Experimental basis of cord blood transplantation.

Efforts are needed to enhance the efficacy of cord blood (CB) transplantation. Laboratory information set the stage for the first and subsequent CB transplants, and will be instrumental in continuing to advance the field. This paper offers a brief understanding of the current state of hematopoietic stem cell (HSC) and hematopoietic progenitor cell (HPC) biology, a look back at laboratory studies leading to the first CB transplants, and a discussion of the possible means to enhance CB transplantation. Results show that physical recovery of greater numbers of HPCs is possible after CB is collected by perfusing the placenta, but how realistic this procedure is for collection of CB to be banked is open to question. We also show that the chemokine stromal cell-derived factor-1/CXCL12 can enhance the ex vivo expansion of CB HPCs beyond that of the combination of SCF, Flt3-ligand and TPO. Advances in cytokine and stromal cell biology, and in intracellular signals mediating the effects of cytokines/stromal cells should be considered in the context of future efforts to enhance functional activities of donor CB HSCs and HPCs and the microenvironmental niche of the recipient, which is required for acceptance and nurturing these HSCs/HPCs.

Human immunodeficiency virus testing in patients with invasive cervical carcinoma: a prospective trial of the gynecologic oncology group.

To determine the frequency of positive human immunodeficiency virus (HIV) serostatus among North American women 50 years of age or younger with invasive cervical cancer and to define their tolerance to treatment. Consenting patients with newly diagnosed invasive cervical cancer, age 50 or younger were tested by enzyme-linked immunosorbent assay. The study design anticipated that approximately 3% of patients would be HIV positive. After the accrual of 913 eligible and evaluable patients, interim analysis revealed that only 9/913 ( approximately 1%) patients were HIV seropositive, indicating that it would not be feasible to achieve the study objective. The study was closed to further accrual. Between 1994 and 1997, the frequency of positive HIV serostatus among North American women with newly diagnosed cervical cancer was quite low. As a consequence, no evaluation of response to treatment or treatment tolerance can be made.

The abandoned radical hysterectomy: a Gynecologic Oncology Group Study.

OBJECTIVE: The aim of this study was to evaluate the frequency with which intended radical hysterectomy for cervical cancer is abandoned and the outcomes for those patients. METHODS: A secondary evaluation of a prospective surgical pathological trial was performed. There were 1127 patients with Stage IB carcinoma of the cervix entered on Gynecologic Oncology Group Protocol No. 49. These patients were to undergo radical hysterectomy and pelvic lymphadenectomy with careful analysis of pathologic findings, complications, and outcomes. RESULTS: Ninety-eight women were found, at operation, to have extrauterine disease and the proposed radical operation was abandoned at the discretion of the operating surgeon. The records of these patients were evaluated. Subgroups of patients with extrapelvic disease (30) and pelvic extension (26), including grossly positive pelvic nodes (12), other pelvic implants (8), and gross serosal extension (2), were identified. Sixty-three (93%) patients subsequently underwent pelvic radiation therapy and one or two intracavitary applications. Para-aortic fields were added for 8 patients who were found to have positive para-aortic nodes. Five patients received radiotherapy and chemotherapy; 4 patients received chemotherapy alone. One patient declined any further therapy. The disease-free survival was shorter for patients whose radical procedure was abandoned than for those patients who underwent radical hysterectomy. Among the abandoned-operation patients, those with extrapelvic disease had the shortest progression-free interval and survival and those with direct pelvic extension the longest. CONCLUSIONS: Retrospective comparisons of radical hysterectomy to radiation therapy are not valid unless the group of patients whose radical operation was abandoned is included. The morbidity of the operation is low even when followed by radiation therapy. However, no recommendations for optimal therapy can be made from this analysis.

The significance of thrombocytosis in patients with locally advanced cervical carcinoma: a Gynecologic Oncology Group study.

