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A Sella

Publications and source records attributed to A Sella.

At least 19 recordsLinked to original sources

Inhibition of adamalysin II and MMPs by phosphonate analogues of snake venom peptides.

Phosphonate analogues of the peptidomimetic N-(Furan-2-yl)carbonyl-Leu-Trp-OH were prepared with the goal of evaluating the effect of phosphonate for carboxylate replacement on binding with snake venom metalloproteinases and MMPs. N-(Furan-2-yl)carbonyl-Leu-L-Trp(P)-(OH)2 showed a 75-fold increase of the inhibiting activity against adamalysin II, a snake venom metalloproteinase structurally related to MMPs and TACE. Both the phosphonate and carboxylate peptidomimetics fit into the active site adopting a retrobinding mode and provide the structural base for a new class of metalloproteinases inhibitors.

Inhibitory Concentration 50

Antiandrogen withdrawal syndrome with cyproterone acetate.

OBJECTIVES: To determine whether the antiandrogen withdrawal syndrome occurs with the steroidal antiandrogen cyproterone acetate. METHODS: Cyproterone acetate was withheld in 12 patients with progressing androgen-independent metastatic prostate cancer. Eight patients had been receiving cyproterone acetate concomitant with androgen ablation, and in 4 patients it was prescribed after failure of androgen suppression. Time to response and to disease progression were defined by serum prostate-specific antigen (PSA) levels and imaging studies. RESULTS: PSA levels decreased in 5 of the 1 2 patients; in 4 of them (33%), the decrease exceeded 50%. The decline lasted a median of 24 weeks (range 9 to 37.8). All 5 patients had received initial concomitant exposure to androgen ablation and cyproterone acetate. CONCLUSIONS: We recommend that the steroidal antiandrogen cyproterone acetate be added to the list of agents capable of inducing antiandrogen withdrawal syndrome.

Aged

Intravesical bacillus Calmette-Guérin treatment for Stage T1 grade 3 transitional cell carcinoma of the bladder.

OBJECTIVES: To retrospectively analyze intravesical bacillus Calmette-Guerin (BCG) treatment for Stage T1 grade 3 (T1G3) transitional cell carcinoma (TCC) of the bladder. METHODS: Between 1984 and 1995, 78 patients with Stage T1 grade 3 tumor were treated by transurethral resection of all visible tumors and adjuvant BCG intravesical instillations. Median follow-up was 56 months (range 12 to 141). RESULTS: After an initial induction course, 52 patients (67%) were tumor-free. Twenty-two patients (28%) had recurrent tumor after a median of 7 months (range 5 to 62). Progression occurred in 6 patients (7.7%) after a median of 18 months (range 5 to 56). CONCLUSIONS: Intravesical BCG appears to be an effective treatment for patients with Stage T1 grade 3 TCC. Patients whose tumors recur after an initial induction course may benefit from a second course of BCG. Intravesical BCG treatment may lower the tumor progression rate. Late recurrence, beyond 2 years, warrants long-term follow-up.

Adjuvants, Immunologic

Combination chemotherapy for metastatic or locally advanced genitourinary squamous cell carcinoma: a phase II study of methotrexate, cisplatin and bleomycin.

