Primary clear cell adenocarcinoma of the rectovaginal septum treated with concurrent chemoradiation therapy: a case report.

Primary clear cell adenocarcinoma of the rectovaginal septum is rare and typically emerges in the setting of endometriosis. We report a case of a 52-year-old woman with clear cell adenocarcinoma of the rectovaginal septum presenting with vaginal hemorrhage. Management with concurrent chemoradiation with cisplatin and paclitaxel is discussed. Six years following the completion of treatment, the patient is without evidence of disease or significant long-term toxicity.

Phase II trial of carboplatin and infusional cyclosporine with alpha-interferon in recurrent ovarian cancer: a California Cancer Consortium Trial.

The purpose of this study was to estimate the response rate of 26-h continuous infusion cyclosporine A (CSA) combined with carboplatin (CBDCA) and subcutaneous alpha-interferon (IFN), in recurrent ovarian cancer (OC), and to measure their effects on CBDCA pharmacokinetics. OC patients relapsing following platinum-based chemotherapy received CBDCA area under the curve (AUC 3) with CSA and IFN, every 3 weeks. The pharmacokinetics of CSA and CBDCA were determined in a subset of patients. Thirty patients received 84 courses of therapy. Three partial responses were observed. Nine patients were stable for >4 months. Toxicity was similar to that observed in our previously reported phase I study and consisted of myelosuppression, nausea, vomiting, and headache. The mean end of infusion CSA level (high-performance liquid chromatographic assay [HPLC]) was 1109 +/- 291 microg/mL (mean +/- SD). CBDCA pharmacokinetics revealed a measured AUC of 3.61 versus a targeted AUC of 3, suggesting a possible effect of IFN on CBDCA levels versus errors in the estimation of CBDCA clearance using measured creatinine clearance. Steady-state levels of >1 microg/mL CSA (HPLC assay) are achievable in vivo. Insufficient clinical resistance reversal was observed in this study to warrant further investigation of this combination.

Tirapazamine plus cisplatin in advanced or recurrent carcinoma of the uterine cervix: a Southwest Oncology Group study.

The objective of this study was to determine objective response and overall survival (OS) and progression-free survival (PFS) following cisplatin plus tirapazamine treatment in eligible consenting patients with metastatic or recurrent squamous or adenosquamous carcinoma of the cervix. Treatment consisted of intravenous tirapazamine, 260 mg/m(2), followed by cisplatin, 75 mg/m(2), every 21 days for six cycles. Of 56 registered cases, 52 were evaluable for toxicity. There were six grade 4 toxicities (anemia [three], dyspnea [one], neutropenia/granulocytopenia [one], and dehydration [one]). Fifty-three patients were evaluable for response, OS, and PFS. The 6-month OS rate was 56.6% (95% CI 43.3-69.9%). The objective response rate was 32.1% (4 complete [2 confirmed and 2 unconfirmed] and 13 partial [8 confirmed and 5 unconfirmed]). Higher response rates (16/34 [47.1%] vs 1/19 [5.3%], P= 0.0018) were observed in patients who had not previously received radiation-sensitizing chemotherapy, as were OS and PFS (13.9 vs 4.0 months, P < 0.0001; 5.3 vs 1.8 months, P= 0.01). The OS was considered too low to warrant further testing in this disease setting. Despite this, tirapazamine plus cisplatin was active in patients who had not received cisplatin previously. Prior use of radiosensitizing chemotherapy impacted response and survival significantly and should be considered in future clinical trials.

Chemoradiation for primary invasive squamous carcinoma of the vagina.