OBJECTIVE: The aim of this study was to determine the incidence of thrombocytosis and its possible impact on survival probability among women with locally advanced cervical carcinoma. METHODS: The database of 294 patients with Stages IIB-IVA cervical carcinoma without periaortic node metastasis who were treated with standardized radiation therapy and concurrent hydroxyurea or misonidazole was analyzed. Pretreatment platelet counts were available for 291 patients who are the subject of this study. RESULTS: Thrombocytosis (platelet count >400 x 10(9)/liter) was present in 86 (29.6%) of the 291 patients. A multivariate Cox proportional hazards model showed that patients without extrapelvic disease and with thrombocytosis had a 55% greater chance of dying than those without thrombocytosis (relative risk = 1.55, 95% confidence interval 1.08-2.21). Patients with thrombocytosis had larger tumors and more frequently had bilateral parametrial involvement, tumor fixation to the sidewall, and positive pelvic lymph nodes than patients without thrombocytosis. Thrombocytosis was not found to be a prognostic factor in patients with positive pelvic nodes. However, in patients with negative pelvic nodes, the presence or absence of thrombocytosis was related to survival. CONCLUSION: Thrombocytosis is a frequent finding among patients with advanced cervical carcinoma and seems to be related to tumor burden. Among patients with locally advanced cervical carcinoma who had negative pelvic nodes, those with thrombocytosis had a poorer survival.

Cisplatin, radiation, and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma.

BACKGROUND: Bulky stage IB cervical cancers have a poorer prognosis than smaller stage I cervical cancers. For the Gynecologic Oncology Group, we conducted a trial to determine whether weekly infusions of cisplatin during radiotherapy improve progression-free and overall survival among patients with bulky stage IB cervical cancer. METHODS: Women with bulky stage IB cervical cancers (tumor, > or =4 cm in diameter) were randomly assigned to receive radiotherapy alone or in combination with cisplatin (40 mg per square meter of body-surface area once a week for up to six doses; maximal weekly dose, 70 mg), followed in all patients by adjuvant hysterectomy. Women with evidence of lymphadenopathy on computed tomographic scanning or lymphangiography were ineligible unless histologic analysis showed that there was no lymph-node involvement. The cumulative dose of external pelvic and intracavitary radiation was 75 Gy to point A (cervical parametrium) and 55 Gy to point B (pelvic wall). Cisplatin was given during external radiotherapy, and adjuvant hysterectomy was performed three to six weeks later. RESULTS: The relative risks of progression of disease and death among the 183 women assigned to receive radiotherapy and chemotherapy with cisplatin, as compared with the 186 women assigned to receive radiotherapy alone, were 0.51 (95 percent confidence interval, 0.34 to 0.75) and 0.54 (95 percent confidence interval, 0.34 to 0.86), respectively. The rates of both progression-free survival (P<0.001) and overall survival (P=0.008) were significantly higher in the combined-therapy group at four years. In the combined-therapy group there were higher frequencies of transient grade 3 (moderate) and grade 4 (severe) adverse hematologic effects (21 percent, vs. 2 percent in the radiotherapy group) and adverse gastrointestinal effects (14 percent vs. 5 percent). CONCLUSIONS: Adding weekly infusions of cisplatin to pelvic radiotherapy followed by hysterectomy significantly reduced the risk of disease recurrence and death in women with bulky stage IB cervical cancers.

Concurrent chemotherapy and radiation therapy in primary cancer of the cervix.

Radiation therapy has been the most active agent for the treatment of patients with locally advanced cervical cancer for many years. Chemotherapy has shown some activity, but data has been lacking to support its routine use. Recently, data from five prospective, randomized trials evaluating this difficult population have matured. Reports from these trials are startlingly similar, leading to the common conclusion that concurrent cisplatin chemotherapy and radiation therapy substantially decrease the risk of relapse and increase the overall survival. These results are compelling evidence for the inclusion of cisplatin with irradiation as a new standard of care for patients with locally advanced cervical cancer.

Gynecologic cancers metastatic to the breast.

