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Antineoplastic Combined Chemotherapy Protocols↗
Biomedical subjects
I Benjamin
Publications and source records attributed to I Benjamin.
Detection of hypoxia in human squamous cell carcinoma by EF5 binding.
Localization and quantitation of 2-nitroimidazole drug binding in low pO2 tumors is a technique that can allow the assessment of hypoxia as a predictive assay. EF5 [2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl) acetamide] is such a drug, and it has been shown to be predictive of radiation response in rodent tumors. Using fluorescence immunohistochemical techniques, we provide data on the presence, distribution, and levels of EF5 binding as a surrogate for hypoxia in human head and neck and uterine cervix squamous cell cancers (SCCs). Six patients with SCC were studied. Four patients had head and neck tumors, and two had uterine cervix cancers. The incubation of fresh tissue cubes in EF3 under hypoxic conditions ("reference binding") demonstrated that all tumors were capable of binding drug, and that this binding varied by a factor of 2.9-fold (174.5-516.1) on an absolute fluorescence scale. In the five patients treated at the lowest drug doses (9 mg/kg), in situ binding was quantitatable. For all six patients, the maximum rate of in situ binding varied by a factor of 6.7 between the lowest and highest binding tumor (24.8-160.3) on an absolute fluorescence scale. In tumors with high binding regions, intratumoral heterogeneity was large, extending from minimal fluorescence (<1%) up to 88.6% of reference binding. In tumors with minimal binding, there was little intratumoral heterogeneity. These studies demonstrate substantial heterogeneity of in situ binding between and within individual squamous cell tumors.
Adult↗
Multi-attenuated herpes simplex virus-1 mutant G207 exerts cytotoxicity against epithelial ovarian cancer but not normal mesothelium and is suitable for intraperitoneal oncolytic therapy.
Recombinant strains of herpes simplex virus-1 (HSV-1) harboring mutations in the infected cell product (ICP)34.5 region lose their neurovirulence and replicate more efficiently in dividing tumor cells than stationary cells, becoming replication-selective oncolytic agents. Additional mutation of the ICP6 gene, which encodes ribonucleotide reductase, further impairs the ability of HSV-1 mutants to replicate in normal cells, enhancing tumor selectivity. The present study investigated the effect of HSV-G207, a recombinant HSV-1 lacking ICP34.5 and ICP6, against epithelial ovarian cancer (EOC) in vitro and in vivo in a mouse xenograft model. To assess the selectivity of multimutated HSV-G207 against malignant cells, HSV-G207 and wild-type HSV-F were comparatively tested against normal human peritoneal mesothelial cells and EOC cells in vitro. HSV-G207 infected both EOC cells and mesothelial cells; however, unlike EOC cells, mesothelial cells provided a poor substrate for replication of HSV-G207. In contrast to wild-type HSV-F, HSV-G207 exerted a potent oncolytic effect on EOC cells but spared normal mesothelial cells in vitro. Primary EOC cells were more sensitive to the virus than established EOC cell lines. A single intraperitoneal injection of HSV-G207 resulted in a significant reduction in tumor volume and tumor spread in vivo. HSV-G207 was shown to penetrate deeply within tumor nodules and caused no apparent intraperitoneal toxicity. Oncolytic therapy with multimutated replication-restricted HSV may offer a novel approach in the treatment of EOC.
Animals↗
Occult bilateral involvement in stage I epithelial ovarian cancer.
OBJECTIVE: The aim of this study was to determine the incidence of occult bilateral involvement in Stage I epithelial ovarian cancer. METHODS: We retrospectively reviewed the records of all patients (n = 135) with Stage I epithelial ovarian cancer treated at the University of Pennsylvania Cancer Center between 1985 and 1996. A study group of patients (n = 118) who underwent a bilateral salpingo-oophorectomy as part of their staging laparotomy was identified. Operative notes, pathology reports, and discharge summaries were reviewed to document stage, grade, histology, intraoperative impression, gross pathological description, and microscopic diagnosis. Clinically occult bilateral involvement was defined as pathologically documented ovarian involvement by tumor in an ovary that appeared normal to the surgeon during staging laparotomy. RESULTS: The study group consisted of mostly Stage IA (79/118, 67%), followed by Stage IC (35/118, 30%) and Stage IB (4/118, 3%), tumors. In 9/118 (7.6%) of these cases, bilateral disease was documented in the pathology report. In 3/118 (2.5%) of these cases, the bilateral involvement by tumor was clinically occult at the time of surgery. In only 1/118 (0.85%) of these cases did a clinically abnormal appearing ovary not contain tumor. CONCLUSION: Occult involvement by early ovarian cancer is uncommon at the time of staging laparotomy. In appropriately counseled patients strongly desiring to preserve fertility, a unilateral salpingo-oophorectomy may be considered as part of a staging procedure for apparent Stage IA epithelial ovarian cancer if the contralateral ovary appears normal to the surgeon. Consideration should be given to a wedge biopsy with intraoperative frozen section to help exclude occult disease in the normal appearing ovary.
