Cutaneous toxicities in patients with melanoma receiving checkpoint inhibitor therapy: a retrospective review. The experience of a single large specialist institution.

Checkpoint inhibitor (CPI) therapy has significantly improved overall survival for metastatic melanoma, and is now approved for use in the adjuvant setting. Modulating the immune system is recognized to cause cutaneous immune-related adverse events (irAEs). We conducted a retrospective observational cohort study of adult patients with melanoma at our tertiary referral centre, who received CPI therapy from 2006 to March 2018. This is the single largest study of cutaneous irAEs occurring on CPI therapy in patients with melanoma to date and encompasses 12 years. The results showed that cutaneous toxicity occurs in 24% of patients but is generally manageable, with < 5% patients discontinuing treatment.

Detection of chromosomal aberrations by fluorescence in situ hybridization in cervicovaginal biopsies from women exposed to diethylstilbestrol in utero.

Epidemiologic studies have associated estrogens with human neoplasms such as those in the endometrium, cervix, vagina, breast, and liver. Perinatal exposure to natural (17beta-estradiol [17beta-E(2)]) and synthetic (diethylstilbestrol [DES]) estrogens induces neoplastic changes in humans and rodents. Previous studies demonstrated that neonatal 17beta-E(2) treatment of mice results in increased nuclear DNA content of cervicovaginal epithelium that precedes histologically evident neoplasia. In order to determine whether this effect was associated with chromosomal changes in humans, the frequencies of trisomy of chromosomes 1, 7, 11, and 17 were evaluated by the fluorescence in situ hybridization (FISH) technique in cervicovaginal tissue from 19 DES-exposed and 19 control women. The trisomic frequencies were significantly elevated in 4 of the 19 (21%) DES-exposed patients. One patient presented with trisomy of chromosomes 1, 7, and 11, while trisomy of chromosome 7 was observed in one patient. There were two patients with trisomy of chromosome 1. Trisomy of chromosomes 1, 7, 11, and 17 was not observed in the cervicovaginal tissue taken from control patients. These data suggest that DES-induced chromosomal trisomy may be an early event in the development of cervicovaginal neoplasia in humans.

Immature ovarian teratoma in an adolescent: a case report and review of the literature.

BACKGROUND: Benign cystic teratomas are relatively common tumors in reproductive age women, but can occur at any age. While the incidence of malignant elements in a teratoma is low (approximately 1-2%), the survival of patients with immature teratoma is poor. Definitive diagnosis is mandatory. CASE: We describe a case of a 13-year-old African American female, gravida 0, presenting with a large pelvic mass, determined to be a benign cystic teratoma by intra-operative frozen section. However, due to the size of the tumor and the preponderance of neural elements we performed a full surgical staging procedure (excluding hysterectomy and complete removal of adnexa). The final pathology report revealed foci of immature neural tissue, with a final diagnosis of an immature cystic teratoma Stage Ia. CONCLUSION: Foci of immature neural elements can be readily missed on frozen section, especially with a large tumor. Full surgical staging at the time of initial laparotomy is justified when encountering an apparently mature cystic teratoma with a preponderance of neural elements on frozen section.

Didelphic uterus and obstructed hemivagina with renal agenesis: case report and review of the literature.

Congenital disorders of development are more common than previously reported and the correct diagnosis is frequently missed leading to suboptimal treatment. Eight cases of uterus didelphys with obstructed hemivagina referred to the Gynecology service at Baylor College of Medicine over a 2-year period were reviewed. Initial presenting symptoms and signs were followed by an incorrect diagnosis by the referring physician 100% of the time. MRI, the most sensitive imaging modality for congenital anomalies (Kublik, RA: Female pelvis. Eur Radiol 1999; 9:1715), was utilized in only 50% of the cases. In this group of patients, hematocolpos and pyocolpos were discovered in equal numbers upon exploration. Ipsilateral renal anomalies were present 100% of the time, while coexisting contralateral anomalies were present 50% of the time. Resection of the vaginal septum was required for abatement of symptoms in all cases presented here. Laparoscopy provided additional information beyond radiologic tests regarding pelvic and urological anatomy. In two cases, resection of the ipsilateral uterine horn was required. These cases demonstrate the difficulty in diagnosis, heterogeneity in presentation, and need for expertise not only in this rare congenital anomaly but also all the other disorders of development of the female genital tract.

Vaginoscopic resection for rhabdomyosarcoma of the vagina: a case report and review of the literature.