PURPOSE: The prognosis of patients with advanced squamous cell carcinoma of genitourinary origin is poor. While single agent chemotherapy results mainly in partial responses of short duration, data on the efficacy of combination chemotherapy are extremely limited. We determined the response rate and toxicity of a combination of 3 of the most active agents, methotrexate, cisplatin and bleomycin, in patients with advanced genitourinary squamous cell carcinoma. MATERIALS AND METHODS: Patients with metastatic or locally advanced genitourinary squamous cell carcinoma were eligible for study. Treatment consisted of 200 mg./m.2 methotrexate on days 1, 15 and 22, and 20 mg./m.2 cisplatin and 10 mg./m.2 bleomycin on days 2 through 6 during a 28-day cycle. RESULTS: Of the 30 patients who enrolled in the trial 29 were evaluable for response. Objective response was achieved in 16 patients (55%, 95% confidence interval 36 to 72), 4 of whom achieved a complete response (14%). Median objective response duration was 4.7 months (range 1.9 to 39.5). Median survival of the entire group was 11.5 months (range 1.5 to 87.0). Of the patients 9 achieved disease-free status, including 6 following consolidation surgery or radiation therapy. Median survival of these 9 patients (34.4 months, range 9.6 to 87.0) was significantly greater (p = 0.0003) than that of patients who did not become disease-free (7.0 months, range 1.5 to 38.6). Grade III or IV hematological toxicity in 116 courses included neutropenia (13%) and thrombocytopenia (6%). Among 30 patients evaluable for toxicity serious nonhematological toxic effects included stomatitis (3%) and renal toxicity (7%). There was 1 death from neutropenic sepsis. CONCLUSIONS: Methotrexate, cisplatin and bleomycin combination chemotherapy for genitourinary squamous cell carcinoma results in a high but short lived overall response rate, and a low complete response rate with manageable toxicity. A multidisciplinary approach to achieve disease-free status may provide the best opportunity to effect survival and should be the focus of future trials.

Adult

Phase II trial of 5-fluorouracil, interferon-alpha and continuous infusion interleukin-2 for patients with metastatic renal cell carcinoma.

BACKGROUND: This study was designed to evaluate the efficacy and toxicity of the combination of 5-fluorouracil, interferon-alpha, and interleukin-2 for patients with metastatic renal cell carcinoma. METHODS: Previously untreated patients with a Zubrod performance status of < or =2; adequate cardiac, pulmonary, and renal function; and absence of brain metastases were eligible. One course of therapy was 28 days. 5-fluorouracil was administered at a dose of 600 mg/m2/day as a continuous infusions on Days 1-5. Interleukin-2 also was administered as a continuous infusion on Days 1-5 at a dose of 2 million Roche U/m2/day. Interferon-alpha was given as a daily subcutaneous injection of 4 million U/m2/day. RESULTS: Fifty-five patients were enrolled in the trial and 52 were evaluable for response. All patients experienced fever and flu-like symptoms. Grade 3 or 4 nonhematologic toxic effects included hypertension (48%), dermatitis (12%), stomatitis (11%), and altered mental status (9%). There was one toxic death. Four complete responses and 12 partial responses were observed for a total response rate of 31% (95% confidence interval, 18-46%). The survival of responding patients was significantly better than that of nonresponding patients. The improvement in survival was even more significant when comparing patients with at least stable disease with those who progressed through treatment. CONCLUSIONS: The three-drug combination described in this study demonstrates activity. However, it appears to be more toxic than other regimens with similar response rates and cannot be recommended for standard practice. Changing the interleukin-2 route to subcutaneous administration may permit more continuous administration with less toxic effects.

Adult

Hyperplasia of axillary nodes in patients undergoing immunotherapy.

OBJECTIVE: CT scans of the chest in 32 patients undergoing immunotherapy for metastatic renal cell carcinoma were evaluated to determine the incidence and significance of axillary lymph node enlargement during therapy. CONCLUSION: Axillary node enlargement in cancer patients undergoing immunotherapy should not be assumed to be metastatic in origin but may result from the stimulation of the immune system during treatment.

Antineoplastic Combined Chemotherapy Protocols

Carpal tunnel syndrome associated with interleukin-2 therapy.

BACKGROUND: Interleukin (IL-2) has been extensively used in our institution in the treatment of cancer and has protean neurologic side effects. Carpal tunnel syndrome developing in patients receiving IL-2 appears to have a good prognosis and may spare the patient unneeded investigation. METHODS: A retrospective evaluation was undertaken for all patients using our institution's Patient Studies database. The patients were examined and their charts reviewed. RESULTS: We found eight patients with renal cell carcinoma who developed carpal tunnel syndrome (CTS) during treatment with IL-2, fluorouracil (5-FU), and alpha-interferon (alpha-IFN). The symptoms were bilateral in five patients and all patients improved with cessation of therapy. Three patients had recurrent symptoms with subsequent courses of therapy. Symptoms occurred during or shortly after IL-2 infusion and resolved after therapy was completed with conservative management. The number of courses given did not seem to correlate with development of symptoms. Neurophysiologic studies demonstrated conduction velocity slowing without evidence of acute denervation. CONCLUSIONS: IL-2 can produce focal entrapment of the median nerve at the wrist, which reverses with drug withdrawal. IL-2 mediates the inflammatory response and can cause interstitial edema that likely causes CTS to develop in predisposed patients undergoing treatment.

