Long term control of luteinized thecoma with sclerosing peritonitis with leuprorelin and tamoxifen treatment.

BACKGROUND: Luteinized thecoma with sclerosing peritonitis (LTSP) is a very rare condition, and its clinical management is not evidence-based. Here we describe a case of long-term disease control achieved with leuprorelin and tamoxifen therapy. CASE PRESENTATION: A 18-year-old woman with acute abdomen underwent surgical removal of an ovarian mass and received diagnosis of LTSP. Treatment plan consisted of leuprorelin and tamoxifen, followed by a good instrumental response. After 5 years, leuprorelin was stopped, and the patient continued tamoxifen alone. Ten years after diagnosis, she is still disease free. CONCLUSION: Even in the absence of solid evidence, the combination of leuprorelin and tamoxifen could be considered as a possible medical treatment of LTSP. Considering the limitations related to the rarity of disease, further studies are needed to improve its management.

Phase II study of vinorelbine with protracted fluorouracil infusion as a second- or third-line approach for advanced breast cancer patients previously treated with anthracyclines.

PURPOSE: To evaluate the feasibility and activity of vinorelbine in association with protracted infusional fluorouracil in patients with advanced breast cancer who were previously treated with anthracycline-containing regimens. PATIENTS AND METHODS: Eighty-three consecutive patients were entered onto the study. Forty-three patients experienced treatment failure or relapse after anthracycline-based, first-line chemotherapy for advanced disease and 29 experienced treatment failure or relapse after first- and second-line approaches; 11 patients experienced progressive disease within 6 months of completion of adjuvant anthracycline therapy. Sites of involvement were as follows: liver involvement, 42 patients (50.6%); lung 24 (28.9%); bone, 49 (59.0%); and skin/lymph nodes, 21 (25.3%). Treatment consisted of vinorelbine 30 mg/m(2) administered on days 1 and 15 every 28 days and fluorouracil 200 mg/m(2)/d given continuously over a 24-hour period. RESULTS: Toxicity was recorded for 441 cycles. The scheme was well tolerated: grade 1/2 nausea/vomiting occurred in 13 patients (15.6%), grade 1/2 diarrhea in nine (10.8%), and grade 2/3 stomatitis in six (7.2%). Three patients (3.6%) experienced grade 3/4 leukopenia and four (4.8%) experienced grade 2/3 anemia. Grade 2/3 neurologic toxicity was observed in three cases (3.6%), and grade 2/3 hand-foot syndrome was observed in three (3.6%). The median relative dose-intensity was 92% and 100% for vinorelbine and fluorouracil, respectively. Six patients (7.2%) attained a complete clinical response and 45 (54.2%) attained a partial response, for an overall response rate of 61.4% (95% confidence interval, 50.9% to 71.9%). Twenty-one patients (25.3%) obtained disease stabilization, and 11 (13.3%) experienced disease progression. Median time to progression in responding patients was 15 months; median overall survival of the entire population was 22 months. CONCLUSION: Vinorelbine associated with protracted infusional fluorouracil is an active and manageable scheme in advanced breast cancer patients previously treated with anthracyclines. The response obtained is durable.

p53 but not bcl-2 immunostaining is predictive of poor clinical complete response to primary chemotherapy in breast cancer patients.

