Effects of a similar amount of regular non-structured or competitive physical activity across late adulthood: a cross-sectional study.

Introduction: Master athletes are examples of successful aging. It is not clear whether it is the competitive-oriented training or just the amount of total regular exercise that reduces the age-related decline in physiological functions. We aimed to compare health-related parameters in competitive (C) and physically active older adults (A) that performed the same weekly physical activity (PA) amount. Methods: Seventeen C and 17 A were matched for age (8 and 9 male participants under and over 70 years old respectively, for both groups) and weekly PA amount (GPAQ). Body composition, leg and arm maximal strength, balance and reaction time were measured; moreover, leg and arm exercise efficiency, estimated VO2max, and VO2/HR relationships were evaluated. Perception of life and sleep quality was also assessed through specific questionnaires (SF-36 and PSQI). The effect of group (C vs. A), age (U70 vs. O70) and their interaction was examined through a Two-Way ANOVA test. Results: C dedicated more time to vigorous PA compared to A (p = 0.03), while less to moderate daily work (p < 0.01) and active commuting (p = 0.06). C exhibited better body composition (all p < 0.05), higher leg maximal strength (p < 0.05) and a trend for elevated arm strength (p = 0.06). Reaction time, leg and arm cycling efficiency were similar in the two groups (all p > 0.05), while balance reduced in A O70. Estimated VO2max was higher for C in leg cycling (p = 0.05) and remained constant across ages (all p > 0.05). VO2/HR relationship, life and sleep quality did not differ for groups and ages. Conclusions: Regular physical exercise of about 6,000 METs/week seems to have a beneficial effect on health-related parameters, both in non-structured and competitive PA, when compared to sedentary behaviour. However, the older adults engaged in competitive training exhibit further advantages: better body composition, higher arm and leg muscle strength, and higher leg VO2max. This study highlights the importance of encouraging active lifestyles for maintaining long-term health, high levels of life quality perception and reducing age-related decline. However, vigorous training suitability needs to be verified by a team of PA specialists.

Independent, additive and interactive effects of acute normobaric hypoxia and cold on submaximal and maximal endurance exercise.

PURPOSE: To evaluate the independent and combined effects of hypoxia (FiO2 = 13.5%) and cold (- 20 °C) on physiological and perceptual responses to endurance exercise. METHODS: 14 trained male subjects ( V . O2max: 64 ± 5 mL/kg/min) randomly performed a discontinuous maximal incremental test to exhaustion on a motorized treadmill under four environmental conditions: Normothermic-Normoxia (N), Normothermic-Hypoxia (H), Cold-Normoxia (C) and Cold-Hypoxia (CH). Performance and physiological and perceptual responses throughout exercise were evaluated. RESULTS: Maximal WorkLoad (WL) and WL at lactate threshold (LT) were reduced in C (- 2.3% and - 3.5%) and H (- 18.0% and - 21.7%) compared to N, with no interactive (p = 0.25 and 0.81) but additive effect in CH (- 21.5% and - 24.6%). Similarly, HRmax and Vemax were reduced in C (- 3.2% and - 14.6%) and H (- 5.0% and - 7%), showing additive effects in CH (- 7.7% and - 16.6%). At LT, additive effect of C (- 2.8%) and H (- 3.8%) on HR reduction in CH (- 5.7%) was maintained, whereas an interactive effect (p = 0.007) of the two stressors combined was noted on Ve (C: - 3.1%, H: + 5.5%, CH: - 10.9%). [La] curve shifted on the left in CH, displaying an interaction effect between the 2 stressors on this parameter. Finally, RPE at LT was exclusively reduced by hypoxia (p < 0.001), whereas TSmax is synergistically reduced by cold and hypoxia (interaction p = 0.047). CONCLUSION: If compared to single stress exposure, exercise performance and physiological and perceptual variables undergo additive or synergistic effects when cold and hypoxia are combined. These results provide new insight into human physiological responses to extreme environments.

Oxynet: A collective intelligence that detects ventilatory thresholds in cardiopulmonary exercise tests.