Adult

Acquired cutaneous adherence in patients with androgen-independent prostate cancer receiving ketoconazole and doxorubicin: medication-induced sticky skin.

BACKGROUND: The phenomenon of sticky skin has been reported in patients with psoriasis who are receiving retinoids. OBJECTIVE: We describe therapy-induced sticky skin in eight patients receiving ketoconazole and doxorubicin for androgen-independent prostate cancer. METHODS: Patients were treated with oral daily ketoconazole (400 mg every 8 hours) and intravenous doxorubicin weekly (20 mg/m2 continuously for 24 hours). Thirty-nine patients were entered into the study; retrospective information regarding sticky skin was obtainable from 28 patients or their spouses. Prostate specific antigen (PSA) values were compared in patients with and without therapy-induced sticky skin. RESULTS: Eight patients (29%) described sticky skin. Six of these patients (75%) had a PSA response. Of the 20 patients without sticky skin a PSA response occurred in 12 (60%). CONCLUSION: Sticky skin occurred in patients with androgen-independent prostate cancer who were simultaneously receiving ketoconazole and doxorubicin. To our knowledge this unique skin manifestation of acquired cutaneous adherence has not been previously described in association with chemotherapeutic or antifungal agents. The pathogenesis of acquired cutaneous adherence in these patients might relate to therapy-induced elevation of endogenous retinoids. The similar PSA response rate in patients with or without sticky skin suggests that retinoids may not play an essential role in the mechanism of antitumor activity of ketoconazole and doxorubicin.

Adhesiveness

Phase I study of tumor necrosis factor plus actinomycin D in patients with androgen-independent prostate cancer.

Based on preclinical studies which reveal enhanced antitumor activity of tumor necrosis factor (TNF) when combined with actinomycin D in human prostate cancer cell lines, we performed a phase I clinical study combining TNF and actinomycin D. All patients had metastatic prostatic carcinoma exhibiting androgen-independent growth. Patients were treated with a combination of a short infusion of actinomycin D followed by a TNF infusion daily for five consecutive days. Soluble TNF receptor p60 was not modulated by treatment but p80 receptor increased significantly following treatment with a combination of TNF and actinomycin D (baseline median 3.4 ng/ml) range 2.5-6.6 ng/ml follow up (9.3 ng/ml) range 6-24 ng/ml. We concluded that the maximum tolerated dose of continuous infusion TNF and short infusion actinomycin D is 400 micrograms/m2 of actinomycin D and 400 micrograms/m2 of TNF. The increased soluble receptor isoform (p80) may account for the lack of clinical activity seen in this trial. Should these results be confirmed, a strategy focused on overcoming the upregulation of the TNF soluble receptor will be required before further study of TNF should be considered.

Aged

A phase I trial of intermittent high-dose alpha-interferon and dexamethasone in metastatic renal cell carcinoma.

