sided P = .009). CONCLUSIONS: The limit of breast cancer dormancy in this patient population appears to be between 20 and 25 years. After this time, recurrences were rare, and the mortality rate was no longer statistically significantly different from that of the general population. Patients surviving to this time without evidence of recurrence or contralateral breast cancer are probably cured.

Heterogeneity of O6-alkylguanine-DNA alkyltransferase activity in peripheral blood lymphocytes: relationship between this activity in lymphocytes and in lymphoblastoid lines from normal controls and from patients with Hodgkin's disease or non-Hodgkin's lymphoma.

We determined O6-alkylguanine-DNA alkyltransferase (AGT) activity in the peripheral blood lymphocytes (PBLs) of normal controls and patients with Hodgkin's disease or non-Hodgkin's lymphoma and compared these values with those of Epstein-Barr virus (EBV)-transformed cell lines prepared from the same PBL samples. PBLs have an AGT level characteristic of the individual from whom the cells were obtained. The AGT activity of lymphoblastoid cell lines obtained from a control group of PBLs was significantly correlated with the activity of the PBLs from which they were derived (r = 0.742). There was no significant correlation between PBLs and EBV-transformed lines derived from these PBLs in Hodgkin's disease/non-Hodgkin's lymphoma patients (r = 0.407, -0.225, and 0.270 for patients prior to, during, or after therapy, respectively). The lack of significant correlation between lines and PBLs was not due to random fluctuations in AGT activity, because multiple lines prepared from the same PBL sample were found to be highly correlated in AGT activity. In order to account for these results, we suppose that PBLs from a given individual are a heterogeneous population with respect to AGT activity. In normal individuals, the AGT activity of early passages of the multi-clonal EBV-transformed cell lines reflect the AGT activity of the PBLs from which they were derived. Malignancy and/or treatment with chemotherapeutic agents may selectively affect those lymphocytes which are targets for EBV-transformation so that the resultant cell line is no longer representative (with respect to AGT activity) of the total PBL population. Long-term culture of lymphoblastoid cell lines results in changes in AGT activity in some but not all cell lines suggesting that with time in culture, subsets with different AGT activities may be selected. There appears to be no growth advantage of low AGT activity and only rarely have we obtained lines with no measurable AGT activity, even after long periods in culture.

Low O6-alkylguanine DNA alkyltransferase activity in the peripheral blood lymphocytes of patients with therapy-related acute nonlymphocytic leukemia.

Chemotherapeutic agents such as procarbazine, which produce methylated bases in DNA, are used to treat many Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL) patients. A small proportion of such patients develop secondary malignancy. We examined the possibility that those patients who develop secondary malignancy have low endogenous levels of O6-alkylguanine DNA alkyltransferase (AGT) activity and are therefore more sensitive to the mutagenic and carcinogenic effects of their treatment. We assayed AGT activity in peripheral blood lymphocytes from patients with HD, NHL, acute nonlymphocytic leukemia (ANLL) de novo, and therapy-related ANLL, as well as a group of normal control subjects. Studies in normal controls showed that at least over a short term of 1 week, individuals have characteristic AGT levels, although some individuals sampled repeatedly over several months showed high variation. Mean AGT activities +/- SE for the various groups studied were (fmol/micrograms of DNA): normal control group, 7.05 +/- 0.36; HD and NHL patients (prior to treatment), 4.97 +/- 0.42; HD-NHL patients receiving procarbazine, 3.88 +/- 0.44; ANLL de novo, 7.78 +/- 1.72; and therapy-related ANLL, 4.30 +/- 0.58. AGT activity decreased in the peripheral blood lymphocytes of some individuals taking procarbazine. The mean AGT activity in the procarbazine-treated patients was low, as was the activity for the therapy-related ANLL patients.

Mitogen-activated protein kinase kinase 4 metastasis suppressor gene expression is inversely related to histological pattern in advancing human prostatic cancers.

