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Biomedical subjects

A M Davidoff

Publications and source records attributed to A M Davidoff.

At least 19 recordsLinked to original sources
PubMed2001

Gene therapy-mediated expression by tumor cells of the angiogenesis inhibitor flk-1 results in inhibition of neuroblastoma growth in vivo.

BACKGROUND/PURPOSE: Preventing tumors from forming new blood vessels appears to be an effective new anticancer approach. Antiangiogenic therapy usually is cytostatic, however, and, therefore, long-term angiogenesis inhibition is likely to be required. The objective of this study was to determine if sustained gene therapy-mediated expression of these agents from tumor cells could restrict tumor growth in vivo. METHODS: Two replication-defective retroviral vectors were made, one encoding both the soluble, truncated vascular endothelial growth factor receptor (VEGF-R2), flk-1, together with green fluorescent protein (GFP), and the other encoding GFP alone. These vectors were then used to transduce murine neuroblastoma cells (NXS2). Stable, high expression of the flk-1 transgene was confirmed in the former population of cells by Western analysis. Flk-1 protein was isolated from cell culture supernatants and tested in human umbilical vein endothelial cell (HUVEC) proliferation and migration assays to confirm that functional protein was being made. Finally, in vivo activity was assessed by injecting 10(6) tumor cells subcutaneously into SCID mice and monitoring subsequent tumor growth. RESULTS: Purified flk-1 (0.1 micromol/L) was able to inhibit basic fibroblast growth factor (bFGF) stimulated HUVEC proliferation by 44% and VEGF-stimulated migration by 30%. In vitro growth rates for the transduced cell lines were similar to the unmodified cell line. In vivo, however, after 23 days, tumors from flk-1 expressing neuroblastoma cells were less than 33% the average volume of tumors from cells expressing only the GFP transgene (mean volume, 1.9 cm(3) v 5.8 cm(3), P<.001). GFP expression alone had no effect on tumor growth when compared with unmodified tumor cells. CONCLUSIONS: Engineered expression of flk-1, a competitive inhibitor of VEGF, by tumor cells results in the production of an inhibitor of endothelial cell proliferation and migration that greatly restricts the growth of the tumor cells in vivo. Gene therapy-mediated delivery of angiogenesis inhibitors may provide an alternative approach to treating refractory tumors such as neuroblastoma.

Animals↗
PubMed2001

The association of elevated percent bands on admission with failure and complications of interval appendectomy.

BACKGROUND/PURPOSE: The routine use of interval appendectomy for the treatment of perforated appendicitis, with or without abscess, remains controversial. The purpose of this study is to confirm the efficacy of this approach and to identify factors associated with failures and complications. METHODS: All patients (n = 101) with their clinical diagnosis of perforated appendicitis confirmed with imaging were treated prospectively with fluids and intravenous antibiotics (clindamycin, ceftazidime) and were discharged home on oral fluids and analgesics regardless of fever. Intravenous antibiotics were continued at home until the patients were afebrile for 48 hours, and their white blood cell and differential counts were normal. Patients were readmitted at 8 to 12 weeks for an interval appendectomy. Failure to improve by 72 hours of antibiotic therapy mandated an early appendectomy. P values were determined by chi(2) analysis and Student's t test. RESULTS: The 79 patients (78%) successfully treated with interval appendectomy had an overall 6.3% complication rate, and total hospitalization averaged 5.2 days. The treatment in 21 of 22 patients (22%) requiring early appendectomy failed because of a clinical picture suggesting small bowel obstruction. The patients with the failed procedures had a complication rate of 50% and were hospitalized an average of 12.8 days. The overall complication rate for the 101 patients was 15.8%, and the overall total hospitalization was 6.9 days. Patients requiring early appendectomy had a more frequent finding resembling a small bowel obstruction on their initial x-ray (50% v 13%, P = .004) and a higher percent band count on their initial differential blood cell count (22.6% v 7.6%, P<0.0001) than did those successfully treated with interval appendectomy. An initial band count <15% was predictive of an uncomplicated course (84% positive predictive value). CONCLUSIONS: Interval appendectomy without complications is successful in the majority of patients with perforated appendicitis. An elevated initial band count > or =15% is associated with an increased likelihood of failure and complications.

Adolescent↗
PubMed2000

Retroviral vector-producer cell mediated angiogenesis inhibition restricts neuroblastoma growth in vivo.