The problem of the automatic determination of the first and second ventilatory thresholds (VT1 and VT2) from cardiopulmonary exercise test (CPET) still leads to controversy. The reliability of the gold standard methodology (i.e. expert visual inspection) feeds into the debate and several authors call for more objective automatic methods to be used in the clinical practice. In this study, we present a framework based on a collaborative approach, where a web-application was used to crowd-source a large number (1245) of CPET data of individuals with different aerobic fitness. The resulting database was used to train and test an artificial intelligence (i.e. a convolutional neural network) algorithm. This automatic classifier is currently implemented in another web-application and was used to detect the ventilatory thresholds in the available CPET. A total of 206 CPET were used to evaluate the accuracy of the estimations against the expert opinions. The neural network was able to detect the ventilatory thresholds with an average mean absolute error of 178 (198) mlO2/min (11.1%, r = 0.97) and 144 (149) mlO2/min (6.1%, r = 0.99), for VT1 and VT2 respectively. The performance of the neural network in detecting VT1 deteriorated in case of individuals with poor aerobic fitness. Our results suggest the potential for a collective intelligence system to outperform isolated experts in ventilatory thresholds detection. However, the inclusion of a larger number of VT1 examples certified by a community of experts will be likely needed before the abilities of this collective intelligence can be translated into the clinical use of CPET.

Disentangling the molecular mechanisms of multiple sclerosis: The contribution of twin studies.

Twin studies of disease concordance are useful to weight the relative contribution of genetic and environmental factors to the cause of common complex disorders. In multiple sclerosis (MS) different twinning rates from geographic areas at different prevalence suggested that heritable and non-heritable factors contribute in different proportions and ways to MS risk in diverse populations. This concept prompted genome-wide association studies, and the implementation of the co-twin control design, that allows stringent experimental approaches in MS-discordant identical pairs, controlling for genetic influences and many other known and unknown factors. The co-twin control design provided important clues on MS molecular model. These studies will be reviewed, focusing on those showing significant differences between affected and healthy co-twins. In some cases, differences that emerged in non-twin patients compared to matched controls were not confirmed in identical MS-discordant pairs, suggesting an 'MS subclinical trait'. Early patterns of magnetic resonance imaging and predictive biomarkers that characterize 'healthy' co-twins may be useful for the identification of a prodromal reversible phase of the disease.

Intestinal Permeability in Relapsing-Remitting Multiple Sclerosis.

Changes of intestinal permeability (IP) have been extensively investigated in inflammatory bowel diseases (IBD) and celiac disease (CD), underpinned by a known unbalance between microbiota, IP and immune responses in the gut. Recently the influence of IP on brain function has greatly been appreciated. Previous works showed an increased IP that preceded experimental autoimmune encephalomyelitis development and worsened during disease with disruption of TJ. Moreover, studying co-morbidity between Crohn's disease and MS, a report described increased IP in a minority of cases with MS. In a recent work we found that an alteration of IP is a relatively frequent event in relapsing-remitting MS, with a possible genetic influence on the determinants of IP changes (as inferable from data on twins); IP changes included a deficit of the active mechanism of absorption from intestinal lumen. The results led us to hypothesize that gut may contribute to the development of MS, as suggested by another previous work of our group: a population of CD8+CD161high T cells, belonging to the mucosal-associated invariant T (MAIT) cells, a gut- and liver-homing subset, proved to be of relevance for MS pathogenesis. We eventually suggest future lines of research on IP in MS: studies on IP changes in patients under first-line oral drugs may result useful to improve their therapeutic index; correlating IP and microbiota changes, or IP and blood-brain barrier changes may help clarify disease pathogenesis; exploiting the IP data to disclose co-morbidities in MS, especially with CD and IBD, may be important for patient care.

IFN-ß and multiple sclerosis: from etiology to therapy and back.

Several immunomodulatory treatments are currently available for relapsing-remitting forms of multiple sclerosis (RRMS). Interferon beta (IFN) was the first therapeutic intervention able to modify the course of the disease and it is still the most used first-line treatment in RRMS. Though two decades have passed since IFN-ß was introduced in the management of MS, it remains a valid approach because of its good benefit/risk profile. This is witnessed by new efforts of pharmaceutical industry to improve this line: a PEGylated form of subcutaneous IFN-ß 1a, (Plegridy(®)) with a longer half-life, has been recently approved in RRMS. This review will survey the various stages of the use of type I IFN in MS, with special attention to the effect of the treatment on the supposed viral etiologic factors associated to the disease. The antiviral activities of IFN (that initially prompted its use as immunomodulatory agent in MS), and the mounting evidences in favor of a viral etiology in MS, allowed us to outline a re-appraisal from etiology to therapy and back.