Rhabdomyosarcoma is the most common soft-tissue sarcoma found in children. Genitourinary sites comprise 20% of the primary location of these tumors. A polypoid form of the embryonal type of rhabdomyosarcoma, sarcoma botyroides, is often found in girls under age 5. These tumors are usually localized to the anterior vaginal wall. Their superficial location and clinical symptoms lead to early diagnosis, and these tumors are therefore considered to be the easiest to treat and most likely to be cured. In the past 30 years we have seen a shift in treatment from radical surgery to conservative surgery with chemotherapy and radiation, with improved survival and preservation of normal anatomy and improved postoperative body imagery. Conservative excision in the past has been performed by sharp curettage of the anterior vaginal wall. We present a case of a 2-yr-old child with a RMS of the vagina for which we utilized vaginoscopy not only to determine the extent of the tumor but also for precise resection using a bipolar electrode with normal saline as the distension medium.

Prospective study of neuropsychologic testing and quality-of-life assessment of adults with primary malignant brain tumors.

PURPOSE: To identify the characteristics of adult patients with newly diagnosed primary brain tumors associated with identifiable deficits in neuropsychologic function to target interventions to improve function and quality of life (QOL). MATERIALS AND METHODS: Adult patients with newly diagnosed primary brain tumors and their caregivers were enrolled and underwent a battery of standardized neuropsychologic tests, allowing for qualitative and quantitative assessment and sensitive to the effects of the brain tumor, QOL, or caregiver stress. RESULTS: We enrolled 68 patients with no prior radiotherapy. Patients with left hemisphere tumors reported significantly more memory problems and depressive symptoms. They also exhibited poorer attention and were more distractible, with poorer verbal fluency and poorer verbal learning. Patients with glioblastoma multiforme demonstrated poorer psychomotor speed and visual tracking than patients with non-glioblastoma multiforme histologic features. Patients and caregivers perceived QOL in a similar fashion, with significant correlation between patient and caregiver on hope testing and general QOL on the Linear Analog Self-Assessment Scale. CONCLUSIONS: Patients with left hemisphere tumors and glioblastoma multiforme histologic features demonstrated testable differences in neuropsychologic function and QOL that may be amenable to improvement with medical therapy or tailored rehabilitation programs. Caregiver assessments can predict patient QOL, which may be useful in patients with declining status.

Depressed mood is a factor in glycemic control in type 1 diabetes.

OBJECTIVE: The diabetes literature contains conflicting evidence on the relationship between depression and glycemic control. This may be due, in part, to the fact that past studies failed to distinguish between patients with type 1 and type 2 diabetes. Because these are actually completely different diseases that are often treated differently and consequently make different demands on patients, the relationship between glycemic control and depressed mood in type 1 and type 2 diabetes was examined separately. METHODS: The relationship between Beck Depression Inventory (BDI) scores and HbA1c, as an index of long-term glycemic control, was measured in samples of 30 patients with type 1 and 34 patients with type 2 diabetes. RESULTS: Groups of patients with type 1 and type 2 diabetes did not differ in mean BDI score or HbA1c level. Correlation analysis revealed a significant positive relationship between BDI scores and HbA1c in the type 1 group (r = .44, p < .02) but not in the type 2 group (r = -0.06, p > .05). This relationship was evident throughout the entire range of BDI scores and was not restricted to scores indicative of clinical depression. Patients with type 1 diabetes who had higher HbA1c and BDI scores reported a lower frequency of home blood glucose monitoring. CONCLUSIONS: Variations in depressive mood, below the level of clinical depression, are associated with meaningful differences in glycemic control in type 1 but not type 2 diabetes. Preliminary data analysis suggests that this effect may be mediated, at least in part, by decreased self-care behaviors in patients with more depressed mood.

Extensive subcutaneous metastases from squamous cell carcinoma of the cervix in patient with HIV.

Advanced human immunodeficiency viral disease is associated with a high prevalence of cervical squamous intraepithelial and invasive lesions and probably with a rapidly progressive course of disease. Metastases to the skin occur rarely in cervical cancer, even in terminal stage of the disease. A patient with human immunodeficiency virus (HIV) for 14 years was diagnosed with squamous cell cancer of the cervix, Stage I-B2 in June 1997. She underwent successful radiotherapy. She then presented in January 1999 with recurrence evidenced by extensive subcutaneous nodules and multiple metastases. The patient developed rapidly progressive disease and died within two months. Patients with HIV and cervical cancer may present with a more aggressive course of disease. Aggressive treatment and closer follow-up may be indicated.