OBJECTIVE: To report outcomes for patients with primary, invasive, squamous carcinoma of the vagina treated with chemoradiation. METHODS: Between 1986 and 1996, 14 patients were treated with primary therapy consisting of synchronous radiation and chemotherapy. Patients were judged not to be surgical candidates based on tumor size, location, and concerns related to urinary, bowel, or sexual function. Three patients were FIGO stage I, ten patients stage II, and one patient stage III. Radiation consisted of teletherapy alone (six patients) or in combination with intravaginal brachytherapy (eight patients). Total radiation dose ranged from 5700 to 7080 cGy (median 6300 cGy). Chemotherapy consisted of 5-fluorouracil alone (seven patients), or with cisplatin (six patients) or mitomycin-C (one patient). RESULTS: One patient failed locally at 7 months and died of disease at 11 months. Four patients died of intercurrent illness (46, 92, 104, 109 months) and nine are alive and cancer-free 74-168 months after treatment (median 100 months). There were no vesicovaginal or enterovaginal fistulae. CONCLUSIONS: Radiation with synchronous chemotherapy is an effective treatment for squamous carcinoma of the vagina. Cancer control outcomes compare favorably with previously published results employing higher dose radiation as monotherapy.

Endometriosis-related malignancies.

The purpose of this study is to describe the clinical findings, treatment, and outcome of patients with endometriosis-related cancers. Patients meeting Sampson and Scott's criteria for cancer associated with endometriosis in the Sacramento region were identified by chart review and pathology reports. Twenty-seven patients were identified with endometriosis-related malignancies (mean age 51.4 years). The site of origin was ovary in 17 (63.0%) and extra-ovarian in 10 (37%) including vagina, fallopian tube or mesosalpinx, pelvic sidewall, colon, and parametrium. The pattern of spread was local in five (18.5%), regional in 20 (74.1%) and distant in two (7.4%). Six patients had taken unopposed estrogen replacement (mean duration 23.4 years) and all six had extragonadal disease. Surgical procedures included hysterectomy, salpingo-oophorectomy, radical local excision, partial colectomy, and surgical staging. Eighteen patients received postoperative chemotherapy since the majority of patients had ovarian involvement. Fifteen patients received regional radiation therapy. Nineteen patients are without evidence of recurrence (70.4%, mean follow-up of 31 months). Endometriosis-related malignancies have a favorable prognosis. Extragonadal disease was commonly associated with unopposed estrogen replacement therapy. The predominance of local and regional disease strongly influence the application of treatment modalities.

Prospective evaluation of cancer clinical trial accrual patterns: identifying potential barriers to enrollment.

PURPOSE: Well-conducted cancer clinical trials are essential for improving patient outcomes. Unfortunately, only 3% of new cancer patients participate in clinical trials. Barriers to patient accrual in cancer clinical trials must be identified and overcome to increase patient participation. MATERIALS AND METHODS: We prospectively tracked factors that potentially affected patient accrual into cancer clinical trials at the University of California Davis Cancer Center. Oncologists seeing new outpatients were asked to complete questionnaires regarding patient characteristics and the physician's decision-making on patient eligibility, protocol availability, and patient opinions on participation. Statistical analysis was performed to correlate these parameters with subsequent protocol accrual. RESULTS: There were 276 assessable patients. At the initial visits, physicians did not consider clinical trials in 38% (105/276) of patients principally because of a perception of protocol unavailability and poor performance status. Physicians considered 62% (171/276) of patients for participation in clinical trials. Of these, only 53% (91/171) had an appropriate protocol available for site and stage of disease. Seventy-six of 90 patients (84%) with available protocols met eligibility criteria for a particular study. Only 39 of 76 patients (51%) agreed to participate in cancer clinical trials, for an overall accrual rate of 14% (39/276). The remainder (37/76, 49%) declined trial participation despite meeting eligibility criteria. The most common reasons were a desire for other treatment (34%), distance from the cancer center (13%), patient refusal to disclose reason (11%), and insurance denial (8%). Patients with private insurance were less likely to enroll in clinical trials compared to those with government-funded insurance (OR, 0.34; P =.03; 95% CI, 0.13 to 0.9). CONCLUSION: Barriers to cancer clinical trial accrual can be prospectively identified and addressed in the development and conduct of future studies, which may potentially lead to more robust clinical trials enrollment. Investigation of patient perceptions regarding the clinical trials process and the role of third party-payers is warranted.