Early prediction of response by ¹8F-FDG PET/CT during preoperative therapy in locally advanced rectal cancer: a systematic review.

AIM: To assess the predictive value of fluorine-18-fluorodeoxyglucose ((18)F-FDG) positron emission tomography/computed tomography (PET/CT) in early assessing response during neo-adjuvant chemoradiotherapy (CRT) in patients with locally advanced rectal cancer. MATERIALS AND METHODS: A systematic review was performed by search of MEDLINE Library for the following terms: "rectal carcinoma OR rectal cancer", "predictive OR prediction OR response assessment OR response OR assessment", "early OR ad interim", "therapy", "FDG OR (18)F-FDG", "PET OR PET/CT". Articles performed by the use of stand-alone PET scanners were excluded. RESULTS: 10 studies met the inclusion criteria, including 302 patients. PET/CT demonstrated a good early predictive value in the global cohort (mean sensitivity = 79%; mean specificity = 78%). SUV and its percentage decrease (response index = RI) were calculated in all studies. A higher accuracy was demonstrated for RI (mean sensitivity = 82%; pooled specificity = 85%) with a mean cut-off of 42%. The mean time point to perform PET scan during CRT resulted to be at 1.85 weeks. Some PET parameters resulted to be both predictive and not statistical predictive of response, maybe due to the small population and few studies bias. CONCLUSION: PET showed high accuracy in early prediction response during preoperative CRT, increased with the use of RI as parameter. In the era of tailored treatment, the precocious assessment of non-responder patients allows modification of the subsequent strategy especially the timing and the type of surgical approach.

Effect of glatiramer acetate on disease reactivation in MS patients discontinuing natalizumab.

BACKGROUND AND PURPOSE: Multiple sclerosis (MS) patients discontinuing natalizumab are at risk of rebound of disease activity. METHODS: In the present multi-center, open-label, non-randomized, prospective, pilot study, we tested whether treatment with glatiramer acetate (GA) is safe and effective after natalizumab in MS patients. The study was performed at academic tertiary medical centers. Forty active relapsing-remitting MS patients who never failed GA therapy and who discontinued natalizumab after 12-18 months of therapy were enrolled. GA was initiated 4 weeks after the last dose of natalizumab. RESULTS: 62.5% of patients were relapse-free 12 months after GA initiation. Annualized relapse rate and time to relapse were significantly lower than before natalizumab. Notably, the frequency of relapses was significantly lower amongst those patients who had experienced ≤2 relapses the year before initiation of natalizumab therapy, compared with patients who had had three or more relapses. No evidence of rebound was observed in magnetic resonance imaging scans. Furthermore, Expanded Disability Status Scale and Multiple Sclerosis Functional Composite were stable in our patients, again suggesting that 12 months of post-natalizumab-GA therapy is not associated with clinical deterioration. CONCLUSIONS: Following discontinuation of natalizumab, 12 months of therapy with GA is safe and well tolerated in MS patients. GA can reduce the risk of early reactivation/rebound of disease activity in this setting.

The CAP-CR study: direct medical costs in Italian metastatic colorectal cancer patients on first-line infusional 5-fluorouracil or oral capecitabine.

AIM: To describe the healthcare resource consumption of metastatic colorectal cancer (MCRC) patients in the Italian healthcare setting. METHODS: A retrospective chart analysis estimating direct medical costs of first-line infusional 5-Fluorouracil (5-FU) or oral Capecitabine (CAP), associated or not with other chemotherapies, from the Italian Healthcare Service (IHCS) and Hospital (H) perspectives. RESULTS: 202 subjects were analysed. CAP patients (N=66) were older, with a more compromised clinical status and received less chemotherapy agents in association than 5-FU patients (N=136). From the IHCS perspective, mean total costs per patient were 12,029 euro and 5,781 euro in the 5-FU and CAP arms respectively; 7,338 euro and 4,688 euro from the H perspective. The infusional administration route of 5-FU was a cost driver from both perspectives. Sensitivity analyses found the results to be robust to variations in base case parameters. CONCLUSIONS: Management of MCRC by oral chemotherapies may be an economically advantageous option to both IHCS and hospitals.