BACKGROUND: The purpose of this study was to determine whether gene therapy-mediated delivery of an angiogenesis inhibitor, a truncated, soluble vascular endothelial growth factor receptor (Flk-1/KDR, VEGFR-2), could suppress tumor growth in a murine model of neuroblastoma. METHODS: Murine fibroblasts producing a replication-defective retrovirus encoding this mutant form of flk-1 were made. These producer cells were mixed with neuroblastoma cells and injected subcutaneously into SCID mice. Subsequent tumor growth was then measured. RESULTS: Murine neuroblastoma growth was decreased by 95% after 25 days. Similar tumor growth inhibitory effects were observed when the flk-1 producer cells were co-injected with cells from two different human neuroblastoma cell lines. CONCLUSIONS: Neuroblastoma growth can be significantly restricted in vivo with a single injection of cells that produce a retroviral vector encoding the gene for an angiogenesis inhibitor. This suggests that gene therapy-mediated delivery can be an effective alternative to chronic administration of these cytostatic anticancer agents.

Animals↗
PubMed2000

Humoral response to vaccination with interleukin-2-expressing allogeneic neuroblastoma cells after primary therapy.

BACKGROUND: Immunotherapy using cytokine-expressing tumor cells has shown promise as an anticancer strategy. We have recently begun a trial of interleukin-2 (IL-2) gene-modified allogeneic neuroblastoma cells administered in a sequence of eight injections to patients with high-risk neuroblastoma following completion of primary therapy. Six patients to date have completed treatment. PROCEDURE: We examined humoral responses to the immunizing cell line and, when available, to the patients' autologous tumor cells using an in vitro binding assay. RESULTS: Five of six patients developed a rise in antitumor antibodies to the immunizing neuroblastoma cell line following vaccination. Two of these patients had autologous tumor available; both demonstrated a humoral response to these cells as well. CONCLUSIONS: Our results demonstrate that vaccination with IL-2-expressing allogeneic tumor cells after intensive primary therapy can elicit a humoral response to the immunizing line. These antibodies are cross-reactive with the patients' own tumor cells in the two cases in which autologous cells were available. This suggests that different patients' tumors may share common antigens that can be exploited in immunotherapy strategies and supports the continued exploration of allogeneic tumor cells as tumor vaccines.

Adolescent↗
PubMed1999

Enhanced neuroblastoma transduction for an improved antitumor vaccine.

BACKGROUND: A recent clinical trial of an antineuroblastoma vaccine used adenovirus serotype 5 (Ad5) vectors to transduce autologous tumor cells with the gene encoding IL-2. A method to improve transduction efficiency was sought to enable the use of lower viral titers, especially when in situ adenoviral-mediated tumor cell transduction is considered. MATERIALS AND METHODS: A chimeric adenoviral delivery vector was utilized in which the fiber head from adenovirus serotype 3 was incorporated into the backbone of Ad5. Since the fiber head protein is responsible for viral attachment to target cells, a different spectrum and range of infectivity might result. Both the chimeric (Av9LacZ4) and Ad5 (Av1LacZ4) vectors were constructed to carry a beta-galactosidase transgene. The relative transduction efficiency of these two vectors was then evaluated in five tumor-derived short-term neuroblastoma cultures and four established neuroblastoma cell lines. Enzyme activity was assessed using three different methods: in situ staining, flow cytometric analysis, and a quantitative assay. RESULTS: A significant improvement in transduction efficiency of the short-term neuroblastoma cultures with the new chimeric adenovector was demonstrated. A similar improvement in transduction efficiency was not observed in the established cell lines, suggesting that the cell surface receptor for the Ad 3 serotype had been lost in vitro. Increased transduction of tumor cells with N-myc amplification was also observed. CONCLUSIONS: The newly constructed chimeric adenoviral vector transduces short-term neuroblastoma cultures more efficiently than the standard Ad5 vector. This vector will permit the use of lower viral titers and may be useful in other adenoviral-based gene-therapy protocols. Increased transgene expression in N-myc-amplified cells offers possible selectivity for in situ gene delivery.

Adenoviruses, Human↗
PubMed1999

Neuroblastoma regression and immunity induced by transgenic expression of interleukin-12.