BACKGROUND: We report a series of gynecologic cancers metastatic to the breast, illustrating the diagnostic and prognostic implications of this rare event. STUDY DESIGN: By reviewing the gynecologic oncology data base, we identified 10 women with gynecologic cancer metastatic to the breast who were treated at Indiana University School of Medicine between August 1978 and February 1995. Medical records were reviewed for pertinent data concerning the presentation, evaluation, and treatment of the primary gynecologic malignancy and the metastatic breast tumor. RESULTS: The mean patient age was 56.8 years (range, 30-80 years). The most common gynecologic malignancy was ovarian cancer (five patients), followed by cervical cancer (two patients) and cancers of the vagina, endometrium, or peritoneum (one patient each). A palpable solitary breast mass was found in 8 of 10 patients (80%), and the upper outer quadrant of the breast was the most common site of tumor involvement. One woman presented with examination findings resembling inflammatory breast cancer, and one patient presented with multiple firm subcutaneous nodules. Despite further treatment, which in all cases consisted of systemic chemotherapy, 83% of the patients died with a breast metastasis within 1 year of presentation. CONCLUSIONS: Secondary breast malignancy should be suspected in any patient with a breast tumor and a known history of gynecologic cancer. A breast metastasis implies widespread tumor dissemination and a poor prognosis. Radical breast surgery should be avoided.

Hydroxyurea, 5-fluorouracil infusion, and cisplatin adjunct to radiation therapy in cervical carcinoma: a phase I-II trial of the Gynecologic Oncology Group.

BACKGROUND: In a previous study, the Gynecologic Oncology Group (GOG) compared hydroxyurea (HDXR) and the combination of cisplatin (C) and 5-fluorouracil (5-FU) infusion as potentiators of radiation therapy. This study was undertaken to determine whether these two regimens could be combined, concurrent with pelvic radiation therapy in patients with locally advanced cervical cancer. METHODS: The GOG entered 75 eligible and evaluable patients on a Phase I-II evaluation of HDXR, C, and 5-FU as adjuncts to radiation therapy for locally advanced carcinoma of the cervix. All patients had histologically verified primary disease and confirmed negative para-aortic lymph nodes. Eligibility was limited to clinical stage IIB through IVA. HDXR was given orally, twice weekly at a dose of 2.5 g/m2; C on Days 1 and 29 at 50 mg/m2; and 5-FU by 96-hr infusion on Days 2-5 and 30-33 at a starting dose of 800 mg/m2. RESULTS: Forty-eight (64%) patients had stage IIB disease, 25 (33%) had stage IIIB, and 2 had stage IVA tumors. Primary tumors 4 cm or less in size were present in 15 patients, between 4 and 6 cm were in 27 patients, and larger than 6-cm were observed in 33 patients. Grade 3/4 acute toxicity was experienced by 41 (54.7%) patients. These acute toxicities caused delays in prescribed radiation therapy of more than 1 week in 14 (18.9%) and low doses of drug in 16 (21.3%), and only 26 (34.7%) patients had the scheduled dose escalation of 5-FU on their second course. Clinical response was excellent with complete and partial response rate of 93.3%. Median time to progression has not been reached. CONCLUSION: Although this dose and schedule could be successfully administered, the delays in therapy should be avoided by a lower starting dose of hydroxyurea. Stomatitis was not a dose-limiting toxicity. These results have formed the basis of a phase III trial comparing this regimen to two other chemoradiation regimens.

A prospective controlled trial of early postoperative oral intake following major abdominal gynecologic surgery.

OBJECTIVE: The objective was to determine whether, when compared with traditional dietary advancement, early oral intake following major gynecologic surgery leads to a reduction in the length of hospitalization. METHODS: Patients undergoing major abdominal gynecologic surgery were invited to participate in this study. After informed consent was obtained, they were randomized to one of two groups. The control group (group 1) was treated traditionally. Oral intake was initiated only after documentation of bowel function, which was defined by two of the following three criteria: (1) bowel sounds; (2) flatus or bowel movement; and (3) subjective hunger. Those assigned to the study group (group 2) were given a clear liquid diet on postoperative day 1. Once 500 cc was tolerated, a regular diet was given. Patients were evaluated on a daily basis for bowel sounds, flatus, bowel movement, hunger, nausea, vomiting, and need for nasogastric tube decompression. The groups were compared with regard to length of hospital stay, length of postoperative ileus, and incidence of adverse effects including nausea, vomiting, and postoperative complications. Statistical analyses were performed with the Student t and chi 2 tests. RESULTS: The demographic characteristics of the control (N = 47) and study groups (N = 49) were similar, with no significant differences in underlying medical conditions, prior abdominal surgery, or diagnosis of a malignancy. The groups did not vary statistically in the number of subjects who required postoperative antiemetics or postoperative biscodyl suppository. There was a statistically significant reduction in the length of hospitalization for those patients on the early feeding regimen. The average length of stay for group 1 was 4.02 days +/- 0.30 (SEM), while that for group 2 was 3.12 days +/- 0.16 (P = 0.008). While there was a significantly higher incidence of emesis in the study population, this was not associated with any untoward outcome, and this group actually tolerated a solid diet nearly one full day earlier (2.72 days +/- 0.14 vs 1.88 days +/- 0.14, P < 0.0001). CONCLUSIONS: Early postoperative oral intake results in a decreased length of hospitalization and is well tolerated when compared with traditional dietary management in patients undergoing abdominal surgery on a university gynecologic oncology service.