Ifosfamide in thymic neoplasms.

The role of systemic chemotherapy and optimal regimen in thymic neoplasms remains uncertain, because they are rare mediastinal tumors, frequently encapsulated or noninvasive at the time of presentation and surgical excision is adequate treatment. Chemotherapy is an essential treatment modality in advanced or recurrent disease and an increased number of publications on this aspect of management has appeared in the last 10 years. Both single-agent and combination chemotherapy have demonstrated activity in the adjuvant and neoadjuvant settings. There are little data concerning the activity of ifosfamide in thymoma and further investigation of the role of this drug in combination chemotherapy regimens, particularly as an alternative to the inclusion of cyclophosphamide, is warranted.

Neoadjuvant moderately high-dose chemotherapy with rh-G-CSF in locally advanced breast carcinoma.

UNLABELLED: The poor results of local treatment for locally advanced breast carcinoma (LABC) justify the use of chemotherapy as primary treatment. Retrospective studies have shown a positive correlation between dose and response rate in advanced breast cancer. G-CSF has shown efficacy in achieving optimal dose intensity and ameliorating chemotherapy-induced myelosuppression. The aim of the present study was to assess the efficacy of a moderately high-dose chemotherapy regimen in terms of response rate, disease-free and overall survival and to assess the role of G-CSF in induced neutropenia. METHODS: Inclusion criteria were the following: age <65 years, WHO performance status <2, histologically proven breast carcinoma, adequate hematologic, renal and hepatic function, stage IIIA or IIIB disease, and no metastatic disease. No prior chemotherapy or radiotherapy was allowed. Three cycles of the following chemotherapy were used preoperatively: epirubicin (100 mg/m2 on day 1), cyclophosphamide (400 mg/m2 for 3 consecutive days) and rh-G-CSF (5 microg/kg/die from day 4 to day 12 every 14 days). After mastectomy or quadrantectomy plus radiotherapy, all patients were treated with 4 courses of adjuvant chemotherapy according to the CMF 1-8 schedule (methotrexate, 40 mg/m2 cyclophosphamide, 600 mg/m2; fluorouracil, 600 mg/m2; all on days 1 and 8, with recycle every 4 weeks). RESULTS: From May 1992 to June 1996, 57 patients with histologically proven LABC were preoperatively treated. Forty-four patients were premenopausal and 13 postmenopausal; the median age was 45 years (range, 29-64). Thirty-five patients had stage IIIA and 22 patients stage IIIB disease (7 with inflammatory disease). Forty-seven patients underwent radical mastectomy and 10 conservative surgery. A clinical response was noted in 93% (95% confidence interval, 83-98%) of patients (12% complete responses and 81% partial responses); 2 pathological complete remissions (3.5%) were obtained. No toxic deaths were observed. All patients had a follow-up of at least 42 months. The overall 5-year survival rate was 76% (standard error--SE), 6%) and the 5-year disease-free survival rate was 68% (SE, 6.3%). CONCLUSIONS: The 14-day regimen was well tolerated and effective in LABC patients, although not superior to standard-dose chemotherapy. To improve results the use of new drugs in controlled clinical trials seems warranted.

Preoperative combined radiotherapy and chemotherapy for middle and lower rectal cancer: preliminary results.

BACKGROUND: Adjuvant treatment for rectal cancer is still controversial. This study reports on overall survival and disease-free survival, toxicity, downstaging, and surgical morbidity in rectal cancer patients who received combined chemoradiation therapy followed by curative surgery. METHODS: Between 1993 and 1998, 51 patients (31 males and 20 females; median age, 60 years; range, 33-73 years) underwent chemoradiation therapy followed by radical surgery for middle and lower rectal adenocarcinoma. Criteria for giving preoperative radiotherapy (total 45 Gy in 25 fractions of 1.8 Gy/day for 5 weeks) and chemotherapy (5-fluorouracil 350 mg/m2/day and leucovorin 10 mg/m2/day, bolus on days 1-5 and 29-33) were an age younger than 75 years; an Eastern Cooperative Oncology Group performance status score of 0 to 2; and clinical preoperative stage II-III. Forty-three low anterior and eight abdominoperineal resections were performed. Median follow-up time was 29 (range, 3-63) months. RESULTS: Although grade 3 to 4 toxicity occurred in 14 cases (27.4%), all patients completed the planned adjuvant therapy. At pathology, a complete response was found in eight (15.7%) cases. Of the remaining 43 cases, 22 were stage I, 12 were stage II, and 9 were stage III. Five-year actuarial disease-free survival and overall survival rates were 86.4% and 85.5%, respectively. Whereas no local recurrences were found, 4 patients had distant metastases. Three patients died (1 of cancer-related causes), 45 are alive and disease free, and 3 are alive with disease. CONCLUSIONS: The combined preoperative chemoradiation approach used by us seems to improve the disease-free survival and overall survival of selected patients with rectal cancer. However, a longer follow-up time is required to confirm these preliminary results.