Advanced primary carcinoma of the Bartholin gland: report of 18 patients.

Conservative surgery plus radiotherapy for vulvar cancer has been established as a therapeutic alternative to extensive radical surgery and produces a similar cumulative 5-year survival. We retrospectively analyzed the cases of 18 patients with advanced primary carcinoma of the Bartholin gland treated with wide local excision (WLE) or radical vulvectomy and lymphadenectomy followed by radiotherapy (RT) at the University of Texas M. D. Anderson Cancer Center from January 1978 through December 1990. All patients have been observed for a minimum of 7 months (maximum follow-up, 15 years; median follow-up, 9 years). Of the 18 patients, 7 were treated with wide local excision (WLE) followed by radiation therapy (RT) (Group 1), 9 had radical vulvectomy (RV) followed by RT to the vulvar and inguinal-femoral and pelvic node areas (Group II), and 2 were treated with RT alone after biopsy of the tumor (Group III). The 5-year disease-free survival rates were 86%, 78%, and 50% for groups I, II, and III, respectively, and 83% for the whole group. Of 2 patients treated with RT alone, one lived for 6 years with no evidence of disease, and the other lived for 20 months. The rate of local tumor control was 100% for all three treatment groups. There were no significant differences among the treatment groups in rate of primary tumor control or 5-year disease-free survival rate (p=0.1300). The present study demonstrated WLE followed by RT is the best treatment for advanced primary carcinoma of the Bartholin gland. Less radical surgery plus RT produces good long-term survival and has fewer complications.

The long term results of radiotherapy with or without surgery in management of advanced vulvar cancer: report of 76 patients.

BACKGROUND: The combination of conservative surgery plus radiotherapy for vulvar cancer has been well established as a therapeutic alternative to extensive radical surgery. This study was undertaken to evaluate the long-term results of radiotherapy with or without surgery in the management of advanced vulvar cancer. PATIENTS AND METHODS: The cases of 76 patients who had advanced carcinoma of the vulva treated with different modalities at the University of Texas M.D. Anderson Cancer Center were retrospectively reviewed. Three patients had unstaged disease as a result of previous surgery, 19 had stage II, 40 had stage III, and 14 had stage IV disease. Follow-up ranged from 4 to 17 years (median, 11 years). RESULTS: Five-year disease-free survivals were 75, 67, 68 and 52% for treatment groups I, II, III, and IV, respectively. Disease was controlled locally in 83, 80, 73 and 56% of patients in groups I through IV, respectively; the overall rate of local control was 79%. There was no significant difference in primary tumor control, 5-year disease-free survival, or overall survival among the different treatment groups (p=0.1300). However, these rates did differ significantly (p<0.006) based on FIGO stage of disease. CONCLUSION: In this report, the cure of vulvar cancers with radiotherapy alone (5-year disease-free survival 52% and local control 56%), the radiotherapeutic salvage of patients with surgical failure and/or large tumors, the improved survival with low morbidity by pre- and postoperative radiotherapy were provocative observations suggesting the value of this therapy for advanced vulvar cancer.

Long-term efficacy of simple behavioral therapy for daytime wetting in children.

PURPOSE: Behavioral therapy has proved benefit for children with daytime wetting but most studies have used biofeedback techniques and provide no long-term assessment of results. We previously reported similar results using simple behavioral therapy without biofeedback. We report the long-term efficacy of behavioral therapy for daytime wetting. MATERIALS AND METHODS: Our program of behavioral therapy included timed voiding, modification of fluid intake, positive reinforcement techniques and pelvic floor (Kegel) exercises to promote pelvic floor strengthening and relaxation. Questionnaires to assess therapeutic efficacy were mailed to patients who had completed therapy more than 1 year previously. RESULTS: A total of 48 patients responded. Mean ages at the time of the initial clinic visit and questionnaire were 8.2 and 12.9 years, respectively. Improvement in symptoms was noted in approximately 74% of the cases during the first year following therapy. At a mean of 4. 7 years after treatment 59.4% of the patients had improved daytime urinary control, 51.1% improved daytime urinary frequency and 45.6% improved daytime urinary urgency. The frequency of urinary tract infections decreased in 56.4% of the cases. Measures of psychological well-being were also noted to be improved in a majority of patients. A total of 77.3% of the patients stated that they would recommend the program to others. CONCLUSIONS: Simple behavioral therapy without biofeedback techniques is an effective and durable first line therapy for children with daytime wetting.

