Thomas F. Hogan

Phase III study of two different dosing schedules of erythropoietin in anemic patients with cancer.

PURPOSE To compare maintenance epoetin alfa administered once every 3 weeks with continued weekly epoetin alfa for patients with cancer-associated anemia. PATIENTS AND METHODS Eligible patients were randomly assigned at enrollment to receive three weekly doses of epoetin alfa 40,000 U subcutaneously (SC), followed by either standard weekly epoetin alfa (40K arm) or 120,000 U of epoetin alfa (120K arm) SC every 3 weeks for 18 additional weeks. RESULTS Three hundred sixty-five patients were enrolled. One hundred eighty-three patients were assigned to the 40K arm, and 182 were assigned to the 120K arm. There was no difference in the proportion of patients requiring transfusions during the study (23% in 40K arm and 18% in 120K arm, P = .22) or specifically during the maintenance phase (13% in 40K arm v 15% in 120K arm, P = .58). Patients randomly assigned to the 40K arm were more likely to have a > or = 2 or > or = 3 g/dL hemoglobin (Hb) increment, were more likely to have a drug dose held because of high Hb, and had higher mean end-of-study Hb levels. Toxicities, including thromboembolism, and overall survival were similar. Patients in the 40K arm had a higher global quality of life (QOL) at baseline for unclear reasons, whereas patients in the 120K arm had a greater global QOL improvement during the study, so end-of-study QOL was equivalent. CONCLUSION After three weekly doses of epoetin alfa 40,000 U, a dose of 120,000 U can be administered safely once every 3 weeks without increasing transfusion needs or sacrificing QOL. The Hb increment is somewhat greater with continued weekly epoetin alfa. Lack of blinding as a result of different treatment schedules may have confounded results.

High Dose Ketoconazole for the Treatment of Hormone Refractory Metastatic Prostate Carcinoma: 16 Cases and Review of the Literature

We treated 16 patients who had hormone refractory metastatic prostate cancer with 400 mg. ketoconazole orally every 8 hours. None of the patients had an objective response, although 6 (37.5 per cent) had stable disease (2 of whom had a subjective decrease in bone pain). The median duration of stable disease was 6.8 months (range 2 to 12 months) and side effects were seen in 14 patients. Nausea, vomiting or anorexia was noted in 10 patients, rash and pruritus in 2, transient abnormal liver function tests in 1 and transient pulmonary infiltrates in 1. Nine prior studies investigating the use of ketoconazole in hormone refractory metastatic prostate cancer were reviewed. Only 1 complete response was reported. A partial response was noted in 14 per cent of the patients. Most of the patients had stable or progressive disease. High dose ketoconazole as a single agent appears to have limited use in patients who have failed prior systemic therapy.

Oncocytic, focally anaplastic, thyroid cancer responding to erlotinib††

Objective. To highlight the molecular findings and clinical response of a patient with rapidly progressing, focally anaplastic, oncocytic thyroid carcinoma (OTC) treated with erlotinib. Case Summary. A 69-year-old woman with recurrent, focally anaplastic OTC was given a therapeutic trial of erlotinib, a small molecule inhibitor of epidermal growth factor receptor (EGFR). Formalin-fixed, paraffin-embedded portions of the tumor were analyzed for EGFR expression, and tumor genomic DNA was amplified by polymerase chain reaction (PCR) and subjected to EGFR mutation analysis. Discussion. An early and dramatic response was achieved with erlotinib. The tumor was focally positive for EGFR by immunostaining and two point mutations were identified, one on exon 18 and one on exon 20 in the tyrosine kinase (TK) domain. Conclusion. Erlotinib or other novel protein kinase pathway inhibitors should be evaluated further in patients with aggressive thyroid cancer variants, who may exhibit these and perhaps other tyrosine kinase mutations. J Oncol Pharm Practice (2009) 15: 111—117.