Preoperative combined radiotherapy and chemotherapy for rectal cancer does not affect early postoperative morbidity and mortality in low anterior resection.

PURPOSE: It is not yet known whether preoperative combined radiotherapy and chemotherapy for rectal cancer affects postoperative mortality and morbidity. We therefore evaluated early postoperative complications in patients given adjuvant radiotherapy and chemotherapy before surgery for middle and lower rectal adenocarcinoma. METHODS: Between 1994 and 1998, 41 patients underwent combined preoperative pelvic radiotherapy and chemotherapy at our institution. Most of the patients had 45 Gy (1.8 Gy/day/25 fractions) during five weeks plus 5-fluorouracil (350 mg/m2/day) and low-dose leucovorin (10 mg/m2/day) bolus on Days 1 to 5 and 29 to 33. Surgery was performed four to six weeks after completion of adjuvant therapy. The 41 patients (Group A) were retrospectively compared with 30 patients (Group B) who, in the same period, underwent surgery without preoperative adjuvant therapy. The groups were homogeneous for age, gender, preoperative risk factors, operating surgeon, and pathologic stage. Mean distance of the tumor from the anal verge was shorter in Group A patients (P = 0.031). RESULTS: There were seven major postoperative complications in each group. No significant differences were found between the groups for morbidity and mortality rates. Considering all patients, more postoperative complications were found in patients scored as American Society of Anesthesiologists 3, in those with a preoperative hemoglobin value < 10 g/dl, and in those without a diverting stoma (P = 0.0048, P = 0.0453, and P = 0.0033, respectively). At multivariate analysis, independent predictors of major complications were American Society of Anesthesiologists score (relative risk, 343; P = 0.022), diverting stoma (relative risk, 159; P = 0.010), type of surgical procedure (relative risk, 38.9; P = 0.048), preoperative hemoglobin value (relative risk, 9.72; P = 0.061), and intraoperative blood loss (relative risk, 1; P = 0.027). In Group A patients, the absence of diverting stomas was associated with major postoperative complications (P = 0.0307), and independent predictors of major complications were American Society of Anesthesiologists score (relative risk, 56; P = 0.111) and absence of a diverting stoma (relative risk, 22.42; P = 0.222). CONCLUSION: Early postoperative complications after resection for middle and lower rectal adenocarcinoma are affected by intraoperative and preoperative risk factors and absence diverting stomas, but not by preoperative adjuvant therapy.

Letrozole, a new oral aromatase inhibitor for advanced breast cancer: double-blind randomized trial showing a dose effect and improved efficacy and tolerability compared with megestrol acetate.

PURPOSE: To compare two doses of letrozole and megestrol acetate (MA) as second-line therapy in postmenopausal women with advanced breast cancer previously treated with antiestrogens. PATIENTS AND METHODS: Five hundred fifty-one patients with locally advanced, locoregionally recurrent or metastatic breast cancer were randomly assigned to receive letrozole 2.5 mg (n = 174), letrozole 0.5 mg (n = 188), or MA 160 mg (n = 189) once daily in a double-blind, multicenter trial. Data were analyzed for tumor response and safety variables up to 33 months of follow-up evaluation and for survival up to 45 months. RESULTS: Letrozole 2.5 mg produced a significantly higher overall objective response rate (24%) compared with MA (16%; logistic regression, P = .04) or letrozole 0.5 mg (13%; P = .004). Duration of objective response was significantly longer for letrozole 2.5 mg compared with MA (Cox regression, P = .02). Letrozole 2.5 mg was significantly superior to MA and letrozole 0.5 mg in time to treatment failure (P = .04 and P = .002, respectively). For time to progression, letrozole 2.5 mg was superior to letrozole 0.5 mg (P = .02), but not to MA (P = .07). There was a significant dose effect in overall survival in favor of letrozole 2.5 mg (P = .03) compared with letrozole 0.5 mg. Letrozole was significantly better tolerated than MA with respect to serious adverse experiences, discontinuation due to poor tolerability, cardiovascular side effects, and weight gain. CONCLUSION: The data show letrozole 2.5 mg once daily to be more effective and better tolerated than MA in the treatment of postmenopausal women with advanced breast cancer previously treated with antiestrogens.