BACKGROUND: Evidence exists that the toxic of alpha-interferon can be ameliorated by co-administration of dexamethasone without compromise of therapeutic efficacy. We therefore conducted a phase I trial to determine the maximum tolerated dose of intermittent interferon when combined with oral dexamethasone. PATIENTS AND METHODS: Thirty patients with metastatic renal cell carcinoma were enrolled. The starting dose of interferon was 20 million IU/m2/day given as a subcutaneous injection days 1 to 4 of each 14 day cycle. Dose levels were escalated at increments of 5 million IU/m2. Dexamethasone 4 mg was administered orally every 6 hours during administration of high-dose interferon. Low-dose maintenance interferon, 3 million IU/m2/day, was administered without dose escalation on days 5 to 14 of each cycle. RESULTS: The maximum tolerated dose of intermittent high-dose interferon was 40 million IU/m2/day. The dose limiting toxicity was fatigue. EEG abnormalities developed in five patients and neuropsychiatric parameters deteriorated significantly in seventeen. CONCLUSIONS: We conclude that co-administration of dexamethasone improves the tolerance of intermittent high-dose interferon. The results of this trial may be useful in designing high-dose interferon regimens for renal cell carcinoma and other interferon-sensitive diseases.

Administration, Oral

Escalated MVAC with or without recombinant human granulocyte-macrophage colony-stimulating factor for the initial treatment of advanced malignant urothelial tumors: results of a randomized trial.

PURPOSE: Hematopoietic growth factors have been shown to ameliorate the side effects of chemotherapy. Here we assess the ability of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) to increase the dose-intensity and reduce the side effects of escalated methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy. PATIENTS AND METHODS: A prospective randomized trial to compare escalated MVAC versus escalated MVAC with rhGM-CSF was conducted. All patients were treated at The University of Texas M.D. Anderson Cancer Center (UTMDACC) and had a metastatic or unresectable urothelial tumor. Forty-eight patients were randomized (25 to MVAC with rhGM-CSF and 23 to escalated MVAC alone). The clinical characteristics of the study populations were similar (ie, degree of tumor dissemination and performance status). RESULTS: The dose-intensity in the two arms of the study did not differ significantly. No difference in the frequency of bacteriologically documented infections occurred between the two study arms. CONCLUSION: The use of the hematopoietic growth factor rhGM-CSF did not result in an increased dose-intensity of escalated MVAC. The inability to increase the dose-intensity of MVAC further was a result of nonhematologic side effects of the chemotherapy. Escalation of treatment delivered at its median-tolerated dose is unlikely to result in additional therapeutic benefit for patients with common solid tumors. Future development of therapy may require the development of new agents or concepts, rather than modification of existing therapies.

Adult

Phase I study of interleukin-2 combined with interferon-alpha and 5-fluorouracil in patients with metastatic renal cell cancer.

Interferon-alpha (IFN-alpha) and interleukin-2 (IL-2) each has produced a 15%-20% response in metastatic renal cell cancer. Combining IFN-alpha with either IL-2 or 5-fluorouracil (5-FU) enhanced IFN-alpha activity. We have therefore conducted a Phase I Study combining IL-2, IFN-alpha, and 5-FU. The patients were continuously infused with IL-2 (1-3 x 10(6) u/m2) and 5-FU (600-750 mg/m2) for a 5-day period every 28 days, and IFN-alpha (4-5 x 10(6) u/m2) was injected subcutaneously daily. Lymphokine-activated killer (LAK) and natural killer (NK) cell activity was measured on days 0 and 8. Twenty-one patients received 76 courses. All primary tumors were controlled by surgery (81%) or angioinfarction. Hematologic toxicity was mild; median nadir of platelets was 117 K/microL and of granulocytes was 1.2 K/microL. Dose-limiting toxicity included mucositis, liver damage, and hypotension. No treatment-related death occurred, and only one patient required intensive-care-unit support. Two patients had an objective response, one of which was a complete response. Increased LAK cell and NK cell activity occurred at all IL-2 dose levels. Simultaneous delivery of IL-2, IFN-alpha, and 5-FU is safe and shows antitumor and biologic activity. 5-FU did not appear to suppress IL-2-induced LAK and NK cell activation. Maximum tolerated dose of the three-drug combination is IL-2, 2 x 10(6) u/m2, 5-FU 600 mg/m2, and IFN-alpha, 4 x 10(6) u/m2.

Adult

Tubular seminoma. An immunohistochemical and DNA flow-cytometric study of four cases.