Multi-drug resistance in chronic lymphocytic leukemia

We evaluated 45 chronic lymphocyte leukemia (CLL) patients for the presence of multi-drug resistance (MDR) by the ex vivo techniques: 1) a functional assay utilizing doxorubicin (dox) retention with modulation; 2) a cytotoxicity assay (MTT) with modulation; 3) and four monoclonal antibodies. Ex vivo tests were correlated with disease stage and prior treatment, and were repeated as patients became resistant to alkylating agents, fludarabine and VAD chemotherapy (infusion of vincristine, dox, and oral dexamethasone). The majority of patients (64.4%) were in early stage and were untreated (62.2%). P-glycoprotein (p-gp 170) was detected most frequently by the monoclonal antibody MRK-16 (48%) and by functional modulation of dox retention by PSC-833 (40.6%) and by functional modulation of the MTT assay with vincristine (0.29) and dox (0.39) with PSC-833 at 1.0 microg/mL. Functional modulation of dox retention with PSC-833 was significantly associated with stage, but not with either the MTT assay or any of the monoclonal antibodies. None of the tests correlated with prior chlorambucil treatment. Correlation of dox retention with the monoclonal antibodies was mild to moderate and became stronger following chlorambucil treatment. Three patients who became resistant to VAD were found to express p-gp 170. We conclude that MDR can frequently be detected in patients with CLL. Furthermore, the expression of p-gp 170 increases with advancing stage, but not prior alkylating agent therapy. The functional expression of p-gp 170 increases with advancing stage and prior treatment and correlates well with monoclonal antibody detection (especially MRK-16). Patients who become resistant to VAD more frequently express p-gp 170 by a variety of techniques. PSC-833 is a more potent modulator of MDR than cyclosporin-A (CsA) ex vivo, and correlates better with stage of disease.

Chromatographic studies of mitomycin C degradation in albumin microspheres.

Serum albumins and polylactic acid (PLA) have been used as bioerodable polymers in the preparation of drug-containing microspheres for parenteral drug delivery. The albumin microsphere may be prepared via either chemical cross-linking or heat denaturation of the protein. Heat-denatured albumin microspheres containing mitomycin C (MMC) have been used in pre-clinical and clinical investigations. Due to the high reactivity of MMC as a bifunctional alkylating agent, a study on the stability of MMC in the albumin and PLA microspheres has been carried out using a high-performance liquid chromatographic (HPLC) method. Human serum albumin (HSA) microspheres were prepared using an emulsion method via either heat denaturation at 120 or 170 degrees C or the use of 0.5 M biacetyl as a cross-linking agent. The PLA microspheres were prepared by an emulsion method at 55 degrees C. HPLC analysis of the HSA microspheres showed that about 37% of MMC was converted to 2,7-diaminomitosene derivatives in microspheres prepared by heat denaturation at 120 degrees C. The degradation increased to 82% when the microspheres were prepared with a denaturation temperature of 170 degrees C. The use of biacetyl as a cross-linking agent in the preparation of HSA microspheres resulted in a complete degradation of the incorporated MMC. Biacetyl was found to interact with MMC leading to the formation of 7-aminomitosene derivatives. In contrast to the albumin system, MMC may be incorporated into PLA microspheres without degradation.

Rapid diagnosis of acute eosinophilic pneumonia (AEP) in a patient with respiratory failure using bronchoalveolar lavage (BAL) with calcofluor white (CW) staining