Immunohistochemical markers of cell cycle control applied to ovarian and primary peritoneal surface epithelial neoplasms: p21(WAF1/CIP1) predicts survival and good response to platinin-based chemotherapy.

Immunohistochemistry for p53, p21(WAF1/CIP1), and Ki-67 provides insight into the molecular events controlling the cell cycle. We tested the hypothesis that these cell cycle markers will aid in the clinical evaluation of ovarian and primary peritoneal surface epithelial neoplasms (SENs). Paraffin sections from a retrospective surgical series of 117 SENs were immunostained with anti-p53 (clone DO7, Novacastra Laboratories, UK), anti-p21(WAF1/CIP1) (clone EA10, Oncogene Science, Cambridge, MA), and anti-Ki-67 (clone MIB-1, Immunotech, Westbrook, ME). The Ki-67 proliferation index (Ki-67PI) and immunoreactivity were evaluated. One hundred seventeen SENs reacted as follows: p53 50%+ and p21(WAF1/CIP1) 65%+. Ki-67PI ranged from 4% to 88% (mean/median = 44/46%). p53 reactivity associated with transitional cell histology, decreased p21(WAF1/CIP1) staining, increased Ki-67PI, architectural/nuclear grade, and stage (P < .05, 1 x 10(-7), .01, .05/.0001, .001,). p21(WAF1/CIP1) staining was associated with endometrioid/clear cell histology, decreased Ki-67PI, architectural/nuclear grade, and stage (P < 05/.05, .05, .01/1 x 10(-8), 1 x 10(-5)). Ki-67PI associated with increased architectural/nuclear grade but not mucinous histology (P < 1 x 10(-5)/1 x 10(-6), .01). Sixty-seven patients had disease at last follow-up; 53 were dead of disease at 0 to 67 months (mean/median, 21/18), and 14 were alive with disease at 12 to 224 months (mean/median, 56/40). Fifty patients were disease free at 5 to 214 months (mean/median, 59/41). Predictors of survival include decreased Ki-67PI, stage, architectural/nuclear grade (P < 1 x 10(-6), 1 x 10(-10), 1 x 10(-10)/.005) and p21(WAF1/CIP1) IMS (multivariate P < 1 x 10(-6)). p21(WAF1/CIP1), a potent inhibitor of cyclin-dependent kinases necessary for cell cycle progression, functions as a key checkpoint in cell cycle control. Immunoreactivity for p21(WAF1/CIP1) provides prognostic information independent of other histological and clinical predictors, p53 IMS, and Ki-67PI in this series of 117 PTs with SENs. Our preliminary data suggest an interrelationship between p21(WAF1/CIP1) expression and an effective clinical response to platinin-based chemotherapy, both associated with apoptosis. Further investigation seems warranted.

Clinicopathologic significance of transitional cell carcinoma pattern in nonlocalized ovarian epithelial tumors (stages 2-4).