PURPOSE: Interleukin-12 (IL-12) is a cytokine with potent antitumor effects. The authors sought to assess its capacity to increase tumor immunogenicity when expressed by tumor cells in a murine model of neuroblastoma. METHODS: Syngeneic A/J mice were inoculated subcutaneously with 2 x 10(6) cells from a murine neuroblastoma-derived cell line (neuro-2a). In situ transduction of the neuroblastoma cells was achieved by intratumoral injection of an adenoviral vector encoding both subunits of the murine IL-12 heterodimer. Growth of the IL-12 gene-modified tumor cells was compared with untreated neuro-2a cells. Tumor immunity was assessed by rechallenging mice that had rejected their tumor with unmodified neuroblastoma cells. The contribution of cytotoxic T lymphocytes (CTLs) was evaluated through cytotoxicity assays. RESULTS: Eighteen (72%) of 25 tumor-bearing mice treated with the mlL-12 adenoviral vector exhibited tumor regression, with 12 mice (48%) completely rejecting their tumors over 2 to 3 weeks. None of the mice that had rejected their tumor and were rechallenged with unmodified neuro-2a cells subsequently developed new tumors. Pooled splenocytes from mice rejecting their tumors showed significant tumor killing (>20% cytolysis) in vitro in 51Cr release assays. CONCLUSIONS: Adenoviral-mediated IL-12 expression by tumor cells in a murine neuroblastoma model produced a significant antitumor response. Most treated tumors demonstrated at least transient regression, whereas many completely regressed. Cured mice exhibited protective immunity and CTL activity against the tumor. These data confirm the immunomodulatory efficacy of IL-12 as part of a vaccine-based antineuroblastoma strategy.

Adenoviridae↗
PubMed1997

Wandering spleen: a challenging diagnosis.

Wandering spleen is rare, particularly in children, and diagnosis is difficult. It usually occurs at 20 to 40 years of age, and most cases are seen in women. Diagnosis is difficult because of lack of symptoms, unless splenic torsion has occurred. Patients usually have an asymptomatic abdominal mass, an acute abdomen, or, most commonly, a mass associated with pain. Laboratory data are nonspecific, but the diagnosis can be confirmed by imaging studies; computed tomography and duplex ultrasonography are preferred modalities. Treatment is operative because of complications of splenic infarction and possible splenectomy. Splenopexy is the treatment of choice for a noninfarcted wandering spleen. Splenectomy should be done only when there is no evidence of splenic blood flow after detorsion of the spleen. We review our experience with wandering spleen in two pediatric patients, one treated with splenopexy and the other with splenectomy.

Abdominal Pain↗
PubMed1996

Epstein-Barr virus-associated hepatic smooth muscle neoplasm in a cardiac transplant recipient.

Host immunosuppression is increasingly recognized as a significant risk factor for the development of a primary neoplasm. Chronic immunosuppressive therapy, as used in organ transplantation, may perturb the immunosurveillance ability of the host, making the patient more susceptible to virus-associated malignancies. We have taken care of a care of a child who received an orthotopic heart transplant and who then developed both a generalized lymphoproliferative disorder and a leiomyoma of the liver a year later. Epstein-Barr virus DNA was detected in a lymph node initially and the hepatic tumor cells subsequently. The former responded to a reduction in the immunosuppressive medications and the latter responded to surgical resection. This is the first report of a hepatic smooth cell neoplasm occurring following cardiac transplant and the development of two sequential Epstein-Barr virus-associated disorders in an immunosuppressed patient.

Child↗
PubMed1996

Esophageal replacement using the colon: is it a good choice?