A diagnosis of exclusion, acute eosinophilic pneumonia (AEP) is an acute febrile illness with respiratory impairment, diffuse pulmonary infiltrates, and bronchoalveolar lavage (BAL) fluid eosinophilia. Whether pulmonary eosinophilia in AEP is primary or secondary remains undetermined. We report here a 22‐year‐old auto mechanic with severe AEP and acute respiratory failure who required intubation and ventilatory support. The patients bronchoalveolar lavage (BAL) fluid was analyzed using cultures, cytology, Wright/Giemsa, Gram, Gomori‐methenamine‐silver (GMS), and calcofluor white (CW) stains (1). Despite extensive evaluation, no infectious etiology was found. CW staining helped us rapidly to exclude Pneumocystis carinii or fungal infection and to focus attention toward the diagnosis of AEP. Transbronchial biopsy was unnecessary and supportive therapy without systemic glucocorticoids was followed by recovery within a few weeks. In this case, bronchoalveolar lavage with CW staining was of great assistance in the rapid diagnosis and initial management of AEP. Our literature review found no prior article using CW staining for evaluation of AEP. J. Clin. Lab. Anal. 11:202–207, 1997.

Atypical t(15;17)(q13;q12) in a patient with all-trans retinoic acid refractory secondary acute promyelocytic leukemia:: a case report and review of the literature

A 69-year-old woman developed microgranular acute promyelocytic leukemia (APL-M3) 10 months after receiving adjuvant cyclophosphamide, doxorubicin, and paclitaxel for breast cancer. Replicate bone marrow aspirate karyotypes contained a translocation between the long arms of chromosomes 15 and 17, but not at breakpoints typical for APL. Fluorescence in situ hybridization paints and RARalpha/PML cosmid probes verified that the breakpoints on chromosomes 15 and 17 were proximal to both the PML and RARalpha genes; t(15;17)(q13;12). Although the patient received induction chemotherapy and a several month trial of all-trans retinoic acid (ATRA), there was no clinical improvement or hematological remission. We suspect that this patient developed postchemotherapy secondary APL with an atypical t(15;17), which rendered her leukemic cells unresponsive to ATRA therapy.

Unusual presentation of a left testicular carcinoid

Testicular carcinoid generally presents either with a palpable (painful or painless) or rarely a nonpalpable mass (when it is diagnosed incidentally on scrotal imaging) of the involved testis. An ipsilateral testicular carcinoid presenting exclusively with contralateral testicular symptoms has never been described in the literature to date. We report a case of nonpalpable left testicular carcinoid diagnosed incidentally on a sonogram done for right testicular pain and swelling, with conspicuous absence of left testicular symptoms. This case highlights the importance of recognizing such an atypical presentation of testicular carcinoid.

Integrative Tumor Board: Medical and Surgical Oncology Approach

Case Review In this case, we are presented with a 70-year-old male retired insurance executive, 35 pack-year smoker, with no other environmental exposure risks but with a history of lithotripsy for renal stones and with noninvasive papillary transitional cell carcinoma (TCC) in the right ureter and bladder (at least 2 sites). The patient presented with hematuria, right flank pain, urinary urgency, and dysuria. Bladder biopsy has been obtained, the right ureter has been stented, and imaging studies (computed tomography and bone scan) show right adrenal prominence and a questionable nodule in the bladder dome. Renal function studies are normal but with suggestion of right collecting system obstruction. Right total nephrectomy has initially been recommended.

In vivo evaluation of mitomycin C–Polylactic acid microcapsules via canine intrahepatic arterial infusion

AbstractThe therapeutic advantages of a microcapsule dosage form (poly-d, l-lactic acid; 150 ± 25 μm; 5% drug loading) for the intrahepatic arterial delivery of mitomycin C (MMC) were evaluated in dogs on the basis of measurements of the hepatic and peripheral venous concentrations. Hepatic arterial and venous catheters were placed via the femoral in the left lobe of the liver in mongrel dogs. MMC was administered via hepatic arterial catheter at a dose of 0.25 mg/kg in solution with or without embolization and in the microencapsulated form. Pharmacokinetic parameters were obtained from the hepatic and peripheral venous MMC concentrations and novel parameters were developed to permit comparison of the systemic and hepatic exposures to MMC. Ratios of area under the serum concentration–time profiles (AUC), maximum serum concentration (Cmax), and mean residence times (MRT) between the hepatic and peripheral veins indicate that embolization with MMC microcapsules results in an up to 2.4-fold reduction in the ...