Preoperative chemotherapy administered to breast cancer (BC) patients is a model for studying in vivo the interaction between cytotoxic treatment and clinical and biological parameters. Apoptosis induced by anticancer agents is a mechanism of treatment activity; therefore, overexpression of genes inhibiting the apoptotic pathway could produce drug resistant tumors. In the present study, the two most studied inhibitors of apoptosis, the bcl-2 gene and the mutant p53, have been evaluated to assess whether they may play a role in modulating response of BC to primary chemotherapy. From August 1990 to January 1997, 143 patients bearing T(2-4)N(0-1)M0 primary BC were submitted to two different chemotherapeutic regimens before surgery. The first 64 received the cyclophosphamide, methotrexate, 5-fluorouracil (CMF) regimen (on days 1 and 8 and every 28 days thereafter) associated with tamoxifen (30 mg daily) in case of estrogen receptor (ER)-positive BC, and the remaining 79 were submitted to single agent epirubicin (120 mg/m2 every 21 days). The expression of p53, bcl-2, Ki67, ER, progesterone receptor, c-erbB2, and the multidrug resistance P-glycoprotein (gp-170) was evaluated in BC specimens obtained at diagnosis by incision biopsy and at postchemotherapy surgery. At the end of chemotherapy administration (median, 3 cycles; range, 2-6), the clinical complete response (cCR) rate was superimposable in the patient subgroups with bcl-2-positive or -negative primary tumors; conversely, p53 expression, at a cutoff of 10% positive cells, was significantly associated with a lower cCR rate (9.4 versus 27.0%; P < 0.04). p53 was a significant predictor for poor cCR in the subset submitted to epirubicin (3.6 versus 25.5%; P < 0.02; in patients with p53+ and p53- BC, respectively); by contrast, only a trend toward lower cCR has been observed in patients with p53+ tumors receiving CMF +/- tamoxifen with respect to p53- ones. The distribution of cCR according to the gp-170-positive or -negative tumors was 8 versus 22% in patients submitted to epirubicin and 29 versus 30% in those receiving CMF +/- tamoxifen, respectively. In a multivariate regression analysis, after adjusting for treatment administered (epirubicin versus CMF +/- tamoxifen), menopausal status, tumor and node status, histology grade, ER, progesterone receptor, c-erbB2, Ki67, bcl-2, and gp-170 expression, the p53 status maintained an independent predictive role for cCR. Most of the tumors undergoing change in percentage of p53 expression after both treatments originally harbored mutant protein, and only four BC specimens that were p53 negative before chemotherapy became positive afterward. These data confirm in vivo the concept that the responsiveness of tumors to chemotherapy in part derives from the capability of BC cells to undergo apoptosis. The role of mutated p53 in preventing response is more evident in patients submitted to epirubicin, and this may be caused by the up-regulation of multidrug resistance gene expression by p53 inactivation. p53 is a stable phenotype and is not inducible by at least three or four chemotherapy cycles.

Prognostic value in predicting overall survival of two mucinous markers: CA 15-3 and CA 125 in breast cancer patients at first relapse of disease.

The role of circulating tumour markers in providing prognostic information has been scarcely studied. We evaluated the prognostic significance of two mucinous markers: CA 15-3 and CA 125 in 115 breast cancer patients at first recurrence of disease. At diagnosis of advanced disease bone involvement was found in 64 patients, lung in 57, skin lymph nodes in 21, liver in 20, and brain in 5. Patients were recruited and treated in the same institution with conventional chemo- or endocrine therapy. The follow-up ranged from 3 to 54+ months (median 35). Serum samples were drawn at first recurrence of disease before the start of any endocrine and/or chemotherapy. Patients with CA 15-3 < 30 U/ml survived significantly longer than those with CA 15-3 > 30 U/ml (median 50+ versus 26 months, P < 0.02). Similarly, overall survival of patients with CA 125 < 35 U/ml was significantly higher in comparison with patients with CA 125 > 35 U/ml (median 34.5 versus 18.5 months, P < 0.001). CA 125, but not CA 15-3, maintained its prognostic value in the subgroup of patients with visceral metastases. Both markers were found to be independent prognostic variables in multivariate analysis according to Cox's model. CA 15-3 and CA 125 appeared to be powerful prognostic indicators, in addition to visceral metastases, in patients with advanced breast cancer.

Multicenter Phase II trial of intermediate dose cisplatin and vinorelbine in inoperable non-small cell lung cancer patients.

Vinorelbine (VNB) and cisplatin (CDDP) combination regimen was found active in the treatment of advanced non-small cell lung cancer (NSCLC) patients, but significant toxicity was observed. We evaluated the activity and toxicity of this combination administered at lower doses than previously reported. From March 1992 to March 1994, 99 patients (pts) were enrolled in a multicentric Phase II study and received intravenous CDDP at 80 mg/m2 on day 1, associated with intravenous VNB at 25 mg/m2 on days 1 and 8. Cycles were repeated every 3 weeks. The reduced doses led to a consistently lower myelotoxicity (8% Grade III-IV leukopenia) in comparison to two related Phase III studies, recently published. Conversely, the incidence of neurological toxicity was superimposable. Considering all eligible patients, the overall response rate was 28.3%, and this is similar to the results commonly observed employing the most active CDDP containing regimens. In conclusion, CDDP and VNB combination chemotherapy at the schedule performed in the present study led to a reduction of hematologic toxicity, while an appreciable activity was maintained.