Prognostic factors in resectable gastric cancer: results of EORTC study no. 40813 on FAM adjuvant chemotherapy.

BACKGROUND: The high incidence of locoregional recurrences and distant metastases after curative surgery for gastric cancer calls for improved locoregional control and systemic adjuvant treatment. METHODS: In a randomized clinical trial on adjuvant FAM2 chemotherapy, quality of surgery was evaluated by comparing surgical and pathology data. Univariate and multivariate analysis was made to evaluate the effect of prognostic factors on survival and time of recurrence in relation to patients, tumor, and therapy. RESULTS: Of 314 patients randomized from 28 European institutions, 159 comprised the control and 155 the FAM2 group. After a median follow-up of 80 months, no statistically significant difference was found between survivals. However, for recurrence time, treated patients had a significant advantage over controls (p = 0.02). At univariate analysis, statistically significant differences in survival and time to progression emerged for T, N, disease stage and "adequacy" of surgery. The multivariate analysis retained preoperative Hb level, T, N, and "adequacy" of surgery for time of survival; and T, N, "adequacy" of surgery and adjuvant chemotherapy for recurrence time. CONCLUSIONS: Disease stage is the most important prognostic factor. "Adequate" surgery has an important effect. Adjuvant FAM2 delayed time of recurrence, but did not influence overall survival.

Combination goserelin and tamoxifen therapy in premenopausal advanced breast cancer: a multicentre study by the ITMO group. Italian Trials in Medical Oncology.

It has been suggested that tamoxifen may improve the efficacy of medical castration with luteinising hormone-releasing hormone analogues, but very few data have so far been published concerning the clinical and endocrinological activity of this therapeutic modality. In this phase II multicentre trial conducted by the Italian Trials in Medical Oncology group (ITMO), 64 premenopausal patients with hormone receptor-positive or unknown breast cancer were treated with monthly s.c. injections of goserelin 3.6 mg, in association with a tamoxifen daily dose of 20 mg, as first-line therapy for their advanced disease. All of the patients were evaluable for efficacy and there was an overall response rate of 41% (95% confidence interval 28-52%), with 7 of the 26 responders achieving complete remission. The median time to response was 4 months (range 2-17), and the median response duration was 13 months (range 6-37 +). Better responses were observed in soft tissues (51%); the response in visceral and bone metastases was respectively 19% and 37%. Serum concentrations of gonadotrophins and oestradiol were significantly decreased by the treatment, oestrogen levels being constantly suppressed to within the range observed in post-menopausal women. No significant change was detected in serum testosterone levels. In our experience, although it was not associated with any increased clinical efficacy, the concurrent use of goserelin and tamoxifen proved to be a feasible approach in the management of premenopausal advanced breast cancer.

Phase II study on neoadjuvant hyperthermic-antiblastic perfusion with doxorubicin in patients with intermediate or high grade limb sarcomas.

