Robert C. Wallach

All-trans retinoic acid and interferon-α-2a in patients with metastatic or recurrent carcinoma of the uterine cervix : Clinical and pharmacokinetic studies

BACKGROUNDnRecent clinical trials with a combination of interferon (IFN alpha) and 13 cis-retinoic acid resulted in high response rates among women with locally advanced and metastatic carcinoma of the uterine cervix. The authors sought to amplify these observations by employing the isomer of 13 cis-retinoic acid, all-trans retinoic acid (tRA), in combination with IFN alpha.nnnMETHODSnSequential clinical trials were initiated by the New York Gynecologic Oncology Group to test the combination of tRA and IFN alpha in women with metastatic or recurrent carcinoma of the cervix who had failed primary therapy. IFN alpha was administered at 6 MU subcutaneously 3 times per week. In the first trial, tRA was administered at 50 mg/m2 orally 3 times per day on a daily schedule (daily regimen), whereas in the second trial, tRA was administered at the same dose 3 times per day, but only on Days 1-3 each week (intermittent schedule). Clinical outcomes included response to therapy and survival. Plasma pharmacokinetic studies of tRA were performed in both trials to assess the effects of different schedules on plasma levels of the drug.nnnRESULTSnFourteen women with metastatic or recurrent squamous cell carcinoma of the cervix were enrolled in the daily trial and 12 women in the intermittent trial. There was no clinical activity for either regimen, and both studies were terminated according to an early stopping rule. Because tRA has been reported to induce its own metabolism, plasma levels of tRA were measured on Days 1, 8, and 28. The change in the area under the time versus tRA concentration curve (AUC) was significantly different between the two groups. The average AUC on Day 8 was 14% of that observed on Day 1 for the daily treatment group; in contrast, it was 107% on Day 1 in the intermittent treatment group. In 6 of 8 patients studied in the daily trial, the AUC decreased at least 60% by either Week 2 or Week 4. In contrast, in the intermittent trial, only 3 of 9 patients experienced >60% decrease in plasma levels of the drug at either Day 8 or Day 28.nnnCONCLUSIONSnThe combination of tRA + IFN alpha was inactive in patients with advanced carcinoma of the cervix when employed at these doses on either the daily or intermittent schedule. The failure of activity of this regimen did not result from induction of metabolism of tRA, suggesting that intrinsic mechanisms of resistance to tRA at the cellular level may be of greater importance.amplify these observations by employing the isomer of 13 cis-retinoic acid, allRonalde Rameau, M.D. trans retinoic acid (tRA), in combination with IFNa. Astrid Quish, M.D. METHODS. Sequential clinical trials were initiated by the New York Gynecologic John Mandeli, M.D. Oncology Group to test the combination of tRA and IFNa in women with metastatic Robert Gallagher, M.D. or recurrent carcinoma of the cervix who had failed primary therapy. IFNa was Steven Hallam, B.S. administered at 6 MU subcutaneously 3 times per week. In the first trial, tRA was Abbie Fields, M.D. administered at 50 mg/m orally 3 times per day on a daily schedule (daily regiGary Goldberg, M.D. men), whereas in the second trial, tRA was administered at the same dose 3 times Frances McGill, M.D. per day, but only on Days 1–3 each week (intermittent schedule). Clinical outcomes Scott Jennings, M.D. included response to therapy and survival. Plasma pharmacokinetic studies of tRA Robert C. Wallach, M.D. were performed in both trials to assess the effects of different schedules on plasma Carolyn D. Runowicz, M.D. levels of the drug. for the New York Gynecologic RESULTS. Fourteen women with metastatic or recurrent squamous cell carcinoma Oncology Group of the cervix were enrolled in the daily trial and 12 women in the intermittent trial.

Coexistent atypical polypoid adenomyoma and endometrial adenocarcinoma

Atypical polypoid adenomyoma (APA) is a rare entity that is believed to follow a benign course. We report a case of APA with coexistent endometrial adenocarcinoma. The example raises the possibility that APA may progress to endometrial adenocarcinoma in some cases.

Ovarian Cancer in BRCA Mutation Carriers: Improved Outcome After Intraperitoneal (IP) Cisplatin

BackgroundOvarian cancer arising in women with BRCA mutations is known to have a more favorable outcome and to be more responsive to platinum-based regimens than in those without a hereditary background. We analyze our previously published intraperitoneal (IP) studies in relation to BRCA mutation status and update their outcomes.MethodsAmong 62 patients with ovarian cancer enrolled in IP platinum doublet studies in clinical trials (with etoposide (nxa0=xa018), with floxuridine (nxa0=xa030), and with topotecan (nxa0=xa014)), a deleterious BRCA mutation was eventually identified in 10 patients. The outcomes in these BRCA mutation carriers are described and compared with survival of others in respective trials.ResultsTen patients that were confirmed to have BRCA mutations—all with high-grade and stages IIC to IV disease—survived a median of 10xa0years (range: 4–18+) after receiving IP cisplatin-based regimens. Two continue with no evidence of disease since their IP treatment, while four others remain alive with recurrences after 8, 9, 10, and 11xa0years, respectively.ConclusionsThis experience suggests that IP cisplatin leads to favorable long term outcomes in advanced ovarian cancer in women with defective homologous recombination (i.e., with deleterious BRCA mutations). Whether such cisplatin dose-intensification from IP relative to (intravenous) IV drug administration leads to superior results in these mutation carriers requires further study.