Multimodal management of stages III-IVa malignant thymoma.

PURPOSE: The optimal therapy for locally advanced malignant thymoma is controversial. We review our experience with a multimodal approach in 63 consecutive cases. PATIENTS AND METHODS: Forty-three patients had stage III and 20 stage IVa disease. Surgery with radical intent was initially performed in 30 cases, while 33 cases not amenable to radical surgery underwent neoadjuvant treatment (radiotherapy in 8 and chemotherapy in 25) before surgical reassessment. All patients, whether or not surgically resected, received radiation therapy. RESULTS: Radical resection (RR) was performed in 20 patients ab initio (all stage III) and in 12 patients after neoadjuvant treatment (eight stage III and four stage IVa). With the addition of patients radically operated with neoadjuvant treatment, the radical resection rate increased from 46 to 65% in stage III patients, and from 0 to 20% in those with stage IVa disease, respectively. Radical surgery was associated with longer progression free survival and overall survival according to both univariate analysis ( P< 0.001 and P<0.01, respectively) and multivariate analysis after adjustment for age, gender, histology and disease stage ( P<0.001 and <0.02, respectively). Progression free survival (median 56.9 months) was slightly lower in patients undergoing radical surgery after neoadjuvant approaches than in those radically resected ab initio (median not achieved), but overall survival (median not achieved) was similar in both groups. Subtotal surgical resection promoted complete response to subsequent radiation therapy. This condition significantly correlated with a better outcome. CONCLUSIONS: Complete surgical resection is an independent prognostic parameter in locally advanced thymoma treated with a multimodal approach. Preoperative treatment to increase the complete resection rate could improve the overall survival of these patients.

Paclitaxel administration on days 1 and 8 every 21 days in anthracycline-pretreated metastatic breast cancer patients. A multicenter phase II trial.

Paclitaxel is now included in second- and even first-line regimens in advanced breast cancer. The optimal dose and schedule of this drug, however, still remain a matter of investigation. A group of 57 consecutive patients with advanced breast cancer previously treated with anthracycline-containing regimens were submitted to treatment with single-agent paclitaxel administered at 130 mg/m2 on days 1 and 8 every 21 days. Of the 57 patients, 56 were fully evaluable, and of these 25 had an absolute anthracycline resistance, 14 a relative resistance and 17 were potentially sensitive. The median age of the patients was 57 years (range 33-71 years), their median performance status was 1 (0-3), and 27 (47%) had liver involvement, 17 (30%) lung involvement, 30 (53%) bone involvement and 15 (26%) skin/lymph node involvement. Toxicity was recorded in 295 cycles. This scheme was well tolerated, the dose-limiting toxicities being hematological and neurological. Grade 3/4 leukopenia was observed in 20% of patients at nadir, while grade 3 leukopenia was observed in 3% of patients at recycle. Only one patient experienced febrile neutropenia. Grade 2/3 neurotoxicity was observed in 26% of patients, leading to drug withdrawal in three. The treatment was given on an outpatient basis in all patients and the median relative dose intensity of 86.6 mg/m2 per week was 100% of the planned dose (range 75-100%). Three patients (5%) attained a complete clinical response and 12 (21%) a partial response for an overall response rate of 26% (95% confidence interval 18-38%), while 30 (53%) attained disease stabilization and 11 progressed (19%). Time to progression in responding patients was 10.3 months, and the median overall survival of the entire population was 15.4 months. To conclude, paclitaxel administration on days 1 and 8 every 21 days was active and manageable in advanced breast cancer patients previously treated with anthracyclines. The response obtained was durable.

Heparin neutralizes serum antiplasmin inhibition of peripheral blood leukocyte fibrinolytic activity.