Thirty-eight children (2 months to 26 years of age) underwent esophageal replacement at our institution between 1962 and 1993. Twenty-four patients had esophageal atresia, with the replacement performed at a mean age of 17 months. The remaining patients (37%) had strictures and were older (mean, 7.4 years). Replacement procedures involved the right colon in 61% of cases and the transverse left colon in the others (39%). Sixty-three percent were placed substernally and 37% were done in transthoracic fashion. The average length of stay in the hospital was 34 days (range, 11 to 256 days.) Early complications (within 30 days) included cervical anastomotic leaks (11 patients; 29%) pneumonia (4), would infection (2), pneumothorax/hemothorax (3), wound dehiscence (1), prolonged ventilation (2), vocal cord paralysis (1), Horner's syndrome (1), pancreatitis (1), and perforated graft (1). Despite the incidence of early leaks, only two persisted long-term (more than 3 months). Other late complications included significant proximal strictures (5), and cologastric strictures developed in five patients. Seven cases were considered graft failures (18%), and all of these eventually require graft replacement. Additional problems included redundant graft requiring revision (4) and dumping syndrome (2). There were six cases of intestinal obstruction caused by adhesions. Four of these involved intrathoracic obstruction of the graft and two involved small bowel obstruction. There was only one death, which occurred late and was not related to the primary disease or procedure. Long-term follow-up data were available for 20 patients (53%). The follow-up period ranged from 1 to 33 years (mean, 12 years). Fourteen had excellent results after the initial interposition, being able to eat and function well without any further intervention. Seven patients (18%) have had poor results and 17 (45%) required additional procedures to obtain good functional results. In our experience, the colon continues to be a good option for esophageal replacement, but additional procedures frequently are necessary to optimize the functional outcome. Good results can be expected in the majority of cases, but late problems (ie, redundant colon and poor emptying) are not unusual, and careful follow-up is essential in the management of such patients.

Adolescent↗
PubMed1996

Endodermal sinus tumor in children.

Malignant germ cell tumors account for about 3% of neoplasms in children, and endodermal sinus tumor (EST) is the most common histological subtype. The authors reviewed 22 years' experience (at their institution) in the management of 37 patients with this tumor. Fifteen of them (41%) had a sacrococcygeal primary, 10 had a testicular tumor (27%), 6 had an ovarian tumor (16%), 3 had a vaginal tumor (8%) and 3 had tumors at other sites (8%). Seven (19%) patients presented with metastatic disease, primarily pulmonary. The serum alpha-fetoprotein (AFP) level was elevated in all cases tested. The initial chemotherapy regimen included vincristine, actinomycin, cyclophosphamide (VAC), and Adriamycin (6 patients), but since 1985 the regimen has been changed to include cisplatin or Carboplatin, etoposide, and bleomycin (21 patients). Eight patients with testicular tumors initially were treated with surgical excision alone. Computed tomography results were a poor predictor of recurrence, but AFP surveillance was extremely sensitive. No second-look operation detected residual tumor in the absence of AFP elevation. Initial relapse for all patients tended to occur early (within 2 years), locally, and often with pulmonary metastases. Although historically the prognosis for patients with EST has been poor, the overall 2-year survival rate in this series was 70%. The best prognosis was among the children who had a testicular primary tumor (survival rate, 100%). The 2-year survival rate for patients with ovarian tumors was 67%; for those with sacrococcygeal primaries it was 60%. These results suggest that the prognosis for children with EST has improved significantly over the past decade. Contributing factors include therapy based on cisplatin, etoposide, and bleomycin, and relapse surveillance with serial AFP determinations. Second-look procedures should be reserved for patients who have an increasing level of serum AFP, suspicious computed tomography findings, and no obvious evidence of metastatic disease.

Adolescent↗
PubMed1996

Management of the gastrointestinal tract and nutrition in patients with cloacal exstrophy.

Cloacal exstrophy is a rare condition in which there is a complex set of congenital anomalies that affect multiple-organ systems, including the gastrointestinal tract. Twenty-six patients with cloacal exstrophy have been treated at the authors' institution during the last 20 years. Gastrointestinal features usually included omphalocele, exstrophy of an everted cecal plate, a short blind-ending distal colon, imperforate anus, and, occasionally, a shortened small bowel. Additional gastrointestinal anomalies included four cases of colonic duplication, one duodenal web, and one malrotation. The average time until the initiation of enteral feeding after initial surgery was 15.6 days, and the time until discontinuation of total parenteral nutrition (TPN) was 36 days. One patient with short bowel syndrome died of TPN-associated liver failure. Five other patients exhibited short bowel physiology, but ultimately each was weaned from supplemental intravenous hyperalimentation. Four patients have undergone posterior sagittal anorectoplasty, and one has had perineal anoplasty. Of these patients, two are continent and one is free of soilage on a bowel management program. In the authors' experience with management of the gastrointestinal tract and nutrition in patients born with cloacal exstrophy, many patients initially exhibited short bowel physiology, although most eventually adapted. However, very few patients have been able to achieve bowel control.