The transitional cell carcinoma (TCC) pattern has been associated with favorable outcome in patients with late-stage ovarian epithelial tumors who receive chemotherapy. We examined the clinicopathologic significance of TCC and explored other histopathologic prognostic indicators for patients with ovarian epithelial tumor. The surgical records of patients at the University of California at Davis Medical Center who underwent treatment for stages 2 to 4 ovarian epithelial tumor were studied retrospectively; the histopathologic features were correlated with outcome. The TCC pattern was identified in 32 of 136 ovarian epithelial tumors (23.5%): 18 (13.2%) as a predominant (> 50%) and 14 (10.3%) as a focal (< or = 50% but > 25%) histologic pattern. The other predominant histopathologic types were serous (65.4%), mucinous (11.7%), endometrioid (3.6%), clear cell (3.6%), and small cell (1.5%) carcinoma. Architectural grade was as follows: low malignant potential, 13 cases; grade I, 34 cases; grade II, 63 cases; grade III, 26 cases. Nuclear grade was as follows: low grade, 27 cases; high grade, 109 cases. One hundred seven patients had dominant ovarian tumors, and 29 had diffuse primary peritoneal epithelial tumor. One hundred twenty-three cases (90%) of peritoneal disease were invasive; 11 (10%) were noninvasive. Peritoneal disease histopathologic density was 50% or less cross-sectional involvement in 68 patients (50%) and greater than 50% in 68 (50%). Follow-up data were available for 118 patients: 46 patients had persistent disease that was unresponsive to chemotherapy; 36 of these patients died of disease at 0 to 41 months (mean, 15.6 months; median, 23.5 months). Ten patients were alive at 16 to 40 months (mean, 24.5 months; median, 20.5 months). Thirty-six patients had recurrent disease after 6 to 66 months (mean, 23.5 months; median, 18.5 months); 20 of these patients died of disease after 10 to 69 months (mean, 33.7 months; median, 30 months), and 16 were alive after 12 to 159 months (mean, 33.7 months; median, 30 months). Thirty-six patients had no evidence of disease at 12 to 159 months of follow-up (mean, 49.5 months; median, 31 months). The TCC pattern, either predominant or focal, was not associated with disease status or survival time (P > .05). Predictors of recurrent or persistent disease and survival, respectively, were invasive peritoneal disease (P < .05, P < .0001) and greater than 50% cross-sectional area histologic density of peritoneal disease (P < .01, P < .01). Grade, histologic type, and diffuse primary peritoneal vs ovarian location were not predictors of outcome. The TCC pattern was present in at least a focal (> 25%) component in 23% of epithelial tumors; however, this finding did not reach significance as a predictor of outcome in this study. The histologic pattern of the peritoneal disease (invasiveness and density) was a much stronger predictor of disease response and survival.

13-cis-retinoic acid or all-trans-retinoic acid plus interferon-alpha in recurrent cervical cancer: a Southwest Oncology Group phase II randomized trial.

PURPOSE: Preclinical and clinical data support the study of retinoids and interferon-alpha (IFN-alpha) in advanced squamous cell carcinoma of the uterine cervix (SCC). This phase II randomized trial of the Southwest Oncology Group sought to estimate the response rate for IFN-alpha plus either 13-cis-retinoic acid (13cRA) or all-trans-retinoic acid (ATRA) in women with recurrent cervical SCC. PATIENTS AND METHODS: Eligibility for this trial required bidimensionally measurable locally recurrent or metastatic squamous or adenosquamous carcinoma of the uterine cervix; SWOG performance status of

Prophylactic chemoradiation of inguinofemoral lymph nodes in patients with locally extensive vulvar cancer.

OBJECTIVE: Primary surgical resection of locally advanced squamous cancer of the vulva may compromise the integrity of important midline structures such as the anus, clitoris, urethra, and vagina. Chemoradiation (synchronous radiation and cytotoxic chemotherapy) has been used as alternative initial treatment which may serve as definitive management for some patients, or may reduce the scope and functional sequelae of subsequent surgery in others. Inguinofemoral node dissection is associated with substantial risk of both acute and late morbidity, prompting consideration of elective inclusion of groin nodes within the irradiated volume and deletion of subsequent groin surgery. Concern that disease relapse in the groins is potentially fatal suggested the prudence of formal outcome assessment of our recent experience with prophylactic treatment of clinically uninvolved groin nodes in the context of concurrent chemoradiation for locally advanced primary vulvar cancer. METHODS: A review was conducted of 23 previously untreated patients with locally advanced squamous cancer of the vulva (2 T2, 20 T3, 1 T4) and clinically uninvolved groin nodes (1969 FIGO stages 14 N0, 4 N1, and 5 N2 with negative node biopsies) who were treated since 1987 with chemoradiation administered to a volume electively including bilateral inguinofemoral nodes. These patients did not undergo subsequent groin surgery. RESULTS: With follow-up from 6 to 98 months (mean, 45.3 months; median, 42 months), no patient has failed in the prophylactically irradiated inguinofemoral nodes. No patient has developed lymphedema, vascular insufficiency, or neurological injury in a lower extremity, and no patient has experienced aseptic necrosis of a femur. CONCLUSIONS: Elective irradiation of the groin nodes in the context of initial chemoradiation for locally advanced vulvar cancer is an effective therapy associated with acceptable acute toxicity and minimal late sequelae. It constitutes a sensible alternative to groin dissection in this patient population.