Adenocarcinoma↗
Use of carrier cells to deliver a replication-selective herpes simplex virus-1 mutant for the intraperitoneal therapy of epithelial ovarian cancer.
Epithelial ovarian cancer (EOC) remains localized within the peritoneal cavity in a large number of patients, lending itself to i.p. approaches of therapy. In the present study, we investigated the effect of replication-selective herpes simplex virus-1 (HSV-1) used as an oncolytic agent against EOC and the use of human teratocarcinoma PA-1 as carrier cells for i.p. therapy. HSV-1716, a replication-competent attenuated strain lacking ICP34.5, caused a direct dose-dependent oncolytic effect on EOC cells in vitro. A single i.p. administration of 5 x 10(6) plaque-forming units resulted in a significant reduction of tumor volume and tumor spread and an increase in survival in a mouse xenograft model. PA-1 cells supported HSV replication in vitro and bound preferentially to human ovarian carcinoma surfaces compared with mesothelial surfaces in vitro and in vivo. In comparison with the administration of HSV-1716 alone, irradiated PA-1 cells, infected at two multiplicities of infection with HSV-1716 and injected i.p. at 5 x 10(6) cells/animal, led to a significant tumor reduction in the two models tested and the significant prolongation of mean survival in one model. Histological evaluation revealed extensive necrosis in tumor areas infected by HSV-1716. Immunohistochemistry against HSV-1 revealed areas of viral infection within tumor nodules, which persisted for several weeks after treatment. Administration of HSV-infected PA-1 carrier cells resulted in larger areas of tumor infected by the virus. Our results indicate that replication-competent attenuated HSV-1 exerts a potent oncolytic effect on EOC, which may be further enhanced by the utilization of a delivery system with carrier cells, based on amplification of the viral load and possibly on preferential binding of carrier cells to tumor surfaces.
Animals↗
Complete hydatidiform mole. A disease with a changing profile.
OBJECTIVE: To retrospectively evaluate the clinical presentation of complete molar pregnancies in an academic primary obstetrics and gynecology practice over the past decade. STUDY DESIGN: All cases of abnormal pregnancy presenting to our institution during the first half of gestation were identified through a computerized database. Clinical presentation and course of complete moles were analyzed. RESULTS: Twenty-four complete molar pregnancies were identified among 2,431 abnormal early gestations (1%). The patients' mean age was 24.5 years, and the mean gestational age was 9.5 weeks of amenorrhea (range, 8-25). Seventy-five percent of the patients presented with vaginal bleeding and 54% with excessive uterine size. None had hyperemesis gravidarum, preeclampsia, clinical hyperthyroidism or ovarian enlargement. All patients had abnormally elevated serum beta-hCG. Transvaginal ultrasound was diagnostic in more than half the patients, while it was suggestive of the diagnosis in the remainder. One patient experienced postevacuation trophoblastic embolization and developed persistent gestational trophoblastic disease. CONCLUSION: Due to the routine use of transvaginal ultrasound and serum beta-hCG in the workup of early gestational abnormalities, complete molar pregnancy rarely presents today with the traditional signs and symptoms. Despite their absence, the potential for persistent trophoblastic disease still exists, and careful follow-up is warranted.
Adult↗
Allelotype analysis of uterine leiomyoma: localization of a potential tumor suppressor gene to a 4-cM region of chromosome 7q.
Uterine leiomyoma is a benign smooth muscle tumor of the myometrium and is the most commonly encountered neoplasm in women of reproductive age. As for most benign tumors, the pathogenesis of leiomyoma remains obscure, especially at the molecular genetic level. The purpose of this study was to perform a genome-wide allelotype analysis to identify potential sites of tumor suppressor gene inactivation. Fifty-two cases of uterine leiomyoma were subjected to allelotype analysis by using matched pairs of tumor and blood DNA. Loss of heterozygosity (LOH) was assessed at 61 microsatellite markers distributed throughout the genome and representing all 41 chromosome arms. In general, LOH was very rare except on chromosome 7q, where LOH was observed in 34% of all informative tumors. Fine-deletion mapping with 25 microsatellite markers from the 7q22 region revealed a minimal deletion unit of approximately 4 cM, bounded by the markers D7S2453 proximally and D7S496 distally, that probably harbors a novel tumor suppressor gene involved in the etiology of this tumor.
