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Notes: The proband was evaluated for abdominal pain at age 61 years and found to have bilateral solid renal masses. He underwent a partial left nephrectomy. Two benign renal cysts were present, and two renal cell adenocarcinomas measuring 5.3 cm and 0.7 cm in greatest diameters were found. Histologically, both tumors contained both clear and granular cell types. He had a total right nephrectomy 2 months later. Fourteen or 15 lesions were scattered over the surface of this kidney, so an adrenal-sparing radical right nephrectomy was performed. On sectioning, the diameter of the largest tumor was 4 cm, and histologically this was described as renal cell carcinoma, clear cell type, Fuhrman grade II. One year later, the patient shows no evidence of recurrent disease.The proband's past medical history was notable for gastroesophageal reflux, degenerative disk disease, hyperlipidemia, and mild hyperglycemia. A genetics consultation was requested because of a family history of renal cancers in three maternal relatives (〈link href="#f3-1"〉Fig. 1). On examination, the proband was a nondysmorphic man of normal stature with no unusual findings, except for widespread skin findings (〈link href="#f3-2"〉Fig. 2). On his face were innumerable, small, slightly yellowish or flesh-colored papules on the forehead and especially over the cheeks. No intraoral lesions were seen. Around the neck were innumerable, dome-shaped, firm, ivory-colored papules ranging in size from 1 to 10 mm. Very tiny, similar papules were present over the trunk and in the antecubital area. Numerous acrochordons and some cherry angiomas were present. Several biopsies from the neck and upper back were obtained and were thought suggestive of papular mucinosis. The patient's mother had had a skin biopsy of a similar lesion from her face in 1947, interpreted as an adenoma sebaceum. No angiofibromas were evident on our patient's slides nor on physical examination.〈figure xml:id="f3-1"〉1〈mediaResource alt="image" href="urn:x-wiley:00119059:IJD1287-4:IJD_1287_f3-1"/〉Pedigree of family with Birt-Hogg–Dube Syndrome〈figure xml:id="f3-2"〉2〈mediaResource alt="image" href="urn:x-wiley:00119059:IJD1287-4:IJD_1287_f3-2"/〉Photograph of the back of the neck of a 61–year-old man with Birt-Hogg–Dube SyndromeAt this point, diagnoses under consideration included von Hippel-Lindau disease (VHL), a familial chromosome no. 3 translocation, hereditary renal cell cancer (gene unknown), tuberous sclerosis (TS), or Birt-Hogg–Dube syndrome (BHDS). The patient underwent a variety of tests to evaluate these possibilities. He had no evidence of hemangioblastomas of the central nervous system, no liver or pancreatic cysts, no ocular findings for VHL or TS, and no hypomelanotic macules on skin exam. Chromosome analysis from peripheral blood showed a normal 46,XY karyotype. Direct DNA mutational analysis of the VHL gene detected no mutations. Additional biopsies from the patient's skin lesions were obtained, and tissue blocks from 1947 from his mother were resectioned (〈link href="#f3-3 #f3-4"〉Figs 3 and 4). Upon further review, multiple fibrofolliculomas were found in both mother and son in skin biopsies. In aggregate, these data established a diagnosis of BHDS.〈figure xml:id="f3-3"〉3〈mediaResource alt="image" href="urn:x-wiley:00119059:IJD1287-4:IJD_1287_f3-3a"/〉〈mediaResource alt="image" href="urn:x-wiley:00119059:IJD1287-4:IJD_1287_f3-3b"/〉(A) Skin biopsy from the upper back of the proband showing a dome shaped papule with abundant mucin in the papillary dermis. Follicular changes are suggestive of fibrofolliculoma. (H&E, 12.5X). (B) Mucinosis in the papillary dermis is highlighted with alcian blue stain (ABPAS, 25X)〈figure xml:id="f3-4"〉4〈mediaResource alt="image" href="urn:x-wiley:00119059:IJD1287-4:IJD_1287_f3-4a"/〉〈mediaResource alt="image" href="urn:x-wiley:00119059:IJD1287-4:IJD_1287_f3-4b"/〉(A) Fibrofolliculoma seen on skin biopsy of a facial papule from the mother of the proband (H&E, 25X). (B) Fibrofolliculoma from the mother of the proband with sebaceous gland enlargement and mucin deposition highlighted by alcian blue stain (ABPAS, 25X)In addition to the renal cancers, the patient's and/or cousin's medical record reported that others in the family had the same skin manifestations, including his mother, maternal grandmother, maternal uncle, and two maternal first cousins by report. Cousin III.6′s medical record showed a clinical diagnosis initially of ‘‘sebaceous hyperplasia’' and upon skin biopsy was said to have ‘‘innumerable trichoepitheliomas over his face’'. He was treated with liquid nitrogen with good results. Unfortunately, we were not able to obtain tissue for review on the other renal cancers in relatives. Additional findings of note are a spontaneous pneumothorax in our patient's daughter and melanoma in our patient's brother and son. This family has been invited to participate in genetic studies underway at the National Cancer Institute.