Sites of failure and times to failure in carcinoma of the vulva treated conservatively: a Gynecologic Oncology Group study.

OBJECTIVE: The objective of this review was to examine the patterns of failure after conservative therapy for vulvar carcinoma to establish a basis for the design of prospective cooperative trials in this disease. STUDY DESIGN: The records and characteristics of all patients in whom cancer recurred after conservative therapy in two prospective clinical trials were analyzed. RESULTS: Of 143 patients who received one or more modifications of therapy, 37 patients had recurrence of cancer and 20 died of the disease. The median intervals to recurrence were 35.9 months for vulvar cancer and 7.0 months for groin cancer (p = 0.0002). There were 12 groin recurrences; 11 (91.7%) of these patients have died of the disease. The median survival time after recurrence was 52.4 months for patients with vulvar cancer and 9.4 months for those with groin cancer (p = 0.0025). CONCLUSIONS: Groin cancer recurs earlier than vulvar cancer among patients treated conservatively. Future trials that evaluate modified therapy to the groin need to include early interim analyses. Follow-up for > 36 months after study entry may not be necessary to evaluate the impact of new treatments.

What is the appropriate management of early stage cervical cancer (International Federation of Gynecology and Obstetrics stages I and IIA), surgical assessment of lymph nodes, and role of therapeutic resection of lymph nodes involved with cancer?

It is well recognized that lesion size, tumor volume, depth of stromal invasion, and lymphatic space permeation are all important predictors of lymph node involvement in early stage cervical cancer. Pelvic lymph node involvement is the most important (negative) predictor of survival for these patients with early stage cervical cancer. The number of involved nodes and the size of involved and unresected nodes may also be prognostically significant. It is uncertain whether lesion size, tumor volume, depth of stromal invasion, or lymphatic space permeation are independent negative predictors of survival when correcting for lymph node positivity. Lymphadenectomy has traditionally been considered a diagnostic procedure. There is accumulating evidence to suggest that lymphadenectomy may have therapeutic benefit for patients with cervical cancer metastatic to lymph nodes. This hypothesis awaits further evidence.

Intraperitoneal 5-fluorouracil for pseudomyxoma peritoneii.

Pseudomyxoma peritoneii has an indolent course but a 5-year survival rate of 40-45%. The role for postoperative intraperitoneal chemotherapy is unclear. Nine patients with pseudomyxoma arising from mucinous neoplasms of the ovary and intestinal tract received a total of 89 courses of intraperitoneal 5-fluorouracil (IP5FU). Each course consisted of eight 4-h exchanges of 1 g of 5FU in 2 l of 1.5% Inpersol(R). Median follow-up after diagnosis was 30 months (range 6-74). All patients were evaluable for toxicity and response. There was one treatment-related death due to renal failure and sepsis. Three patients developed disease progression prior to scheduled second-look laparotomy. At second-look laparotomy two patients demonstrated pathologic complete responses, one had stable disease and one had progression of disease. One patient remained clinically free of progression after refusing second-look laparotomy. The projected 5-year survival by Kaplan-Meier estimate was 87% for patients treated with IP5FU compared to a 52% 5-year survival seen in a series of 11 patients treated prior to the use of IP5FU (P = 0.12). This preliminary analysis suggests that IPFU in the described schedule fails to improve survival statistically compared to previously used regimens for patients with pseudomyxoma peritoneii.