The histomorphologic features, immunohistochemical reactivity, and DNA content of four cases of a rare tubular variant of seminoma are presented. These neoplasms were characterized by a predominantly tubular architectural pattern that resembled yolk sac tumor, embryonal carcinoma, and sex cord-stromal tumors. The patients' ages were 15, 24, 27, and 44 years. On initial examination, three patients had painless testicular enlargement, and one had a large retroperitoneal mass and a clinically occult primary testicular tumor. The size of the tumors ranged from 1.7 to 6.0 (mean, 4.0) cm. Microscopically, the tumor cells had a tubular or tubulopapillary pattern that consisted of a single layer of cells, often in a back-to-back arrangement with intervening fibrovascular septa. Areas of classic seminoma were present in all cases. Scattered syncytiotrophoblastic giant cells were seen in two tumors. The tumor cells of both the classic and the tubular components of the seminomas were diffusely positive for placental alkaline phosphatase but were negative for cytokeratin and alpha-fetoprotein. DNA flow-cytometric analysis demonstrated abnormal stemlines with hypotetraploid DNA and a mean DNA index of 1.7 in both the classic and the tubular components. The presence of concurrent areas of classic seminoma, similar cytologic features in the tubular and classic seminoma areas, and the identical immunohistochemical and DNA flow-cytometric findings indicate that tubular seminoma is a histologic variant of seminoma. Although the behavior of the tubular variant appeared not to differ from that of classic seminoma in our small series, its recognition is important in the differential diagnosis and management of testicular masses.

Adolescent

Phase II study of ketoconazole combined with weekly doxorubicin in patients with androgen-independent prostate cancer.

PURPOSE: A phase II clinical trial was performed to assess the antitumor activity and toxicity of ketoconazole in combination with doxorubicin (Adriamycin; Adria Laboratories, Columbus, OH) in patients with androgen-independent prostate cancer (AI PCa). PATIENTS AND METHODS: Thirty-nine consecutive patients whose disease progressed following castration were treated with oral ketoconazole (1,200 mg) daily and Adriamycin (20 mg/m2 in a 24-hour infusion) once weekly. Antitumor activity was assessed by the level of prostatic-specific antigen (PSA) decline. RESULTS: PSA levels decreased > or = 50% from baseline in 21 (55%; 95% confidence interval, 38% to 71%) of 38 assessable patients. We observed partial responses (PRs) in seven (58%) of 12 patients with measurable soft tissue disease (in the lung, lymph nodes, and liver). Two patients with history of atherosclerotic heart disease had a sudden cardiac death. Serious toxic reactions included grade III to V stomatitis and grade III to IV acral erythema in 11 patients (29%), and grade III to IV anal and urethral mucositis in five patients (13%). Grade III to IV neutropenia occurred in 11 patients (29%). Seventeen patients (45%) required hospitalization for complications. Fifteen patients (39%) developed hypokalemia, and 24 patients (63%) developed clinical adrenal insufficiency. CONCLUSION: The combination of ketoconazole and Adriamycin has a 55% PSA response rate in patients with AI PCa and is worthy of additional study. This treatment results in frequent adrenal insufficiency. Therefore, future studies should incorporate routine corticosteroid replacement. The cardiac complications caused by this combination should be studied further before it is widely used.

Administration, Oral

Primary carcinoid of the kidney. Immunohistochemical and ultrastructural studies of five patients.