Serum inhibition of peripheral blood fibrinolytic activity has been evaluated with the 125I-fibrin coated well method. The inhibitory activity was found in a 140,000 d serum fraction that contained alpha 2-antiplasmin. Addition of heparin to cell cultures at concentrations in the range of values obtained during anticoagulant therapy has been demonstrated to counteract such inhibitory activity. The phenomenon has been shown to be linked with plasminogen activation in the presence of fibrin, to lead to a weakening of antiplasmin activity. By clarifying an important aspect of the mechanism of heparin action, our findings support the view that heparin can be usefully employed in treating thrombotic syndromes, not only as an anticoagulant, but also as a "profibrinolytic" agent.

Evaluation by dual energy X-ray absorptiometry of changed bone density in metastatic bone sites as a consequence of systemic treatment.

Fourteen cancer patients with bone metastases from various primary malignancies were submitted to repeated dual X-ray absorptiometry (DEXA) scan before and after systemic antineoplastic treatments. In the nine patients with lytic lesions the Bone Mineral Density (BMD) increased after chemotherapy + pamidronate in four (by +11.2%, +7.5%, +5.0% and +6.6%, respectively), decreased in four (by -19.9%, -8.1%, -7.5%, and -7.0%, respectively) and remained unchanged in one. BMD changes paralleled variations in painful symptomatology and biochemical markers. In patients with blastic metastases the BMD on target metastatic lesions did not change after hormone therapy or chemotherapy in one case but showed a significant increase in four. BMD increase was associated to bone pain improvement and PSA decrease in two cases, and with a worsening in skeletal pain and/or serum PSA in the remaining two. Our data suggest that BMD evaluation by DEXA instrument may be a reliable tool in assessing the response of bone metastases to treatment.

Hypertriglyceridemia during long-term interferon-alpha therapy: efficacy of diet and gemfibrosil treatment. A case report.

Interferon-alpha might increase triglyceride serum levels through the enhancement of hepatic lipogenesis and/or inhibition of the peripheral lipoprotein lipase. Hypertriglyceridemia during interferon-alpha therapy has been only recently described, mostly in patients with previous abnormalities of lipid metabolism. The authors report here a case of a 65-year-old male bearing advanced colon carcinoma who developed hypertriglyceridemia during long-term interferon-alpha treatment in association with 5 fluorouracil administration. Hypertriglyceridemia was maintained within acceptable levels, without adjusting the treatment plan, by an appropriate diet and gemfibrosil administration.

Acute myeloblastic leukemia associated with mediastinal nonseminomatous germ cell tumors. Report on two cases.

The demonstrated association with hematologic neoplasms may partially account for the poor survival of patients with mediastinal nonseminomatous germ cell tumors (MNSGCT) compared to patients with testicular and retroperitoneal counterparts. It has been shown that the median interval from the diagnosis of MNSGCT to the diagnosis of the hematologic disorders is 6 months, which contrasts sharply with the average time of 2 to 3 years for the development of therapy-related leukemias. The 2 cases herein described, 1 male and 1 female, developed acute M2 leukemia 4 and 2 years after the diagnosis of MNSGCT. In the second patient (the first female ever described), we cannot exclude a pathogenetic role of the PEB regimen (platinum, etoposide, bleomicin), even though the total dose of etoposide administered has been demonstrated to have a mild leukemogenic potential. This is not the case of the first patient, who did not receive adjuvant chemotherapy after the radical resection of primary MNGSCT and developed the hematologic disorder a few months after local recurrence. In conclusion, the time elapsed from chemotherapy administration does not discriminate the hematologic neoplasms associated to MNGSCT from those related to therapy.

[Cryptococcosis in a female patient with angioimmunoblastic lymphadenopathy and dysproteinemia]. / Criptococcosi in una paziente affetta da linfoadenopatia angioimmunoblastica con disproteinemia.

A case of a 72-year-old woman affected by angioimmunoblastic lymphadenopathy with dysproteinemia is described. She was admitted to the hospital for serious cutaneous lesions and dementia. The patient had been treated with corticosteroids for the previous two years. Cryptococcosis was diagnosed by cutaneous biopsy. Antimycotic therapy together with corticosteroid withdrawal cured the cutaneous lesions and improved her psychiatric symptoms.