Alleles↗
Endometrial adenocarcinoma with trophoblastic differentiation.
OBJECTIVE: To report a case of stage IIIc poorly differentiated endometrial adenocarcinoma with trophoblastic differentiation and to review previously reported cases. METHODS: The clinical course and histopathology of the case were reviewed, and a literature search for other reported cases was performed. RESULTS: The tumor contained syncytiotrophoblast-like giant cells that stained positively for the beta subunit of human chorionic gonadotropin (beta-hCG), and the patient's serum beta-hCG level was elevated (95 mIU/ml), but became undetectable after treatment. Beta-hCG was used as a tumor marker during further therapy. At 16 months' survival, she remains without evidence of disease and with a beta-hCG (level < 5 mIU/ml). Nine other cases of trophoblastic differentiation in gynecologic nontrophoblastic tumors have been reported, five in endometrial carcinomas which we review. CONCLUSIONS: Trophoblastic differentiation in gynecologic nontrophoblastic tumors is rare. Beta-hCG may be useful as a tumor marker in these cases. The clinical behavior of these tumors has been aggressive, with advanced stages at diagnosis, early widespread metastases or recurrences and poor patient outcomes. The patient presented in this report, however, remains without evidence of disease 16 months following diagnosis and may be the longest survivor with this tumor reported to date.
Adenocarcinoma↗
Clinical characteristics of clear cell carcinoma of the ovary.
OBJECTIVE: The aim of this study is to evaluate the clinical characteristics of clear cell carcinoma of the ovary. METHODS: Between 1986 and 1996, 45 patients with clear cell carcinoma of the ovary were identified by scanning the medical records department and the tumor registry at our institution. RESULTS: Median age was 55 years (range 31-80 years). Tumors were 60% (27/45) stage I, 11% (5/45) stage II, 20% (9/45) stage III, and 9% (4/45) stage IV. All patients presented with a pelvic mass ranging in size from 2 x 3 to 20 x 30 cm and all except 1 had optimal cytoreduction. All patients received postoperative platinum-based chemotherapy, 47% (21/45) in combination with paclitaxel. One stage Ia patient refused therapy. Of the 6 stage III/IV patients with measurable residual tumor, 67% (4/6) partially responded to first line chemotherapy by CT scan or second look laparotomy. Recurrences occurred in 37% (10/27) stage I patients, including 18% (2/11) stage Ia, 33% (1/3) stage Ib, and 54% (7/13) stage Ic. Time to recurrence was 16 and 38 months for the two stage Ia patients and 35 months (median, range 18-56 months) for the stage Ic patients. Survival after recurrence was significantly related to disease-free interval after primary chemotherapy. With a median follow-up of 40 months (range 4-145 months), 93% (25/27) of stage I patients are alive, 20% (5/25) with disease, while 46% (6/13) of stage III/IV patients are alive. Median survival for the stage III/IV patients was 22 months (range 4-70 months). CONCLUSIONS: Clear cell tumors of ovary frequently present at early stages. However, these tumors have a propensity for recurrence even after primary chemotherapy in early stage tumors.
Adenocarcinoma, Clear Cell↗
Advances in cytoreductive surgery of gynecologic cancers.
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Female↗
BRCA1, BRCA2, and hereditary nonpolyposis colorectal cancer gene mutations in an unselected ovarian cancer population: relationship to family history and implications for genetic testing.
OBJECTIVE: Our purpose was to determine the prevalence of BRCA1, BRCA2, and hereditary nonpolyposis colorectal cancer gene mutations in a large, unselected population of ovarian cancer patients and to evaluate the relationship between mutation status and a routinely obtained family history of cancer. STUDY DESIGN: One hundred sixteen consecutive ovarian cancer patients seen for routine clinical care were examined for BRCA1, BRCA2, hMSH2, and hMLH1 gene mutations with use of the polymerase chain reaction, single-strand conformation polymorphism analysis, and direct gene sequencing. Fisher's exact test was used to evaluate possible associations between BRCA1 and BRCA2 mutation status and specific familial characteristics. RESULTS: Among 116 unselected ovarian cancer patients we identified a total of 13 germline mutations in 12 patients: 10 in BRCA1, one each in hMSH2 and hMLH1, and a single BRCA2 mutation, which occurred in a patient also carrying a BRCA1 mutation. More than half the patients with BRCA1 mutations had family histories that would generally be considered unremarkable. Of 22 family history variables analyzed, only two (maternal family history of breast or ovarian cancer, p=0.037, and maternal family history of any cancer, p=0.020) conferred a significantly increased risk of carrying a BRCA1 mutation compared with ovarian cancer patients without such a history. However, the majority of ovarian cancer patients with these family histories and other suggestive histories tested negative for mutations. CONCLUSIONS: Approximately 10% of ovarian cancers occur in association with genetic mutations known to predispose to the disease. A routinely obtained family history is an unreliable way to identify patients who might harbor mutations. The majority of ovarian cancer patients with suggestive family histories test negative for known gene mutations, perhaps suggesting the existence of additional undiscovered genes predisposing to ovarian cancer.