Abnormalities, Multiple↗
PubMed1996

Thoracoscopic management of empyema in children.

The appropriate management of empyema in children is controversial. Traditional surgical approaches have included thoracotomy and open drainage, decortication, and thoracoplasty. While generally effective, these procedures can be associated with considerable morbidity. We have sought to assess the utility of video-assisted thoracoscopic adhesiolysis and pleural debridement for the treatment of empyema in children. Nine children with postpneumonic empyema unsuccessfully managed with a single attempt at closed tube thoracostomy underwent thoracoscopic drainage during the past 2 years. The empyema was successfully treated with this technique in seven patients with no further interventions being required. Procedures performed early in the fibrinopurulent stage were technically easier. The average time before chest tube removal was 8.5 days. An immunocompromised patient required a subsequent open decortication and a patient with a coagulopathy required two subsequent open procedures for drainage of a recurrent hemothorax. We conclude from this experience that video-assisted thoracoscopic adhesiolysis and pleural debridement can be successfully performed in children. Benefits include good visualization of the entire thoracic cavity for more effective debridement and efficient drainage, and subjectively diminished postoperative pain and associated morbidity.

Adolescent↗
PubMed1996

Intestinal perforation due to an ingested foreign body: laparoscopic management.

The authors report the case of a previously healthy 10-year-old boy who accidentally ingested a toothpick. He presented to the hospital 7 days after the incident with left lower quadrant abdominal pain and fever; there was evidence of localized peritoneal irritation by exam. He had mild leukocytosis. An abdominal CT scan showed the toothpick in the sigmoid colon with extension through the bowel wall. Laparoscopic exploration was undertaken and an 8-cm toothpick was identified and removed from the perforation site in the sigmoid colon. Via a small suprapubic incision the sigmoid was delivered and repaired. The patient had an uneventful recovery and was discharged home 2 days after the procedure.Laparoscopic exploration can be diagnostic and therapeutic in the management of ingested foreign bodies with suspected intestinal perforation.

Child↗
PubMed1996

Laparoscopic oophorectomy in children.

Laparoscopy is a well-established diagnostic and therapeutic modality for adult gynecologic surgery. We have sought to assess the feasibility of the laparoscopic approach to a particular gynecologic procedure, oophorectomy, in the pediatric population. Five patients under-went laparoscopic oophorectomy during the past year. The indication for oophorectomy in three cases was ovarian torsion---one in association with a hemorrhagic cyst another with a benign teratoma, and one that occurred prenatally. The fourth patient had a teratoma with significant solid component and the final patient was a young with Turner's syndrome who had laparoscopic exploration and removal of bilateral streak ovaries. Oophorectomy was successfully completed laparoscopically in each patient. In two cases a trocar site had to be widened to remove the specimen from the abdominal cavity. Post operative recovery was prompt, with time to discharge being an average of 2 days. From this experience we conclude that laparoscopic oophorectomy can be successfully accomplished in infants and children. It is technically an easy procedure and has the benefits of excellent visualization of the entire lower abdomen and pelvis including the contralateral ovary, rapid postoperative recovery, and good cosmetic result.

Adolescent↗
PubMed1995

The role of surgery in the management of stage IV neuroblastoma: a single institution study.

The role of surgery in the management of Stage IV neuroblastoma is still far from clear. Seventy-nine patients with this diagnosis presented to the Children's Hospital of Philadelphia during the 10-year period, 1977 to 1986. Four-year survival was 23%. A major resection of the primary tumor was undertaken in 54 patients. The timing of the procedure (at presentation or delayed) had no effect on survival. The patients were divided into three groups based on the extent of surgical resection: Group 1, no surgery or biopsy only (25); Group 2, complete gross resection (34); Group 3, incomplete resection with residual gross disease (20). Four-year survival was 16, 15, and 45%, respectively. The patients were then classified as favorable or unfavorable, on the basis of biological prognostic factors at presentation. When this analysis was combined with the extent of surgery it was discovered that Group 3 contained a higher proportion of favorable patients, accounting for the better survival. Within each group survival correlated with the expected prognosis. The outcome for a patient with Stage IV neuroblastoma depends on the biological characteristics of the tumor, and there is currently no evidence that these can be favorably altered by the timing or extent of surgical resection. Defining the appropriate role of surgery in the management of these patients will require a prospective randomized study which takes into account the inherent biological variability of the disease.