Prognostic significance of disordered calcium metabolism in hormone-refractory prostate cancer patients with metastatic bone disease.

Bone metabolic disruption that occurs in bone metastatic prostate cancer could lead to disturbances of calcium metabolism. The prognostic role of either hypocalcemia or hypercalcemia was assessed in a consecutive series of hormone-refractory bone metastatic prostate cancer patients. Serum calcium was measured in 192 patients. The presence of hypocalcemia and hypercalcemia was related with baseline biochemical and clinical characteristics and the role of these two calcium disturbances in predicting prognosis and adverse skeletal-related events (SREs) was assessed. As compared to normocalcemic patients, hypocalcemic patients (n=51) had higher tumor load in bone (P=0.005), higher plasma chromogranin A (CgA, P=0.01), serum alkaline phosphatase (P=0.01), urinary N-telopeptide (NTX, P=0.002) and lower hemoglobin values (P=0.01), while hypercalcemic patients (n=16) had higher plasma CgA (P=0.001) and serum lactate dehydrogenase values (P=0.001), higher bone pain (P=0.003) and a lower frequency of pure osteoblastic lesions (P=0.001). Hypercalcemia was significantly associated with poor prognosis: hazard ratio (HR), 1.9 (95% confidence Interval (CI) 1.2-3.3) and higher risk to develop SREs HR, 2.5 (95% CI 1.2-5.2, P=0.01), while hypocalcemia was not associated with poor prognosis. The prognostic role of hypercalcemia was maintained in multivariate analysis after adjusting for validated prognostic parameters: HR, 2.72 (95% CI 1.1-6.8, P=0.03). These data suggest that serum calcium levels should be taken into account in the clinical decision-making process of bone metastatic prostate cancer patients. Patients with asymptomatic hypercalcemia could benefit of a strict follow-up and an immediate bisphosphonate treatment. Further prospective clinical trials are needed to confirm this finding.

Long-term disease free survival in a patient with metastatic adreno-cortical carcinoma after complete pathological response to chemotherapy plus mitotane.

Adreno-cortical carcinoma (ACC) is a rare cancer with poor prognosis. Complete surgical resection of the primary tumor and, when feasible, of the local and distant metastases offers the best prospects for long-term survival; conversely, the role of systemic therapy in patients developing unresectable metastatic disease is unclear. We describe the case of a young female patient (36 yr) who presented with an androgen-releasing metastatic ACC. Treatment consisted of five courses of chemotherapy with etoposide, doxorubicin and cisplatin (EDP scheme) plus oral mitotane, which caused the complete disappearance of distant metastases and reduction of the primary tumor, as documented by serial computed tomography (CT) scans of the chest and the abdomen. Moreover, during treatment, clinical and biochemical resolution of the hypersecretory status occurred. The left adrenal gland was then removed and histopathological examination showed extensive tumor necrosis and the absence of viable cancer cells. The patient is currently alive without evidence of recurrence 3 yr after surgery. This report shows that chemotherapy plus mitotane could result in complete pathological remission, which may be a surrogate for long-term progression- free survival in metastatic ACC patients.

The role of haemoglobin level in predicting the response to first-line chemotherapy in advanced colorectal cancer patients.

