Charles Shapiro

Multi-Institutional Study of the Angiogenesis Inhibitor TNP-470 in Metastatic Renal Carcinoma

PURPOSE Renal cell carcinoma is resistant to most chemotherapy, and only a minority of patients respond to immunotherapy. Its highly vascular nature suggests that antiangiogenesis therapy might be useful. We thus performed a phase II study of the fumigillin analog TNP-470 in previously treated patients with metastatic renal cell carcinoma. PATIENTS AND METHODS Metastatic renal cell carcinoma patients with good organ function were entered onto the study through five separate institutions. There were no exclusion criteria for prior therapy. All patients were treated at a dose of 60 mg/m(2) of TNP-470 infused over 1 hour three times per week. RESULTS Thirty-three patients were enrolled. Therapy was generally well tolerated, but asthenia, fatigue, vertigo, dizziness, sense of imbalance, and loss of concentration were common and severe enough to lead to therapy discontinuation in five patients. There was only one partial response of short duration (response rate, 3%, 95% confidence interval, 0% to 16%), but six patients (18%) remained on study for 6 or more months without toxicity or disease progression. CONCLUSION Long-term therapy with TNP-470 has manageable toxicities and is feasible in patients with metastatic renal cell carcinoma but does not lead to any significant objective responses. Further studies in this population using TNP-470 schedules that produce more prolonged drug levels and clinical trial end points other than objective tumor regression may be indicated.

What do we really know about cosmic acceleration

Essentially all of our knowledge of the acceleration history of the universe (even the discovery of the acceleration itself) is predicated on the validity of general relativity through the Friedmann equation. Assuming only a flat spacetime that is homogenous and isotropic on large scales and described by a metric theory of gravity, we use SNe Ia to analyze the acceleration history. We infer robust conclusions about cosmic acceleration that are independent of a particular parameterization of the acceleration history. Specifically, we find (1) very strong (5 σ) evidence for a period of acceleration, (2) strong evidence that the acceleration has not been constant, (3) evidence for an earlier period of deceleration, and (4) only weak evidence that the universe has been accelerating since z ~ 0.3.

Pharmacobiologically Based Scheduling of Capecitabine and Docetaxel Results in Antitumor Activity in Resistant Human Malignancies

PURPOSE Capecitabine and docetaxel have demonstrated preclinical antitumor synergy. This synergy is thought to occur from docetaxel-mediated upregulation of thymidine phosphorylase (dThdPase), an enzyme responsible for the relative tumor selectivity of capecitabine. On the basis of the time-dependency and transiency for this upregulation, we performed a phase I study of capecitabine in combination with weekly docetaxel. We hypothesized that weekly docetaxel would result in sustained dThdPase expression and that capecitabine administration at times of maximum dThdPase upregulation would increase the therapeutic index for this combination. PATIENTS AND METHODS Patients with advanced solid malignancies received docetaxel on days 1, 8, and 15, and capecitabine bid on days 5 to 18, every 4 weeks. Docetaxel was fixed at 36 mg/m(2)/wk, whereas capecitabine was escalated in successive patients cohorts. RESULTS Sixteen patients received 77 courses at capecitabine doses from 950 to 1,500 mg/m(2)/d. The most common toxicities were hand-foot syndrome, diarrhea, nausea/vomiting, and asthenia. Grades 3 to 4 hematologic toxicities were infrequent and no treatment-related hospitalizations occurred. Three of three patients treated at 1,500/36 mg/m(2) capecitabine/docetaxel developed grade 3 hand-foot syndrome or diarrhea during either their first or second course, whereas only two of 13 patients at 1,250/36 mg/m(2) doses developed significant toxicity. Antitumor responses (n = 7) occurred in patients with hepatocellular, non-small-cell lung, and chemotherapy-refractory breast, bladder, and colorectal carcinomas. Prolonged stabilizations occurred in patients with metastatic mesothelioma (n = 2), chemorefractory non-small-cell lung carcinoma, and bronchioloalveolar carcinoma. CONCLUSION Capecitabine in combination with weekly docetaxel is well tolerated. Recommended doses are capecitabine 1,250 mg/m(2)/d (625 mg/m(2) bid) with docetaxel 36 mg/m(2)/wk. The acceptable toxicity profile in this dose schedule, and the antitumor activity observed, warrant further evaluation of this regimen.

Disseminated trichosporon beigelii (cutaneum)

Two cases of invasive Trichosporon beigelii (syn. cutaneunt) infection are reported and are compared with the eight other previous reports. All affected patients were either immunosuppressed or had recently undergone a surgical procedure. The diagnosis had been delayed and the prognosis was poor. Only two patients recovered after vigorous antimycotic therapy and concomitant remission of their leukemia. A biopsy of the skin lesion, as illustrated in one of our patients, may prove to be useful in the early diagnosis.