Xanthogranulomatous Tubo-Ovarian Abscess Resulting from Chronic Diverticulitis

We report a case of xanthogranulomatous tubo-ovarian abscess which was preoperatively suspected to be an adnexal neoplasm. With foreign body material found in the abscess wall and vegetable fiber in the tubal lumen, a previously treated chronic diverticulitis was the presumed cause. Culture studies showed polymicrobial isolates which included Escherichia coli, an enteric pathogen. After surgery, administration of antibiotics, and revision of delayed subcutaneous wound healing, the patient is reportedly well.

Phase 1/pharmacology study of intraperitoneal topotecan alone and with cisplatin: potential for consolidation in ovarian cancer

PurposeMost ovarian cancers recur after first-line treatment. We studied the pharmacology, tolerability, and therapeutic potential of intraperitoneal (IP) topotecan, alone and with IP cisplatin.MethodsPatients received IP topotecan 1.5xa0mg (flat dose) daily on days 1–5 (level 0) via IP catheter. Subsequent cohorts received IP cisplatin 50xa0mg/m2 on day 1 added to topotecan 1.5xa0mg on days 1–3 (level I), topotecan 1.25xa0mg on days 1–3 (level II), or topotecan 1.25xa0mg on days 1–5 (level III). Plasma and IP concentrations of total and lactone (E-ring closed) topotecan were measured on days 1 and 2 in cycles 1 and 2.ResultsSixteen patients (15 tubo-ovarian, 1 gastric cancers) were entered at levels 0 (3), I (4), II (4), or III (5). Dose-limiting neutropenias occurred in seven patients at dose levels I and III; grade 3 thrombocytopenia occurred in two at level III. Other toxicities included grade 1 hives in two, serum creatinine elevations in two, and Staphylococcus epidermidis and chemical peritonitis (one each). A median progression-free survival of 13xa0months was recorded among ovarian cancer patients who had minimal (6) or no residuum (3) after platinum-based induction; 5 are alive at 4xa0years. Topotecan’s AUC IP/AUC plasma ratios ranged from 13 to 119.ConclusionTopotecan IP for 3–5xa0days is tolerable; occasionally, myelosuppression is dose-limiting. Topotecan 1.25xa0mg (days 1–3) with IP cisplatin 50xa0mg/m2 (day 1) is a regimen suitable for consolidation in phase 3 trials.

Origin, Frequency and Clinical Significance of Glandular Cells in Liquid-Based Pap Tests from Patients Posthysterectomy

OBJECTIVEnTo quantify the frequency and significance of glandular cells in posthysterectomy liquid-based (SurePath, TriPath Imaging, Burlington, North Carolina, U.S.A.) vaginal Pap tests.nnnSTUDY DESIGNnThe presence of benign glandular cells in vaginal Pap tests from posthysterectomy patients represents a diagnostic challenge and may pose management issues. We investigated the presence, frequency and significance of glandular cells in 52 liquid-based (SurePath) vaginal Pap tests from posthysterectomy patients by combining cytomorphologic findings with adjunctive immunohistochemistry and mucin stains performed on cell block preparations and correlated the findings with clinical data.nnnRESULTSnAfter performing these special studies, the frequency of reporting glandular cells in posthysterectomy Pap tests decreased from 3.5% to 1.2% of all vaginal Pap tests performed in a 6-month period.nnnCONCLUSIONnA strong association of the presence of benign appearing glandular cells and a previous history of gynecological malignancy (71%) and chemotherapy/radiation (59%) were noted, likely representing a regenerative process in response to injury or therapy.

Meiotic chromosomal changes and sterility produced by nitrogen mustard and procarbazine in mice**Supported in part by the Lenore Weinstein Fund.

Treatment and survival of reproductive-age patients with chemotherapy raises the question of possible effects on procreative ability. An attempt has been made to establish an animal model system. The anticancer agents nitrogen mustard and procarbazine caused decreased fertility in mice of both sexes and induced meiotic chromosomal abnormalities, at least in the male. Progeny of treated mice showed similar meiotic chromosomal changes. The possibility of similar effects in human beings receiving chemotherapy must be considered.