BACKGROUND: Locoregional control of soft tissue sarcomas of the limbs is achieved generally using a multidisciplinary approach consisting of conservative surgery combined with radiation therapy, intraarterial chemotherapy, or hyperthermic antiblastic perfusion (HAP). Before surgery, HAP seems to be the more suitable tool in decreasing tumor mass and allowing limb-sparing surgery. The authors' aim was to ascertain the activity of HAP with doxorubicin against intermediate or high grade limb tumors. METHODS: In 23 patients with limb sarcomas (2 patients International Union Against Cancer Stage IIA, 4 stage IIB, 1 stage IIIA, 11 stage IIIB, and 5 stage IVB) doxorubicin was administered via HAP 4-6 weeks before surgery. The drug (bolus, 0.7-1.4 mg/kg) was perfused for 60 minutes with a tumor temperature of at least 40.5 degrees C (range, 40.5-42.6 degrees). Tumor necrosis was then assessed radiologically and pathologically. RESULTS: Systemic toxicity was hematologic grade (G) 2 in 2 patients, gastrointestinal (hepatic) in 6, G1 in 2, G2 in 3, and G3 in 1; 2 patients had alopecia; locoregional toxicity (graded according to Wieberdink) was G1 or G2 in 18, G3 in 4, and G4 in 1. Tumor necrosis was more than 50% in 17 patients (74%). Limb-sparing surgery was feasible in 20 patients (91%). At present, 14 patients are alive. Six had local recurrences, and eight had distant metastases. CONCLUSIONS: Our findings show that HAP with doxorubicin is an active and well-tolerated procedure within a multidisciplinary approach to treatment of limb sarcomas.

Chemotherapy and operation for invasive thymoma.

Sixteen patients with invasive thymoma (stage III and stage IVA) were treated with chemotherapy and then operation. All tumors were considered nonresectable after first staging, and patients were treated with the following chemotherapy in 4-day courses, administered intravenously: cisplatin (50 mg/m2) and doxorubicin (40 mg/m2) on day 1, vincristine (0.6 mg/m2) on day 3, and cyclophosphamide (700 mg/m2) on day 4. The courses were repeated every 3 weeks, and toxic effects were well tolerated. Seven patients (43%) had a complete remission, and nine patients (57%) had a partial remission, with an overall complete remission plus partial remission rate of 100%. After chemotherapy all patients underwent operation. We performed 12 sternotomies and four posterolateral thoracotomies. At operation 11 patients had radical resection and five had partial resection. We administered radiotherapy in 11 patients who had histologically demonstrated tumor after operation. In five patients, the specimen showed only fibrosis; these patients received three cycles of chemotherapy but not radiotherapy. Median survival was 66 months with a 3-year survival of 70%. We believe that neoadjuvant chemotherapy with surgical intervention is justified for advanced invasive thymoma; a longer follow-up and a larger number of patients will determine the impact of this treatment on long-term survival.

Deflazacort and fluoximesterone in advanced, pretreated breast cancer.

A very simple, low dose, orally administered regime (10 to 15 mg of fluoximesterone + 6 mg of deflazacort daily for periods of 1 to several months) resulting in mild-acceptable toxicity (essentially some weight gain) determined subjective improvement in 2/3 of 34 evaluable patients (out of 36 treated) and an objective measurable tumor reduction in 1/3, although most patients had been previously treated with chemotherapy and hormone treatment and proved primarily or secondarily refractory. The receptor status at the beginning of fluoximesterone+deflazacort treatment was not known, except in one negative-receptor patient, who responded to the combination after becoming resistant to tamoxifen (see photo). In some patients the condition of hormone refractoriness would suggest a no-treatment policy, but a trial with this regime is always convenient as it may improve both duration and quality of life.

Prospective controlled trial with antiestrogen drug tamoxifen in patients with unresectable hepatocellular carcinoma.

Clinical and experimental evidence indicates that estrogens are involved in the control of hepatocyte proliferation both in normal and in neoplastic conditions. Thirty-two cirrhotic patients with unresectable or otherwise untreatable hepatocellular carcinoma were allocated to receive either tamoxifen (30 mg/day) or no treatment. The patients in the two groups were matched for age, male/female ratio, Child-Pugh class, approximate tumor volume (US and CT scan), and etiology of the underlying cirrhosis. Survival of the tamoxifen-treated patients (life-table, Wilcoxon-Breslow) was significantly prolonged (P = 0.0038), with 35% (vs 0%) survival at 12 months. No difference was observed between males and females or between alcoholic and nonalcoholic cirrhosis. In 40% of tamoxifen-treated patients, the levels of alpha-fetoprotein declined. In conclusion, the antiestrogen tamoxifen appears to be effective in the palliative treatment of hepatocellular carcinoma. An initial decline in alpha-fetoprotein levels may represent an early favorable prognostic sign.