The purpose of the study was to evaluate the influence of baseline haemoglobin level in predicting response to 5-fluorouracil (5FU)-based first-line chemotherapy in advanced colorectal cancer patients. Data from 631 patients were collected from three different institutions. Globally, overall response rate was 35.8% (226 out of 631). Factors influencing response rate were 5FU dose intensity (high: 43.1%, low: 34.0%, P = 0.03); oxaliplatin (yes: 45.8%, no: 22.9%, P < 0.0001), performance status (PS 0: 46.1%, 1: 28.8%, 2: 26.7%, P < 0.0001), and haemoglobin levels (> or = 12 g dl(-1): 40.4%, < 12 g dl(-1): 29.2%, P = 0.004). In subgroup analysis significant differences in response rate between anaemic and nonanaemic patients were recorded in those patients treated with infusional chemotherapies (45.7 vs 25.5%, P < 0.0001), with high 5FU dose intensity (50.3 vs 32.7%, P = 0.005), with PS = 0 (49.8 vs 37.9%, P = 0.03), and with liver metastases (44.8 vs 33.8%, P = 0.002), whereas no difference was evident in those subjects treated with bolus schedules or according to gender. Anaemia was a strong predictor for activity of first-line 5FU-based chemotherapy especially in those groups that showed the best responses, for example high performance status, infusionally treated, higher 5FU dose and those with liver secondaries. Patients with higher haemoglobin levels recorded a greater response rate and a longer time to progression and survival than anaemic subjects. Prospective evaluation of role of correcting anaemia on response to therapy is justified by these results.

Predictive factors for skeletal complications in hormone-refractory prostate cancer patients with metastatic bone disease.

Factors predictive of skeletal-related events (SREs) in bone metastatic prostate cancer patients with hormone-refractory disease were investigated. We evaluated the frequency of SREs in 200 hormone-refractory patients consecutively observed at our Institution and followed until death or the last follow-up. Baseline parameters were evaluated in univariate and multivariate analysis as potential predictive factors of SREs. Skeletal-related events were observed in 86 patients (43.0%), 10 of which (5.0%) occurred before the onset of hormone-refractory disease. In univariate analysis, patient performance status (P=0.002), disease extent (DE) in bone (P=0.0001), bone pain (P=0.0001), serum alkaline phosphatase (P=0.0001) and urinary N-telopeptide of type one collagen (P=0.0001) directly correlated with a greater risk to develop SREs, whereas Gleason score at diagnosis, serum PSA, Hb, serum albumin, serum calcium, types of bone lesions and duration of androgen deprivation therapy did not. Both DE in bone (hazard ratio (HR): 1.16, 95% confidence interval (CI): 1.07-1.25, P=0.000) and pain score (HR: 1.13, 95% CI: 1.06-1.20, P=0.000) were independent variables predicting for the onset of SREs in multivariate analysis. In patients with heavy tumour load in bone and great bone pain, the percentage of SREs was almost twice as high as (26 vs 52%, P<0.02) and occurred significantly earlier (P=0.000) than SREs in patients with limited DE in bone and low pain. Bone pain and DE in bone independently predict the occurrence of SREs in bone metastatic prostate cancer patients with hormone-refractory disease. These findings could help physicians in tailoring the skeletal follow-up most appropriate to individual patients and may prove useful for stratifying patients enrolled in bisphosphonate clinical trials.

Paclitaxel, vinorelbine and 5-fluorouracil in breast cancer patients pretreated with adjuvant anthracyclines.

We investigated the activity and toxicity of a combination of vinorelbine (VNB), paclitaxel (PTX) and 5-fluorouracil (5-FU) continuous infusion administered as first-line chemotherapy in metastatic breast cancer patients pretreated with adjuvant anthracyclines. A total of 61 patients received a regimen consisting of VNB 25 mg m(-2) on days 1 and 15, PTX 60 mg m(-2) on days 1, 8 and 15 and continuous infusion of 5-FU at 200 mg m(-2) every day. Cycles were repeated every 28 days. Disease response was evaluated by both RECIST and World Health Organization (WHO) criteria. Objective responses were recorded in 39 of 61 patients (64.0%) assessed by WHO and in 36 of 50 patients (72.0%) assessable by RECIST criteria. Complete remission occurred in 15 (24.6%) and 14 patients (28.0%), respectively. The median time to progression and overall survival of entire population was 10.6 and 27.3 months, respectively, and median duration of complete response was 14.8 months. The dose-limiting toxicity was myelosuppression (leucopenia grade 3/4 in 52.5% of patients). Grade 3/4 nonhaematologic toxicities included mucositis/diarrhoea in 13.1%, skin in 3.3% and cardiac in 1.6% of patients. Grade 2/3 neurotoxicity was observed in five patients (7.2%). The VNB, PTX and 5-FU continuous infusion combination regimen was active and manageable. Complete responses were frequent and durable.