We have shown recently (B. A. Yoshida et al., Cancer Res., 59: 5483-5487) that mitogen-activated protein kinase kinase 4 (MKK4) can suppress AT6.1 rat prostate cancer metastases in vivo. Evaluation of the expression of components of the MKK4 signaling cascade showed a loss or down-regulation of expression of MKK4 or c-Jun, a downstream mediator of MKK4, in six of eight human prostate cancer cell lines. Given these findings, we next assessed whether MKK4 dysregulation occurs during the development of clinical prostate cancer. Immunohistochemical studies showed high levels of MKK4 expression in the epithelial but not the stromal compartment of normal prostatic tissues. In neoplastic tissues, a statistically significant, direct, inverse relationship between Gleason pattern and MKK4 was established. These results demonstrate that MKK4 protein is consistently down-regulated during prostate cancer progression and support a role for dysregulation of its signaling cascade in clinical disease. To test the possibility that down-regulation of MKK4 protein is the result of allelic loss, metastatic prostate cancer lesions were examined for loss of heterozygosity (LOH) within the MKK4 locus (D17S969). These studies showed a 31% (5 of 16) LOH of MKK4 that is not associated with coding region mutations, which suggests that the nucleotide sequence of the gene in the remaining allele is infrequently mutated.

Identification of high-risk amino-acid substitutions in hematopoietic cell transplantation: a challenging task.

Allogeneic hematopoietic cell transplantation (HCT) offers the potential to cure hematologic malignancies. In the absence of an HLA-matched donor, HLA mismatched unrelated donors may be used, although risks of GvHD and treatment-related mortality (TRM) are higher. Identification and avoidance of amino-acid substitution and position types (AASPT) conferring higher risks of TRM and GvHD would potentially improve the success of transplantation from single HLA mismatched unrelated donors. Using random forest and logistic regression analyses, we identified 19 AASPT associated with greater risks for at least one adverse transplant outcome: grade III-IV acute GvHD, TRM, lower disease-free survival or worse overall survival relative to HLA-matched unrelated donors and to other AASPT. When tested in an independent validation cohort of 3530 patients, none of the AASPT from the training set were validated as high risk, however. Review of the literature shows that failure to validate original observations is the rule and not the exception in immunobiology and emphasizes the importance of independent validation before clinical application. Our current data do not support avoiding any specific class I AASPT for unrelated donors. Additional studies should be performed to fully understand the role of AASPT in HCT outcomes.

The limitations to and valid use of C-peptide as a marker of the secretion of insulin.

The accuracy with which the secretion rate of insulin can be calculated from peripheral concentrations of C-peptide was investigated in conscious mongrel dogs. Biosynthetic human C-peptide and insulin were infused intraportally and their concentrations measured in the femoral artery. During steady-state infusions of C-peptide, the peripheral concentration changed in proportion to the infusion rate and the metabolic clearance rate (5.2 +/- 0.3 ml/kg/min) remained constant over a wide range of plasma concentrations. Application of a two-compartment mathematical model, in which the model parameters were estimated from analysis of C-peptide decay curves after intravenous bolus injections, allowed the intraportal infusion rate of C-peptide to be derived from peripheral C-peptide concentrations, even under non-steady-state conditions. Estimates of the intraportal infusion rate based on this model were 102.4 +/- 2.6% of the actual infusion rate as it was increasing and 102.3 +/- 5.5% of this rate as it was falling. The peripheral C-peptide: insulin molar ratio was influenced by the rate at which equimolar intraportal infusions of C-peptide and insulin were changed. The baseline C-peptide: insulin molar ratio (4.1 +/- 0.9) increased to peak values of 8.2 +/- 0.6, 10.3 +/- 2.0, and 14.9 +/- 1.3 when the infusion rate was increased and then decreased rapidly. Peak values of only 5.7 +/- 1.2 were found if the intraportal infusion rate was changed slowly.(ABSTRACT TRUNCATED AT 250 WORDS)

Human breast cancer susceptibility to paclitaxel therapy is independent of Bcl-2 expression.