Comparison of hematopoietic progenitor cells in human umbilical cord blood collected from neonatal infants who are small and appropriate for gestational age.

BACKGROUND: Cord blood has been used for transplantation. The purpose of this study was to compare numbers of hematopoietic progenitors in cord blood collected from neonatal infants who are small for their gestational age and those who are normal. STUDY DESIGN AND METHODS: Sixteen pregnant women diagnosed with intrauterine growth restriction were prospectively identified. Cord blood was collected at delivery. Fourteen cord blood samples were obtained from gestational age-matched, appropriately grown newborns. In vitro assays for hematopoietic progenitors were performed and results of the two compared. Comparisons were also made with numbers of hematopoietic progenitor cells previously found by this laboratory in samples collected with the possibility of use for transplantation. RESULTS: Gestational age, the women's pregnancy and delivery histories, maternal risk factors for intrauterine growth restriction, maternal age, delivery method, umbilical cord blood gases, and 5-minute Apgar scores were similar in the two groups. Newborns who were small for their gestational age had significantly lower birth weights and longer stays in the neonatal intensive care unit with no evidence for viral infections in the immediate neonatal period. The mean number of progenitors per collection of cord blood in the small newborns was about half that per collection from appropriately grown newborns, but in most cases, these differences were not significant in the two groups, and many numbers in the small newborns fell within the range associated with successfully engrafting cord blood collections. CONCLUSION: Hematopoietic progenitor cells in the small newborns may be adequate for transplantation purposes in many cases. Their possible use in this context should, however, involve careful consideration of the numbers of progenitors collected as well as of possible viral or other contamination.

The fate of the ovaries after radical hysterectomy and ovarian transposition.

To assess the effectiveness of lateral ovarian transposition in preserving normal ovarian function, the medical records of 200 consecutive women with stage I-IIA cervical cancer treated primarily with radical hysterectomy and pelvic lymphadenectomy were reviewed. Lateral ovarian transposition was performed at the time of radical hysterectomy in 132 (66%) patients and 28 (21%) received postoperative pelvic radiation therapy. Menopausal symptoms (vaginal dryness, hot flushes) and follicle-stimulating hormone (FSH) levels were used to define ovarian function. Only 3/104 (2.9%) patients who underwent lateral ovarian transposition without postoperative pelvic radiotherapy experienced menopausal symptoms; however, FSH levels in all three cases suggested continued ovarian function. In 14/28 (50%) patients who received postoperative pelvic radiation therapy ovarian failure occurred. The risk of ovarian failure with pelvic radiation therapy after lateral ovarian transposition was significant (RR = 17.3; 95% CI = 5.35-56.13). The incidence of adnexal disease in transposed ovaries requiring analgesics or further surgery was 3%. These data suggest minimal risk to the patient when the ovaries are conserved. Unfortunately, lateral ovarian transposition preserves ovarian function in only 50% of patients undergoing pelvic radiotherapy following radical hysterectomy.

Quality assessment and assurance programs in the Gynecologic Oncology Group.

The Gynecologic Oncology Group (GOG), a program of ACOG, is one of 12 cooperative groups conducting clinical trials supported by the National Cancer Institute. Recently, an occurrence of research fraud was found in one of the other cooperative groups. The GOG maintains a quality assessment and assurance program that includes three primary functions: Original source documentation is examined to verify accuracy of treatment modalities, all protocols are regularly scrutinized for consistency and validity, and regular on-site audits are conducted at all institutions. The group endeavors to reassure physicians and their patients that research fraud is not rampant in the cooperative group system and that data published by the cooperative groups are reliable.

Malignant melanoma of the vulva treated by radical hemivulvectomy. A prospective study of the Gynecologic Oncology Group.