Outcome of Patients With Early-Stage Breast Cancer Treated With Doxorubicin-Based Adjuvant Chemotherapy As a Function of HER2 and TOP2A Status

PURPOSE Amplification and deletion of the TOP2A gene have been reported as positive predictive markers of response to anthracycline-based therapy. We determined the status of the HER2 and TOP2A genes in a large cohort of breast cancer patients treated with adjuvant doxorubicin (A) and cyclophosphamide (C). PATIENTS AND METHODS TOP2A/CEP17 and HER2/CEP17 fluorescent in situ hybridization (FISH) were performed on tissue microarrays (TMAs) constructed from 2,123 of the 3,125 women with moderate-risk primary breast cancer who received equivalent doses of either concurrent adjuvant chemotherapy with A plus C (n = 1,592) or sequential A followed by C (n = 1,533). RESULTS An abnormal TOP2A genotype was identified for 153 (9.4%) of 1,626 patients (4.0% amplified; 5.4% deleted). An abnormal HER2 genotype was identified for 303 (20.4%) of 1,483 patients (18.8% amplified; 1.6% deleted). No significant differences in either overall survival (OS) or disease-free survival (DFS) were identified for TOP2A. In univariate analysis, OS and DFS rates were strongly and adversely associated only with higher levels of HER2 amplification (ratio > or = 4.0). Survival was not associated with low-level HER2 amplification (ratio > or = 2; OS hazard ratio [HR], 1.14; P = .39; DFS HR, 1.07; P = .62), but it was associated for a ratio > or = 4 (OS HR, 1.45; P = .03; DFS HR, 1.38; P = .033), in which analysis was adjusted for menopausal status, hormone receptor status, treatment, number of positive nodes, and tumor size. CONCLUSION In this population of patients with early-stage breast cancer who were treated with adjuvant AC chemotherapy, TOP2A abnormalities were not associated with outcome. HER2 high-level amplification was a prognostic marker in anthracycline-treated patients.

Acute nephrotoxicity following cis‐dichlorodiammine‐platinum

The effects of a single dose of cis‐diamminedichloroplatinum (DDP) on the kidney function were investigated in 14 patients with disseminated malignancy and normal renal function. A single dose of DDP (30–50 mg/m2) caused severe proximal tubular dysfunction with increased urinary losses of calcium, magnesium, and amino acids. Phosphate excretion was not affected. DDP can cause proximal tubular dysfunction and close attention must be paid to serum calcium and magnesium levels.

The Born and lens–lens corrections to weak gravitational lensing angular power spectra

We revisit the estimation of higher order corrections to the angular power spectra of weak gravitational lensing. Extending a previous calculation of Cooray and Hu, we find two additional terms to the fourth order in potential perturbations of large-scale structure corresponding to corrections associated with the Born approximation and the neglect of line-of-sight coupling of two foreground lenses in the standard first order result. These terms alter the convergence (κκ), the lensing shear E-mode (), and their cross-correlation (κ) power spectra on large angular scales, but leave the power spectra of the lensing shear B-mode (ββ) and rotational (ωω) component unchanged as compared to previous estimates. The new terms complete the calculation of corrections to weak lensing angular power spectra associated with both the Born approximation and the lens–lens coupling to an order in which the contributions are most significant. Taking these features together, we find that these corrections are unimportant for any weak lensing survey, including for a full sky survey limited by cosmic variance.

Staging and therapy of orbital lymphomas

Ten patients with non‐Hodgkins lymphoma primarily affecting the orbital region were evaluated at Michael Reese Hospital and Medical Center, Chicago, between 1976 and 1983. Diagnoses were based on the histopathologic classification systems of the Working Formulation of the Non‐Hodgkins Lymphomas and Rappoport. Sequential staging procedures performed at the time of diagnosis included liver‐spleen scans, Technecium‐99 bone scans, gallium 67 scans, computerized axial tomograms of the orbit and abdomen, bone marrow examination and cerebral spinal fluid analyses. Adverse prognostic factors included the following: orbital bone erosions, Stage IV disease, and large cell or mixed cell, diffuse histologic features. The type of histopathologic findings combined with the results of sequential staging procedures is useful in identifying those patients who would benefit most from systemic chemotherapy.

Bronchial carcinoid metastatic to skin. Light and electron microscopic findings.

This case report illustrates the value of ultrastructural examination of an undifferentiated carcinoma metastatic to skin. In this patient, ultrastructural study of a cutaneous nodule demonstrated cytoplasmic neurosecrctory granules characteristic of an amino precursor‐uptake and decarboxylation cells (APUD) tumor and supported the diagnosis of metastatic bronchial carcinoid. Additional nine cases of bronchial carcinoids metastatic to skin are also briefly reviewed.

Response to secondary therapy in patients with adenocarcinoma of the breast previously treated with adjuvant chemotherapy

The response to secondary therapy, chemotherapy or hormonal, is examined in 26 patients with adenocarcinoma of breast who failed adjuvant chemotherapy. Response rates to tamoxifen or combination chemotherapy, cyclophosphamide, methotrexate, and 5‐FU (CMF) or Adriamycin and vincristine (AV) were similar to response rates reported for Stage IV patients, never exposed to cytotoxic agents. Survivals in these 26 patients were similar to those reported for Stage IV patients never exposed to cytotoxics. It is concluded that adjuvant chemotherapy does not lessen future response to secondary therapies or decrease survival.