Transient effects of long-term leptin supplementation in the prevention of diet-induced obesity in mice.

Low plasma leptin levels have been shown to be associated with the development of obesity in mice as well as in humans. The present study was undertaken to determine if raising plasma leptin levels of obesity-prone C57BL/6J (B6) mice to those seen in obesity-resistant A/J mice would prevent the development of diet-induced obesity. Four-week-old B6 (n = 40) and A/J (n = 10) male mice were weaned onto a low-fat (11% kcal) diet. When the animals weighed 20 g, their diets were changed to a high-fat (HF) diet (58% kcal), and a continuous infusion of leptin (0.4 mg x kg(-1) x day(-1)) or phosphate-buffered saline (control) was started using Alzet minipumps. The A/J mice were not treated but were included to monitor the efficacy of the minipumps in raising plasma leptin in B6 mice. The mice were followed for 12 weeks. Chronic treatment with leptin for 4 weeks raised plasma levels in B6 mice to that of A/J mice. Plasma leptin in B6 control mice remained significantly lower than A/J mice through week 4. By week 8, leptin levels in the B6 control group had risen and were similar to A/J mice. Although there were significant weight differences between B6 treated and B6 control groups for 2-3 weeks after pump implantation, these differences were transient. Ultimately, there were no weight differences between the B6 treated and B6 control groups. There were no differences in plasma glucose between B6 treated and control groups. Plasma insulin values were also not different between the 2 groups. There was no effect of leptin supplementation on locomotor activity or food intake in B6 mice. In summary, this study demonstrates that leptin supplementation in animals that show low plasma leptin levels in response to fat feeding may slow but does not prevent the subsequent development of diet-induced obesity.

Clinical and biological effects of intraperitoneal injections of recombinant interferon-gamma and recombinant interleukin 2 with or without tumor-infiltrating lymphocytes in patients with ovarian or peritoneal carcinoma.

To identify strategies that enhance tumor-specific immunity in patients with ovarian carcinoma, 22 patients received four to six doses of i.p. recombinant IFN-gamma (rIFN-gamma), 200 microg/m2 on days 1, 3, 5, 8, 10, and 12, and i.p. recombinant interleukin 2 (rIL-2), either 6.0 x 10(5) IU/m2 (group A) or 1.0 x 10(5) IU/m2 (group B), on days 9, 10, and 11. Two patients in group A also received T-cell lines expanded from peritoneal tumor-infiltrating lymphocytes (TILs) obtained after i.p. rIFN-gamma/rIL-2 administration. Toxicity was manageable and included five nonhematological grade 3 or 4 events in 22 patients (23%). A patient had normalization of CA-125 values and a progression-free interval of 18 months, after receiving i.p. rIFN-gamma/rIL-2 without TILs. Another patient who received i.p. rIFN-gamma/rIL-2 plus TILs had stabilization of ascites and intra-abdominal tumors and >50% reduction in serum CA-125 values over 6 months. A third patient who received i.p. rIFN-gamma/rIL-2 had stabilization of intra-abdominal tumors and ascites accompanied by CA-125 values of 50 to 100 units over 6 months. T-cell lines for adoptive immunotherapy were developed for only 3 of 20 patients who were treated with rIFN-gamma/rIL-2. Large numbers of CD3- CD56+ adherent cells were expanded in rIL-2 in the remaining patients, precluding the development of T-cell lines. i.p. rIFN-gamma, either alone or followed by rIL-2, increased proportions of human leukocyte antigen (HLA) class I+ and class II+ tumor cells and increased HLA class I staining intensity on peritoneal carcinoma cells. i.p. rIFN-gamma plus rIL-2 also enhanced cytotoxic activity against Daudi and K562 cells and against allogeneic ovarian tumor cells. Increased cytotoxic activity was associated with an increase in the proportion of CD56+ cells. IFN-gamma and IL-2 transcripts were expressed more frequently after rIFN-gamma and rIL-2 treatment. In addition, the proportions of CD45RA+ (naive lymphocytes) were increased, and CD8+ DR+ lymphocytes were increased relative to CD8+ CD69+ cells, which were decreased. IL-10 concentrations in peritoneal fluids were increased after treatment with rIFN-gamma and the higher rIL-2 dosing (group A) but not in those treated with rIFN-gamma and the lower rIL-2 dosing (group B). These results demonstrated that patients with ovarian carcinoma can tolerate treatment with rIFN-gamma and rIL-2 and that rIFN-gamma alone or rIFN-gamma combined with rIL-2 enhances the expression of HLA class I and class II antigens on ovarian tumor cells, although immunosuppressive cytokines, such as transforming growth factor-beta and IL-10, may persist. Treatment with rIFN-gamma/rIL-2 i.p. did not facilitate the production of TIL-derived T-cell lines ex vivo.