BACKGROUND: Primary carcinoid tumor of the kidney is rare; only 18 patients have been reported. Because of the rarity of the lesion, its prognosis and clinicopathologic features are not well characterized, and its histogenesis is unknown. METHODS: Clinicopathologic, immunohistochemical, and ultrastructural studies were performed on five patients with primary carcinoid tumor of the kidney. RESULTS: Age of the patients ranged from 42 to 63 years, with a mean of 53.2 years. Only one patient had a carcinoid syndrome. Three were men, and two were women. In each patient, the tumor was solitary and confined to the kidney. All tumors had histologic features identical to those of carcinoid tumors affecting other sites. The cytoplasmic granules of the tumor cells were reactive with Grimelius stain in all patients. All tumors also were immunoreactive for keratin, neuron-specific enolase, and chromogranin, but only two patients had tumors that reacted for serotonin, pancreatic polypeptide, and vasoactive intestinal polypeptide. Ultrastructural studies showed numerous intracytoplasmic neuroendocrine granules in four tumors. One patient had Robson Stage I cancer, and two each had Stage II and IV cancer. The two patients with Stage IV tumor died of disease at 36 months and 28 months after diagnosis; one patient with Stage II carcinoid is alive without clinical evidence of residual disease 8 years after control of metastases; the other patient with Stage II and the patient with Stage I cancer are alive and well without evidence of disease at 36 months, and 2 months, respectively. CONCLUSION: Tumor stage at presentation appears to be the most important factor in determining outcome. The number of mitoses and degree of cellular atypia appear to be important pathologic parameters in predicting prognosis, despite the limited number of patients reported in this report.

Adult

Fine-needle aspiration cytology of sarcomatoid renal cell carcinoma: a morphologic and immunocytochemical study of 15 cases.

Sarcomatoid renal cell carcinoma (SRCC), which accounts for 5% of all renal cell carcinomas (RCC), has a worse prognosis than conventional nonsarcomatoid RCC, making accurate diagnosis important. This study reports on the morphologic and immunocytochemical features of 15 cases of SRCC (9 primary tumors and 6 metastases) diagnosed by fine-needle aspiration (FNA) biopsy. All but three cases showed a dimorphic cell population consisting of varying proportions of a high-grade epithelial component, either clear or granular-cell type and a spindle cell (sarcomatoid) component, of either fibrosarcomatous, malignant fibrous histiocytoma (MFH), or unclassified types. The sarcomatoid component in the biphasic and monophasic tumors stained positively for cytokeratin in 12 of 14 (85%) cases, for vimentin in 10 of 11 (91%) cases, and for muscle-specific action in 4 of 11 (36%) cases. Of note, the three cases that demonstrated a purely sarcomatoid morphology stained positively for cytokeratin. Unlike in studies performed on surgically resected specimens, neither the proportion of the sarcomatoid component nor the presence of necrosis had prognostic significance, the discrepancy most likely being related to the sampling. We conclude that SRCC, both primary and metastatic, can be accurately diagnosed by FNA when cytologic features are evaluated in conjunction with immunocytochemical findings.

Adult

Surgery following response to interferon-alpha-based therapy for residual renal cell carcinoma.

The role of aggressive surgery for metastatic renal cancer in the era of biological therapy is not clear. Therefore, we reviewed 17 patients who, between February 1987 and August 1990, underwent surgical resection of residual masses following initial response to interferon-alpha-based therapy. Viable tumor persisted in 15 patients (88%), whereas only inflammatory response was detected in 2. Of the patients 11 (65%) remained disease-free at a median of 12 months postoperatively (range 5 to 29), with an overall median survival of 26 months (range 6 to 34) from treatment initiation. These data suggest that surgery may be of therapeutic benefit in select patients with renal cell carcinoma who do not meet traditional criteria for surgical resection. Prospective trials are being performed to determine whether there is a role for aggressive surgical resection of persistent disease in patients with advanced renal cell carcinoma who have previously responded to interferon-alpha-based therapy.

Adult

Collecting duct carcinoma of the kidney.

Collecting duct carcinoma (CDC) is a recently recognised histological variety of renal carcinoma (RC) considered to arise from the epithelium of the collecting ducts. Diagnosis of this entity depends on well defined gross and microscopic criteria and is supported by a characteristic immunostaining pattern. The clinical features of these patients, the natural course of the disease and its response to treatment have not been clearly established. Between 1980 and 1990 we treated 12 patients (median age 43 years, range 16-62) with collecting duct carcinoma of the kidney. In addition to being relatively young, each patient had a strong family history of associated malignancies. Survival was short (median 22 months) and 11 patients presented with locally advanced or metastatic disease.

Adolescent