Adult↗
Modern treatment options in epithelial ovarian carcinoma.
Treatment options for epithelial ovarian cancers are under constant evolution. Recent advances have occurred in both first-line and second-line chemotherapeutic regimens. A newly published approach to first-line therapy incorporating intraperitoneal chemotherapy has demonstrated a benefit in selected patients. There are several new drugs showing activity in platinum-resistant epithelial ovarian cancer.
Antineoplastic Agents, Phytogenic↗
Deletion mapping of two potential chromosome 14 tumor suppressor gene loci in ovarian carcinoma.
Previous allelotyping studies of epithelial ovarian carcinoma suggest that loss of heterozygosity on chromosome 14q may be a common genetic alteration in this tumor type. The purpose of this study was to determine a precise frequency of chromosome 14q allelic loss in ovarian carcinomas and to define a minimal region(s) of deletion. Seventy-six ovarian carcinomas representative of the complete spectrum of grade, stage, and histological subtype were selected for PCR-based deletion mapping analysis using 15 highly polymorphic microsatellite markers spanning the length of this chromosome arm. Loss of heterozygosity was observed in 49% of the tumors studied, placing 14q among the most frequently affected chromosomal regions in ovarian cancer. Deletions were observed in all tumor grades and stages and in all histological subtypes except tumors of low malignant potential. Deletion of the entire chromosome arm was rare; the majority of tumors displayed partial losses, providing an informative basis for detailed deletion mapping. Two distinct minimal regions of deletion were delineated. One region was defined by markers D14S80 and D14S75 at 14q12-13, and the other region was defined by markers D14S65 and D14S267 at 14q32. These data implicate the involvement of two tumor suppressor genes on chromosome 14q in a substantial fraction of ovarian carcinomas.
Chromosome Deletion↗
Effect of surgical debulking on survival in stage IV ovarian cancer.
In order to determine whether optimal surgical debulking in Stage IV epithelial ovarian cancer impacts survival, a retrospective review of patients treated at the University of Pennsylvania Cancer Center (UPCC) from 1984 to 1995 diagnosed with Stage IV epithelial ovarian cancer was performed. Data were collected regarding grade, histology, reason for allocation to Stage IV, extent of surgery performed and residual disease at initial staging procedure, major perioperative complications, first-line chemotherapy regimen, length of inpatient hospital stay, outcome at second-look laparotomy, follow-up, and survival. For the purposes of this study, optimal cytoreduction was defined as a residual disease of 2 cm or less. Forty-seven patients with Stage IV epithelial ovarian cancer identified in the Society of Gynecologic Oncologists (SGO) Database at UPCC are included. Fourteen of 47 (30%) were optimally cytoreduced at the time of their staging procedure. Twenty-six of 47 (55%) were deemed Stage IV by virtue of positive pleural effusion cytology only. Twenty-one of 47 (45%) had intraparenchymal liver involvement or metastatic disease outside of the abdomen. The median survival of the suboptimally debulked group was 17 months, while median survival in the optimal group was 37 months (P = 0.0295). These data suggest that Stage IV epithelial ovarian cancer patients with less than 2 cm residual disease have a survival advantage over patients with greater than 2 cm residual.
Female↗
Cycles of dose-intensive chemotherapy with peripheral stem cell support in persistent or recurrent platinum-sensitive ovarian cancer.