The diagnostic value of power Doppler measurements in the endometrium of women with postmenopausal bleeding.

OBJECTIVE: The objective was to evaluate the accuracy of blood flow measurements by power Doppler in endometrial vessels in women with postmenopausal bleeding (PMB). METHODS: Sixty consecutive patients with PMB participated in the study. Endometrial thickness and power Doppler measurements of small vessels in the endometrium and subendometrial tissue were performed prior to dilatation and curettage. Correlation between Doppler indices, endometrial thickness (by transvaginal sonography), and histopathologic examination was performed. A Student t test was used for statistical analysis with P < 0.05 as the level of significance. RESULTS: Fourteen positive cases were found: 11 endometrial cancers, 1 sarcoma, 1 simple hyperplasia, and 1 complex hyperplasia with atypia. Measurements of endometrial thickness using a cutoff point of 5 mm revealed a sensitivity of 78% and specificity of 45.6% (P > 0.05, NS) for detecting endometrial pathology. Power Doppler measurements (pulsatility index cutoff point = 1.0) revealed a sensitivity of 85. 7% and specificity of 89% (P = 0.001) for detecting endometrial pathology. CONCLUSIONS: The noninvasive methods for endometrial evaluation are not sensitive enough to exclude endometrial pathology. When invasive methods could not be performed, the combination of transvaginal sonography and power Doppler imaging provided the best results. When both modalities are negative, the probability of cancer is less than 5%.

Recombinant human thrombopoietin attenuates carboplatin-induced severe thrombocytopenia and the need for platelet transfusions in patients with gynecologic cancer.

BACKGROUND: Thrombocytopenia is a significant problem in the treatment of cancer. OBJECTIVE: To assess the clinical safety of therapy with recombinant human thrombopoietin (rhTPO) and its ability to ameliorate chemotherapy-induced severe thrombocytopenia. DESIGN: Phase I/II clinical cohort study. SETTING: The University of Texas M.D. Anderson Cancer Center, Houston, Texas. PATIENTS: 29 patients with gynecologic cancer. INTERVENTION: Recombinant human thrombopoietin was given before chemotherapy and after a second cycle of carboplatin therapy. MEASUREMENTS: Peripheral blood counts and platelet transfusions. RESULTS: Administration of rhTPO after chemotherapy significantly reduced the degree and duration of thrombocytopenia and enhanced platelet recovery. In patients who received the optimal biological dose of rhTPO (1.2 microg/kg of body weight) in cycle 2 (carboplatin plus rhTPO), the mean platelet count nadir was higher (44x10(9) cells/L and 20x10(9) cells/L; P = 0.002) and the duration of thrombocytopenia was shorter (days with a platelet count <20x10(9) cells/L, 1 and 4 [P = 0.002]; days with a platelet count <50x10(9) cells/L, 4 and 7 [P = 0.006]) than in cycle 1 (carboplatin only). The need for platelet transfusion in this group was reduced from 75% of patients in cycle 1 to 25% of patients in cycle 2 (P = 0.013). CONCLUSIONS: Therapy with rhTPO seems to be safe and may attenuate chemotherapy-induced severe thrombocytopenia and reduce the need for platelet transfusions.

Synchronous primary cancers of the breast and cervix: planning multidisciplinary primary treatment [clinico-pathological conference].