BACKGROUND: Beginning in 1983, the Gynecologic Oncology Group (GOG) conducted a prospective clinicopathologic study of primary malignant melanoma of the vulva. The objectives of this study were to determine the relationship of histopathologic parameters and microstaging to the International Federation of Gynaecology and Obstetrics (FIGO) staging and prognosis. METHODS: All patients with primary untreated malignant melanoma of the vulva and no history of previous or subsequent other primary invasive malignancy were eligible for study entry. All patients were required to have modified radical hemivulvectomy as minimal therapy. Groin dissection was optional. Histopathologic specimens were reviewed for capillary space involvement, Clark's level, Breslow's depth of invasion, cell type, and melanin distribution. Patient characteristics were analyzed in their relationship to groin node status and recurrence-free interval. RESULTS: Between 1983 and 1990, 81 patients were entered in the study. Of these, 71 were evaluable. Thirty-four patients underwent radical hemivulvectomy, and 37 patients underwent radical vulvectomy. In addition, 56 patients underwent groin node dissection. The factors that were independently correlated with groin node status were: capillary lymphatic space involvement (p = 0.0001) and central primary tumor location (i.e., bilateral/clitoral/T3) (P = 0.003). The other factors that were significant--clinical tumor size, vulvar staging (FIGO), GOG performance status, and Breslow's depth of invasion--were not independent predictors of positive nodes. The factor with the highest significant correlation with recurrence-free interval was the 1992 staging system of the American Joint Committee on Cancer (AJCC) for malignant melanoma of the skin. Using multiple regression, AJCC stage was the only independent prognostic factor. In the absence of AJCC stage, Breslow's depth of invasion was the most prognostic. CONCLUSION: The biologic behavior of vulvar melanoma is similar to other nongenital cutaneous malignant melanoma.

Evaluation and comparison of histopathologic grading systems of epithelial carcinoma of the uterine cervix: Gynecologic Oncology Group studies.

The subjects of this study are 445 patients with advanced cervical cancer treated by standardized radiation therapy. Upon entry into one of two Gynecologic Oncology Group (GOG) protocols, original pathologic diagnoses and histologic tumor descriptions for each patient were compared with separate evaluations made by a consensus opinion of two GOG pathologists. A review diagnosis using grade, cell type, and the Stendahl scoring system was then made by the first author (R.J.S.) without knowledge of the prior diagnoses. Of the original pathologists' diagnoses, 21% did not include grade or cell type. There was little agreement among the different pathologists as to the use of either specific grade or cell type. Histologic grade, irrespective of the pathologists making the diagnosis, had no correlation to prognosis. The Reagan and Wentz large-cell keratinizing (LCK) cell type, when applied by the author to tumors with any form of squamous keratinization present, identified a group of patients with a poorer prognosis, although not independently of other prognostic factors. The Stendahl scoring system identified a number of patients with both a poorer and better prognosis. This was statistically significant and independent of other risk factors. A major limitation, however, was the number of patients evaluable because of inadequate biopsy material in 23.6% of the study group.

Proliferative and cytotoxic responses of human cord blood T lymphocytes following allogeneic stimulation.

On the basis of the success of recent cord blood transplants, we undertook a comparison of the proliferative and cytotoxic potential, following allogeneic stimulation, of E-rosetted T cells from cord blood or adult peripheral blood (PB3) or bone marrow (BM). The magnitude of the proliferative response of cord blood (CB) T cells to alloantigen was greater than or equal to that of adult PB or BM T cells. Proliferation following culture with IL-2, IL-4, or IL-7 produced a similar result. In contrast, the cytotoxic activity in 1(0), 2(0), or 3(0) mixed leukocyte culture of CB T cells was minimal, typically less than 20% at an effector:target ratio of 100:1. Cytometric analysis of CB T cell populations before and after culture with allostimulation demonstrated similar ratios of CD4+ and CD8+ cells in cultures of CB and adult T cells. Down-regulation of CD45RA antigen expression, a measure of CD4+ cell activation, was comparable in adult and CB cultures. Activation of CD8+ CTL effectors was assessed by the acquisition of CD28 antigen expression. After culture, a smaller proportion of CD8+CD28+ effector cells was present in CB cultures as compared to adult T cell cultures. Thus, following in vitro priming with alloantigen CB T cells generate a vigorous proliferative response yet produce little antigen-specific cytotoxicity. This diminished cytotoxicity may, in part, be related to the low incidence of graft vs host disease thus far noted in human CB transplants.