Urinary gonadotropin peptide (UGP) as a marker of gynecologic malignancies.

Urinary gonadotropin peptide (UGP) was measured in 866 urines from normal women and women with benign and malignant gynecologic disease using the Triton UGP enzyme immunoassay. The greatest level of overexpression of the marker was observed in patients with ovarian cancer. Using a cutoff of 4 fmol/mg creatinine, UGP was overexpressed in samples from 2% of normal premenopausal women, 15% of normal postmenopausal women, 5% of women with benign gynecologic disease, and 59% of women with ovarian cancer. UGP expression was independent of the histologic type of ovarian cancer. The expression of UGP and CA 125 were not correlated and use of the two markers in tandem increased the sensitivity of detection of disease by greater than 20% over that which was observed using each marker individually. UGP levels were correlated with clinical status, and doubled in value in 67% of patients with progressive disease, and were halved in 93% of patients who were in remission at the time of the study.

Synchronous radiation and cytotoxic chemotherapy for locally advanced or recurrent squamous cancer of the vulva.

Between July 1987 and September 1991 a program of external beam radiation and synchronous, radiopotentiating chemotherapy was employed to treat 25 women with locoregionally advanced or locoregionally recurrent squamous cancer of the vulva. Of 18 previously untreated patients, 1 was Stage II, 10 were Stage III, 6 were Stage IVA, and 1 was Stage IVB. Reasons for patient referral for nonsurgical management included the presence of initially unresectable disease (5 patients), disease extent which would have necessitated partial or total exenteration if treated surgically (9 patients), disease extent predictive of inadequate surgical margins (less than 1 cm gross margin) if treated by less than exenterative surgery (8 patients), and severe comorbid illness precluding surgical management (3 patients). Complete clinical response was obtained in 16 of 18 previously untreated patients (89%) and in 4 of 7 patients with recurrent disease following vulvar surgery (57%). Of 20 patients achieving a complete clinical response, 3 patients have relapsed within the irradiated volume at 11, 38, and 48 months following completion of treatment. Fourteen patients remain alive and continuously cancer free from 2-52 months after completion of treatment (median follow-up 24 months). This experience suggests that initial management with radiation and chemotherapy may offer some patients with locally advanced squamous cancer of the vulva an alternative to exenterative surgery and may hold curative potential for some patients with surgically unresectable or medically inoperable disease.

The integration of computed tomography and magnetic resonance imaging in treatment planning for gynecologic cancer.

Both CT and MRI may play an important role in the initial assessment and subsequent management of patients with gynecologic cancer. The different capabilities of these examinations make the choice of test dependent on what portion of the body is visualized (e.g., chest, upper abdomen, or pelvis) and what information is sought. Body imaging can be scheduled appropriately when the findings from the study will have a significant impact on patient management (e.g., operative versus nonoperative management, selection of treating physician, and initial modality of treatment). However, the limitations of each modality must be appreciated. In general, a negative CT or MRI will not exclude the possibility of small volume disease involvement, and a critical positive study should, when practical, be histologically confirmed. Neither test stands alone, but each plays a role when integrated with careful clinical history, physical examination, and other laboratory and radiologic examinations.

A phase I study including pharmacokinetics of polyethylene glycol conjugated interleukin-2.