Multiple metachronous primary malignancies are becoming increasingly frequent; however, multiple synchronous primary malignancies are still unusual. We report the case of a 61-year-old woman with synchronous stage IIIB ductal carcinoma of the left breast and FIGO stage IB2 squamous cell carcinoma of the cervix. The patient was treated initially every 4 weeks with a 24-h intravenous infusion of paclitaxel (175 mg/m2) followed by a 1-h infusion of carboplatin (area under the curve of 5 mg/ml x min) with concurrent irradiation of the pelvis. Significant toxic reactions including nausea, vomiting, and diarrhea required hospitalization or outpatient intravenous fluids and antiemetics. After four cycles of chemotherapy, the breast cancer was in complete clinical remission, and the patient underwent a modified radical mastectomy with axillary lymph node dissection. Pathologic findings revealed a few microscopic foci of residual infiltrating ductal carcinoma exhibiting a marked treatment effect; none of the 14 axillary lymph nodes removed showed evidence of metastatic tumor. A near-complete pathologic response of the breast cancer and a complete clinical response of the cervical cancer were obtained. Adjuvant chemotherapy for the breast cancer was then initiated, followed by radiation and hormonal therapy.

Intraoperative gold grain implants for pelvic wall recurrences of various malignancies: toxicity, results, and failure analysis in 37 patients.

PURPOSE: We conducted this study to determine the complications and long-term results of intraoperative gold-grain implants as therapy for pelvic wall recurrences of various malignancies. MATERIALS AND METHODS: We retrospectively analyzed complications and long-term results of intraoperative radioactive 198Au gold grain implants of 4-mc radon equivalent in 37 patients with pelvic wall recurrences of various malignancies treated at the University of Texas M. D. Anderson Cancer Center. The estimated dose was 30-100 Gy, which was increased to 100-120 Gy plus external-beam irradiation if the dose to the tumor volume was too low. All patients had follow-up of 4 months to 12 years. Of the 37 patients, 34 had lower leg edema, 22 had lower limb pain, and 22 had ureteral obstruction. RESULTS: Six of 34 patients with lower limb pain had partial relief and nine had complete relief. Of 22 patients with ureteral obstruction, ten had complete resolution and four had partial relief. Lower limb edema was improved in 16 of 22 patients. Of the 37 patients studied, 14 are alive and 23 have died. CONCLUSION: In selected patients, gold grain implantation to a dose of 70-100 Gy relieved some symptoms of unresectable pelvic wall recurrences of various malignancies. We believe that intraoperative gold grain implants appear to be the only useful treatment for patients with recurrent malignancies fixed to the pelvic wall and provide these patients with better and longer palliation and a good quality of life.

Electromyographic (EMG) biofeedback in the comprehensive treatment of central pain and ataxic tremor following thalamic stroke.

Peripheral pain and ataxic tremor can appear suddenly following thalamic stroke and can significantly alter a patient's psychological, social, and physical functioning. The present paper reports the case of a 70-year-old Caucasian female who sustained an acute left posterior cerebral artery infarction involving the thalamus and left mesiotemporal regions. She subsequently developed Central Poststroke Pain and ataxic movement of her right arm and hand in addition to a significant right-side claudication. She was treated over 16 weeks (6 weeks of EMG biofeedback and 10 weeks of psychotherapy) with a combination of EMG biofeedback, progressive muscle relaxation, behavioral pain coping skills training, Forced Use Therapy, and Cognitive Behavioral Therapy 7 years after her initial cerebral accident. The case demonstrates the utility of biofeedback when combined as part of a comprehensive treatment program to address the multiple complications associated with thalamic stroke.

A phase II clinical and pharmacological study of oral 9-nitrocamptothecin in patients with refractory epithelial ovarian, tubal or peritoneal cancer.

9-Nitrocamptothecin (9-NC) is a water-insoluble topoisomerase I inhibitor with a broad antitumor activity in animal models. A phase II study was performed in patients with heavily refractory ovarian, tubal or peritoneal cancer (median number of previous chemotherapy regimens > 3) to determine the activity of a daily oral dose of 9-NC. 9-NC dose was 1.5 mg/m2/day for four consecutive days every week. Increments of 0.25 mg/day were authorized in patients without significant side effects. Of 29 evaluable patients, a 7% remission rate was observed. Thirty-four percent of patients had stable disease. The median survival was 8 months. Toxicity was evaluated in 31 patients. Grade 3 or 4 hematologic toxicity consisted of anemia in 10 patients (32%), neutropenia in eight (26%) and thrombocytopenia in three (10%). Grade > or = 2 non-hematologic toxic effects were nausea and vomiting in 26 (84%), diarrhea in 12 (39%), weight loss in seven (22%), chemical cystitis in six (19%) and neutropenic sepsis in six (19%). 9-NC was tolerated for sustained periods of time in some patients (up to 47 weeks). The observed 8-month survival in such a refractory patient population is noteworthy. Further clinical research of prolonged exposure to less toxic analogs of 9-NC is warranted.