OBJECTIVE: The objective was to determine the toxicity and surgically documented response rate of sequential high-dose chemotherapy with peripheral stem cell support in patients with persistent or recurrent cisplatin-sensitive ovarian cancer. METHODS: Fourteen patients (average age, 45 years) were treated with cyclophosphamide (4.5 g/m2), followed by granulocyte colony-stimulating factor (G-CSF)-stimulated peripheral stem cell harvests. The subsequent regimen prescribed three courses of carboplatin (1 g/m2) and cyclophosphamide (1.5 g/m2 with 2-mercaptoethanesulfonate) every 2 weeks with stem cell support. This was followed by three courses of paclitaxel at 250 mg/m2 every 2 weeks with G-CSF support only. Six patients were entered on the basis of a positive second-look laparotomy and 8 patients had a first recurrence after at least a 6-month disease-free interval. RESULTS: Fourteen patients were entered and 12 patients completed all planned courses of therapy (mean time, 13 weeks). Normal hematopoiesis was reestablished after each cycle. Hospitalization for neutropenic fever occurred in 11/93 cycles (11.8%). Thirteen patients required blood transfusions and in 12 patients platelet transfusions were given. One patient had grade 3 neurotoxicity. An initial elevated CA 125 returned to normal in 7/8 patients (88%) and 71% of patients with measurable disease responded to therapy. There were 2 pathologic complete responders (PCR), making the PCR rate 2/14 or 14% (0-35%). CONCLUSION: Although this regimen was well tolerated and clinical response rates were high, the surgically documented response rate was not clearly superior to conventional salvage regimens in platinum-sensitive patients.
Adult↗
Postoperative day 1 serum human chorionic gonadotropin level as a predictor of persistent ectopic pregnancy after conservative surgical management.
OBJECTIVE: To determine characteristics predictive of persistent ectopic pregnancy (EP). DESIGN: Retrospective cohort study. SETTING: Tertiary care, university hospital. PATIENT(S): All women treated surgically for an EP whose postoperative hCG levels were followed until complete resolution or determination of a persistent EP over a 54-month period. MAIN OUTCOME MEASURE(S): Final outcome defined as successful treatment or persistent EP. RESULT(S): Twenty-six (17.7%) of 147 patients were diagnosed with a persistent EP. An inverse relationship was noted between the percent decrease in hCG at postoperative day 1 and the incidence of persistent EP. A significantly greater percentage of persistent EPs were noted when the postoperative day 1 hCG fell < 50% from the initial preoperative hCG level (relative risk = 3.51 [1.25 to 6.68]). No case of persistent EP was noted if the postoperative day 1 hCG declined by > or = 77%. Surgical time differed significantly (129 minutes versus 101 minutes) between cases treated successfully as compared with cases in which conservative treatment failed. No other preoperative or intraoperative variables were found to be significantly different. CONCLUSION(S): Although no single postoperative hCG value is predictive of conservative surgical treatment for EP, a day-1 postoperative hCG value may be used as a predictor of persistent EP.
Chorionic Gonadotropin↗
MnDPDP-enhanced MR imaging of the liver. Correlation with surgical findings.
PURPOSE: To compare lesion detection and characterisation predicted by MnDPDP-enhanced MR imaging with surgical excision and pathological examination. MATERIAL AND METHODS: Ninety patients were intravenously infused at a rate of 2 to 3 ml/min with 5 mumol/kg mangafodipir trisodium (MnDPDP, Teslascan). The patients were examined with spin-echo and gradient-echo T1-weighted MR imaging at 1 h and 24 h after the end of infusion. The results were compared with identical pre-contrast sequences. In 20 of these patients, the pre-operative MR findings were compared with intra-operative ultrasonography and histology of the resected liver specimens. RESULTS: In those with liver metastases, there was a good correlation between MR and the hepatic disease in 11 out of 14 cases. In the group with primary liver tumours, MR findings correlated with hepatic disease in 5 out of 6 cases. CONCLUSION: Liver lesion characterisation is possible with MnDPDP, and MR contrast enhancement with this agent is considered to be an important adjunct to the radiological assessment of patients with neoplastic liver disease where accurate decisions for surgical planning are imperative.
Adolescent↗
Disposition of atovaquone in humans.
Atovaquone is an antiprotozoal compound with good in vitro stability against metabolic inactivation. Previous human studies which did not involve radiolabelling had not accounted for a substantial proportion of the dose. The possible metabolism of atovaquone in men was examined in a radiolabelling study involving four healthy male volunteers. Radioactivity was eliminated almost exclusively via the feces. All radioactivity in plasma, urine, and feces was accounted for by atovaquone, with no evidence of metabolites. Radiolabelled atovaquone was administered to a patient with an indwelling biliary tube after surgery. Biliary radioactivity was approximately 10- to 40-fold higher than that in plasma and was accounted for by atovaquone. Atovaquone is not significantly metabolized in humans but is excreted into bile against a high concentration gradient.
Adult↗