A more soluble formulation of recombinant interleukin-2 with a prolonged half-life would allow alternate routes or schedules of administration and enhance patient comfort. The covalent attachment of polyethylene glycol to recombinant interleukin-2 provides an analog with preclinical data suggesting those desired characteristics while maintaining biologic activity. This is the report of a phase I study in which we sought to determine the maximum tolerated dose of polyethylene glycol interleukin-2, observe biologic activity, and confirm the prolonged half-life in vivo. Sixty-six patients were entered into the study during 19 months. Polyethylene glycol interleukin-2 was administered intravenously once a week over 15 minutes. The maximum tolerated dose was 20 x 10(6) U/M2. The pattern of toxicity was quite similar to that of the parent compound. Four patients had evidence of tumor regression (three partial remission; one minor response). The pharmacokinetic data confirmed a 10- to 20-fold prolongation in half-life compared with recombinant interleukin-2. No neutralizing antibodies were detected. This study provides sufficient impetus for the ongoing phase II studies of polyethylene glycol interleukin-2.

Weekly 24-hour continuous infusion interleukin-2 for metastatic melanoma and renal cell carcinoma: a phase I study.

Twenty-nine patients with biopsy-confirmed metastatic melanoma (17) or metastatic renal cell carcinoma (12) were treated with escalating doses or recombinant human interleukin-2 (IL-2) administered as weekly 24-h intravenous infusions. Patients received from 3 to 12 x 10(6) C.U./m2 (18-72 x 10(6) I.U./m2) weekly over a treatment period of 1 to 16 weeks, with a median of eight weekly cycles administered. Patients in all treatment groups experienced non-life-threatening systemic side effects consisting of fever, nausea, vomiting, fluid retention, and diarrhea. Grade III hypotension was seen in four of six patients (67%) at 12 x 10(6) C.U./m2, and represented the dose-limiting toxicity. Grade IV hypotension occurred in 1 of 14 patients at 6 x 10(6) C.U./m2; no other grade IV toxicities were observed. Grade III fever occurred in 3 of 11 patients (27%) treated at 3 x 10(6) C.U./m2, 3 of 14 patients (21%) at 6 x 10(6) C.U./m2, and 3 of 6 patients (50%) at 9 x 10(6) C.U./m2. An objective response was observed in 3 of 28 evaluable patients (10%): 1 complete response and 1 partial response in renal cell cancer, and 1 partial response in a melanoma patient. We conclude that for future studies, the recommended dose of IL-2 given as a weekly 24-h infusion is 9 x 10(6) C.U./m2 and that a low rate of objective tumor response can be obtained in patients with melanoma and renal cell carcinoma using this regimen.

DNA cross-linking and cytotoxicity of the alkylating cyanomorpholino derivative of doxorubicin in multidrug-resistant cells.

The cyanomorpholino derivative of doxorubicin (MRA-CN) is an anthracycline that is extremely potent and non-cross-resistant with doxorubicin (DOX) in multidrug-resistant cells. MRA-CN binds to and cross-links DNA and thus has been proposed to act as a targeted alkylating agent. In our study, the number of DNA interstrand and DNA-protein cross-links produced by MRA-CN was identical in multidrug-resistant Dx5 and parental MES-SA cells, as shown by alkaline elution analysis. The amount of cross-linking was directly proportional to drug concentration at concentrations from 10(-11) to 10(-7) M MRA-CN. Extensive DNA cross-linking was evident within 30 minutes of drug exposure. After 1 hour of drug exposure, the number of DNA cross-links increased for 90 minutes, reached a plateau, and then began to decrease after 120 minutes. Loss of cell viability was also observed as early as 3 hours after exposure to MRA-CN. The finding of the same number of DNA cross-links in MES-SA and Dx5 cells indicates that similar amounts of MRA-CN are likely to enter the nuclei of multidrug-resistant and sensitive cells. Other anthracyclines have major differences in nuclear distribution in sensitive and resistant cells. Several factors may contribute to the non-cross-resistance of MRA-CN in multidrug-resistant cells. (a) The lipophilicity of MRA-CN facilitates cell entry. (b) The substitution and loss of basicity at the amino nitrogen may reduce the affinity of the drug for the P-glycoprotein efflux pump, compared with that of DOX. (c) The detoxification function of P-glycoprotein may be less effective for drugs that produce rapid and irreversible cell damage, such as the DNA-targeted alkylation caused by MRA-CN.