Adolescent↗
PubMed1994

Malignant melanoma in children.

BACKGROUND: Cutaneous melanoma is an uncommon malignancy in children and for this reason, there is little information available regarding the timing and patterns of recurrence in children with this disease. This study reviews the experience at a single institution (Duke University Melanoma Clinic) in treating children with malignant melanoma. METHODS: Eighty-five patients < or = 18 years of age with malignant melanoma have been treated. All but three patients were over the age of 10; 73% of them were > 14. As for adults, treatment consisted of wide local excision of all primary lesions with primary closure or split-thickness skin graft, as needed. In addition, 22 patients underwent dissection of regional lymph nodes. Patients whose tumors had aggressive pathologic characteristics were treated with an adjuvant immunotherapy protocol. Patients with recurrence at distant sites were offered combination chemotherapy. RESULTS: Patients and pathologic characteristics of sex, race, primary site, histologic type, tumor thickness, and Clark level were similar to those observed in adults. Actuarial survival rates (79% versus 77% at 5 years) of the pediatric and adult Stage I melanoma patients were also not significantly different. Children had a greater incidence of recurrence after initial treatment, although recurrence tended to happen after a longer disease-free interval than for adults. Half of the 79 children who were first seen with Stage I disease have suffered a relapse, but more than one-third were disease free for > or = 5 years after initial treatment. Of the 18 patients who were disease free for > or = 7 years, 12 (67%) ultimately had recurrent disease, including five patients who had recurrences > 13 years after initial diagnosis. CONCLUSIONS: The early age at which malignant melanoma may occur and the significant potential for very late recurrence mandate that pediatricians and other primary care physicians consider the diagnosis of melanoma even in young patients with new skin lesions and that patients treated for melanoma be carefully followed for a lifetime.

Adolescent↗
PubMed1993

Spectrum of mutation and frequency of allelic deletion of the p53 gene in ovarian cancer.

BACKGROUND: The p53 gene encodes a nuclear phosphoprotein present in low levels in normal human cells. The wild-type form of this protein functions to restrain inappropriate cellular proliferation. Approximately one half of human epithelial ovarian cancers have mutations in the p53 gene and overexpress the mutant protein product. Deletion of one allele of the p53 gene also frequently occurs in these cancers. PURPOSE: We sought to define the spectrum of mutations in the p53 gene in epithelial ovarian cancer with respect to both the specific codons involved and the type of mutations observed. We also examined the frequency of allelic deletion of the p53 gene in cancers containing p53 gene mutations. METHODS: Tissue samples from the epithelial ovarian cancers of 62 patients were obtained during initial laparotomy. Histologic examination was done to ensure that the experimental samples used in this study contained more than 75% cancer cells. Total RNA was extracted from these samples and separately from matched control noncancerous regions of the surgical specimen or white blood cells. The purified RNAs were reverse transcribed to generate cDNA copies of exons 4-10 of the p53 gene. Two rounds of polymerase chain reaction (PCR) were conducted to produce enough template for DNA sequence analysis of the regions of interest within the p53 gene. Dideoxy sequencing of at least two independent productions of each amplified DNA template was done to confirm the validity of the mutations found. Allelic deletions were identified by PCR and gel electrophoretic techniques to examine three polymorphisms within the p53 gene in cancer-normal DNA pairs. RESULTS: We identified 45 mutations in exons 5-8 of the p53 gene, where mutations frequently have been found in other cancer types. An additional mutation was identified in exon 4. Overall, 72% of the mutations were transitions, 24% transversions, and 4% microdeletions. Allelic deletion of the other p53 allele was seen in 67% of ovarian cancers in which a p53 mutation was present. Germ-line p53 mutations were not found in any patients whose cancers had p53 mutations. CONCLUSIONS AND IMPLICATIONS: Like p53 mutations in other types of human cancers, those in epithelial ovarian cancers are diverse and occur frequently in exons 5-8. The predominance of transition mutations suggests that p53 mutations in ovarian cancer arise because of spontaneous errors in DNA synthesis and repair rather than the direct interaction of carcinogens with DNA. These molecular data are consistent with data from epidemiologic studies that have failed to demonstrate a convincing relationship between exposure to environmental carcinogens and the development of ovarian cancer.

Alleles↗