In laboratory studies, ectopic overexpression of the antiapoptotic protein Bcl-2 has been shown to result in resistance to the cytotoxic effects of many chemotherapeutic drugs. Furthermore, posttranslational modification of moderately expressed endogenous Bcl-2 has been correlated with susceptibility to paclitaxel treatment in vitro. To determine whether tumor expression of Bcl-2 protein correlates with response and ultimate outcome in vivo, we quantified Bcl-2 expression by immunohistochemical analysis of archived biopsy specimens from metastatic breast cancer patients treated with single-agent paclitaxel. The statistical association between the degree of Bcl-2 expression, objective tumor response, and clinical outcome was then determined. In patients (n = 39) whose tumors had low (< or = 10% cells positive) Bcl-2 levels by immunohistochemical analysis, the overall response (complete response + partial response) rate was 21% versus an overall response rate of 22% in patients (n = 36) with high (>10% cells positive) Bcl-2 expression (P = 0.92). In patients with low Bcl-2 expression, the median time to progression was 126 days [95% confidence interval (CI), 63-160 days]. This was not significantly different than the 105 days for patients with high tumor Bcl-2 expression (95% CI, 84-214 days). The median survival time from initiation of paclitaxel therapy for patients with low Bcl-2 expression was 663 days (95% CI, 456-1119 days) and was not significantly different than the 450 days (95% CI, 239-1058 days) observed for patients with high Bcl-2 expression. In conclusion, we found that in metastatic breast cancer, there is no significant association between tumor Bcl-2 expression and response to paclitaxel, median time to progression, or survival, suggesting that the main mechanism of paclitaxelinduced cytotoxicity in breast tumors is independent of Bcl-2 expression.

The PATHWAYS church-based weight loss program for urban African-American women at risk for diabetes.

OBJECTIVE: This study was carried out to test the effectiveness of PATHWAYS, a weight loss program designed specifically for urban African-American women, when administered in urban churches by trained lay facilitators. RESEARCH DESIGN AND METHODS: Thirty-nine obese women were recruited from three urban African-American churches. After randomization and the collection of baseline data on weight and lifestyle practices, subjects in the experimental group (n = 19) were assigned to receive a 14-week weight loss program (PATHWAYS) conducted by trained lay volunteers; control group subjects (n = 20) were put on a waiting list to receive the program at the conclusion of the study period. RESULTS: Of the 39 women enrolled, 15 experimental group subjects and 18 control group subjects were available for posttreatment data collection. After completing the program, PATHWAYS participants lost an average of 10.0 lb, and the control group subjects gained an average of 1.9 lb. Posttreatment difference in weight loss between the groups was statistically significant (P < 0.0001). Waist circumference among PATHWAYS participants decreased 2.5 inches, while waist circumference among control group subjects remained relatively the same. This difference between the groups was statistically significant (P < 0.05). CONCLUSIONS: A weight loss program administered by trained lay volunteers was effective in producing significant and clinically meaningful weight loss among African-American women who often do not benefit from typical weight loss programs. Ongoing research is focusing on whether the weight loss can be maintained or enhanced through monthly reinforcement sessions.

Calculation of the systemic delivery rate of insulin in normal man.

The accuracy with which the systemic delivery rate of insulin can be estimated from peripheral insulin concentrations was investigated in eight normal men. Endogenous insulin secretion was suppressed by somatostatin, and insulin was infused exogenously via a peripheral vein. The infusion rate was progressively increased and then decreased to stimulate the changes in insulin secretion that occur after a secretory stimulus. The infusion rate of insulin was then estimated by analyzing peripheral insulin concentrations using both single and two-compartment mathematical models and was compared with the actual infusion rates. Model parameters were measured in each subject by analysis of the insulin decay curve after a bolus injection. Estimated infusion rates based on the single compartment model were 84.3 +/- 3.0% (mean +/- SE) of the actual infusion rate as it was increasing and 110.3 +/- 3.7% of the infusion rate as it was decreasing. The mean overall absolute percent error associated with this approach was 14.1 +/- 1.0% (range, 10.2-18.8%), and model estimates of the total amount of insulin infused over the duration of the experiment were 97.1 +/- 3.2% of the quantity actually infused (range, 85.4-110.7%). Estimates of the infusion rate based on a two-compartment model represented 90.3 +/- 3.1% of the actual infusion rate as it was increasing and 98.2 +/- 3.2% of the actual rate as it was falling. The area under the derived infusion rate curve was 94.8 +/- 2.8% of the area under the actual curve. The overall error associated with the use of the two-compartment model was 12.9 +/- 1.1% (range, 8.8-18.6%). Differences between the single and two-compartment models were minor and not statistically significant. These data demonstrate that under euglycemic conditions, changes in the plasma insulin concentration within the physiological range are not associated with changes in the clearance kinetic rate constants of the hormone. Furthermore, the systemic delivery rate of insulin can be accurately derived from peripheral insulin concentrations using either a single or two-compartmental model if model parameters are accurately measured in individual subjects by analysis of insulin decay curves.