High-dose megestrol acetate therapy of ovarian carcinoma: a phase II study by the Northern California Oncology Group.

The activity of high-dose megestrol acetate was studied in 47 patients with epithelial ovarian cancers after failure of initial chemotherapy. The dose of megestrol acetate was 800 mg/d orally (PO) for 4 weeks and then 400 mg/d until tumor progression. Patients generally had far-advanced disease. Prior therapy included cisplatin, doxorubicin, and cyclophosphamide (PAC) or other cisplatin-containing regimens in 37, other combinations in eight, and single agents in only two patients. Seventeen patients (36%) developed intestinal obstructions within the first 2 months on study. Tumor histology was serous in 37, endometrioid in six, and clear-cell in two. Two thirds of the tumors were histologic grade 3, and the others were grade 2. Complete remission was obtained in one patient, with time to progression of 4 months. There were three partial remissions, with times to progression of 4, 5, and 18 months. The overall response rate (complete and partial) was 8%. Three additional patients had minor remissions (3, 5, and 8 months), and five had stable disease, for 3, 4, 5, 6, and 9 months. There was no correlation of response with grade, histologic type, or site of disease, but responding patients had a longer survival from diagnosis to protocol entry and from protocol failure to death than did nonresponding patients. The major side effect of megestrol acetate was increased appetite, which caused one patient to withdraw from the study, and resulted in a 10- to 20-kg weight gain in five patients. Plasma levels of megestrol acetate averaged 600 ng/mL in the first month of therapy and decreased to approximately 400 ng/mL at 8 and 12 weeks, after the drug dosage had been reduced. Serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels were markedly lower during megestrol therapy compared with pretreatment values. Megestrol acetate at 1 microgram/mL in vitro inhibited soft agar colony formation from one of 17 specimens of ovarian carcinomas. We conclude that megestrol acetate in high doses has modest, but definite, palliative effects in some patients with advanced ovarian carcinoma in whom chemotherapy has failed. A controlled trial of megestrol plus combination chemotherapy as first-line treatment of advanced ovarian carcinoma should be considered.

The biochemistry of vitamin B6 is basic to the cause of the Chinese restaurant syndrome.

The concept of this basic research was that monosodium L-glutamate could reveal a deficiency of vitamin B6 by the neurological reactions known as the Chinese Restaurant Syndrome. An other amino acid, tryptophan, administered to subjects, is known to reveal a deficiency of vitamin B6 by the excretory xanthurenic acid, etc. The presence and degree of a deficiency of vitamin B6 in 155 students on no supplemental B6 was determined by the differential assay of aspartate transaminase of erythrocytes which also allows each subject to be a control. Twenty-seven of 155 students had extraordinarily low basal specific activities of the transaminase, less than 0.26 mumol pyruvate/(h X 10(8) erythrocytes). These 27 were challenged with glutamate and a placebo. Twelve of 27 revealed the Chinese Restaurant Syndrome, and 15 did not. By double blind trials, the 12 "responders" were treated with pyridoxine and a placebo for twelve weeks, and then were rechallenged with glutamate and a placebo. Decoding showed 3 of 12 received placebo to pyridoxine and then revealed the symptoms of the syndrome again to glutamate; 9 of 12 received pyridoxine and then 8 of 9 failed to respond to glutamate. These results show, p less than 0.01, that the symptoms of the Chinese Restaurant Syndrome to oral glutamate fail to reoccur after treatment which pyridoxine, and that the biochemistry of vitamin B6 is basic to the cause of the Chinese Restaurant Syndrome.