Notes: Summary Amonafide, a novel imide derivative with broad preclinical antitumor activity, achieves significant cerebrospinal fluid levels in animal models. In order to test its antitumor activity in patients with recurrent diffuse infiltrative glioma of the astrocytic and oligodendroglial type, we performed a phase II clinical trial. Of the 22 eligible and evaluable patients treated, 2 (9%) experienced tumor regression lasting more than one year. No other patients experienced tumor regression; one remained stable more than six months. Toxicities consisted primarily of myelosuppression, vomiting, and venous irritation at the infusion site. We conclude that amonafide has minimal activity in recurrent glioma patients. Further investigations are not warranted in this study population.

Notes: Abstract Interferons alpha and beta have been reported to cause tumor regression in a small proportion of patients with recurrent glioma. Eflornithine, an irreversible inhibitor of ornithine decarboxylase, reduces cellular polyamine levels and has also been reported to cause tumor regression in patients with recurrent anaplastic astrocytoma and glioblastoma multiforme. In vitro evidence suggests that interferon and eflornithine are synergistic. In this phase II trial, we investigated the combination of recombinant alpha interferon (36 × 106 units/m2 subcutaneously days 3 to 7) and eflornithine (2.25 g/m2 QID PO days 1 to 7) repeated every 28 days. All 29 patients entered in the study were evaluable for toxicity and efficacy. Toxicity consisted primarily of fever, chills, myalgia, weakness and fatigue as well as cortical dysfunction including somnolence, confusion, and exacerbation of underlying neurologic deficits. One patient died from cerebral herniation attributable to interferon. None of the patients experienced objective tumor regression. Seven patients (24%) were stable for more than six months, but the disease stability could also be explained by indolent underlying disease or inability to distinguish recurrent tumor from delayed radiation effects. Intermittent high-dose recombinant interferon alpha plus eflornithine demonstrated no definite antitumor effects in this trial.

Notes: Abstract Background: Chemotherapeutic agents are playing an increasing role in the management of urothelial carcinoma. Despite recent advances in the treatment of this disease there continues to be a need to identify new active agents and their toxicity spectra. Topotecan is an agent as yet unstudied in bladder cancer. Methods: Ambulatory patients with progressive advanced urothelial carcinoma following prior systemic chemotherapy were treated with topotecan 1.5 mg/m2 intravenously (IV) daily for 5 days every three weeks for 6 cycles. Doses were modified for leukopenic fever, thrombocytopenic bleeding, and any grade 3 or 4 (NCI common toxicity criteria) toxicity. Results: Forty-four eligible patients entered the trial. There were 4 partial responses for an overall response rate of 9.1% (exact 95% two-stage binomial CI, 2.9% to 25.5%). Major identified toxicities were gastrointestinal nd myelosuppression. There were no treatment-related deaths. Conclusions: Topotecan at this dose and schedule has minimal activity in previously treated patients with advanced urothelial carcinoma. Toxicities can be severe but are manageable.

Notes: Abstract Current systemic treatment options for patientswith relapsed gliomas are limited. Thetopoisomerase I inhibitor topotecan has demonstrated broadantitumor activity in both preclinicalstudies as well as a number of phase I and II trials in humans.Studies in primates have shown goodcerebrospinal fluid levels of topotecan following systemicadministration. We therefore performed this phase II trial in patients who developed evidence of progressive glioma after definitive radiation therapy. Patients were treated with 1.5mg/m2 intravenously daily for 5 consecutive days repeatedevery three weeks. For patients who had received priornitrosourea-containing chemotherapy, thestarting dose was 1.25 mg/m2. Thirty-three patients wereentered on this study. All patients wereeligible and evaluable for both response and toxicity. Sevenpatients experienced grade 4 leukopeniawith 2 of these patients dying of infection-relatedcomplications. Six of these seven patients werenot taking anticonvulsants during treatment. Nine patientsdeveloped grade 3-4 thrombocytopenia,seven of whom were not taking anticonvulsants. Nonhematologicside effects were infrequent andmanageable. One patient experienced a partial response to thistreatment for an overall response rateof 3% (95% binomial confidence interval 0.3%-20.4%). The median time to progression was 14.9weeks and median survival 19.9 weeks. Topotecan at this dose andschedule showed no substantial activity in relapsed gliomas.