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.

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.

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.

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.

Chemotherapy of invasive thymoma.

Thirty-two patients with stage III or IV invasive thymoma (14 women and 18 men; median age, 40 years) were treated at the Padua Medical Oncology Department from 1977 to 1988. All patients received the following chemotherapy in 4-day courses: 50 mg/m2 of cisplatin intravenously (IV) and 40 mg/m2 of doxorubicin IV on day 1; 0.6 mg/m2 of vincristine IV on day 3; and 700 mg/m2 of cyclophosphamide IV on day 4 (ADOC). The courses were repeated every 3 weeks, and toxic effects were tolerable. The radiologically defined overall clinical response rate (complete plus partial response) was 91% with 47% clinical complete remissions; median time to progression was 11 months (range, 0 to 96) and the median estimated (Kaplan-Meier) progression-free interval was 22 months. Five of the 15 clinical complete remissions were pathologically confirmed at thoracotomy. We believe the ADOC regimen qualifies for adjuvant and preoperative treatment of invasive thymoma due to the high complete response and overall response rates.

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.

Phase III randomized study of fluorouracil, epirubicin, and cyclophosphamide v fluorouracil, doxorubicin, and cyclophosphamide in advanced breast cancer: an Italian multicentre trial.

From February 1983 to January 1985, 497 patients with advanced breast cancer were randomly allocated to receive either epirubicin or doxorubicin in the following combination chemotherapy regimen: fluorouracil (5-FU) 500 mg/m2 intravenous (IV) on days 1 and 8; epirubicin or doxorubicin 50 mg/m2 IV on day 1; cyclophosphamide 500 mg/m2 IV on day 1 (FEC or FAC). Cycles were repeated every 21 days until progression or to cumulative doses of 700 mg/m2 for epirubicin and 550 mg/m2 for doxorubicin. Dose reductions were applied according to the standard criteria. Activity was evaluated in 443 patients (222 in the FEC arm and 221 in the FAC arm). The two experimental groups were comparable in age, performance status, menopausal status, histology, previous treatments, and site of the disease. The overall response rate (complete response and partial response [CR + PR]) was not significantly different: 53.6% for FEC and 56.5% for FAC. The median time to progression was 273 days for FEC and 314 days for FAC; the median survival time was 591 and 613 days, respectively. Leukopenia, anemia, nausea, and vomiting were significantly lower in patients treated with FEC. As for cardiotoxicity, four cases of congestive heart failure (CHF) were recorded among patients treated with FAC while only one was observed in the FEC group. These results indicate that epirubicin in a combination chemotherapy regimen is as active as doxorubicin and is significantly less toxic.

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.

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.

Response and toxicity of cisplatin and 120-h 5-fluorouracil infusion in pretreated and untreated patients with advanced epidermoid cancer of the head and neck.

Eighty-two patients with advanced or recurrent squamous cell carcinoma of the head and neck were treated with bolus cisplatin and 120-h infusion of 5-fluorouracil. Among 49 pretreated patients, there were 9 complete and 12 partial responses, for an overall response rate of 43% and a median estimated survival of 8 months. Hematologic toxicity in this group was relevant, with 4 early deaths and 30% of cases with moderate to severe leukopenia; mucosal and renal toxicities were also important. Among 33 patients with no prior therapy, there were 8 complete and 17 partial responses, for an overall response rate of 76%. Fifteen of the 25 responding patients received subsequent locoregional treatment. The median estimated survival in this group was 29 months. Hematologic, mucosal, and renal toxicities were only mild to moderate. Episodes of possible 5-fluorouracil-related cardiotoxicity were recorded in both pretreated and untreated patients. Twelve of 41 partial responses observed after the second cycle of therapy were converted to complete responses with a third (8 cases) and also a fourth (4 cases) course. This study confirmed that cisplatin plus 5-fluorouracil is a first-choice combination in previously untreated patients. Definitive evidence that chemotherapy can favorable influence survival awaits confirmation by randomized trials, using a control arm with conventional locoregional treatment. In previously treated patients with recurrent disease, less intensive regimens not requiring hospitalization seem more useful for the quality of life.

Modulating fluorouracil with different drugs: the Padua experience.

Several clinical experiences from Padua, Italy confirm that 5-fluorouracil may be usefully modulated by the addition of leucovorin, and especially by platinum and alpha interferon. The intra-arterial and intraperitoneal administration of such synergistic combinations has also proved to be of benefit in special subsets of patients. Perspectives of further studies are examined.

Tamoxifen treatment for advanced renal cell cancer.

Twelve patients with metastatic clear cell renal cancer received a course of tamoxifen. Three showed stable disease for a period from 2 to 12 months and 1 a mixed response for a short time. It does not appear that tamoxifen may be a useful agent in the treatment of metastatic renal cell carcinoma.

FAM2 regimen in disseminated gastric cancer.

Forty-four previously untreated patients with advanced inoperable and/or disseminated gastric carcinoma were given an i.v. combination (FAM2) chemotherapy of 5-fluorouracil, 400 mg/m2 on days 1, 2 and 3, and 21, 22 and 23; adriamycin, 40 mg/m2 on days 2 and 22; and mitomycin C, 10 mg/m2 on day 1, with a recycle on day 42 (1 cycle = 41 days). Forty patients have completed 2 cycles and are evaluable (median number of cycles 5; range 3 to 8): 26 of these achieved a partial remission, with a response rate of 65%; 4 (10%) gained a stable situation for 3 to 6 months, and 10 (25%) showed progression of disease. Median duration of partial remissions was 10 months, and median survival was 15 months for responders and 5 months for nonresponders. A fall in WBC (less than 2500/microliter) occurred in 7% and of platelets (less than 80,000/microliter) in 4.5%. Total alopecia occurred in 20 of 40 patients and nausea and or weakness were common findings. No drug-related infection, bleeding or death was observed. Patients with advanced gastric carcinoma can derive useful palliation from FAM2 chemotherapy.

[Toxicity of high-dose bleomycin administered by continuous infusion]. / Tossicità della bleomicina somministrata in infusione continua ad alte dosi.

Fifteen patients with nonseminomatous testicular cancer underwent multidrug treatment which included cis platinum, Velban and bleomycin. The latter drug was administered in monthly 5 day courses of 100 mg/m2. No impairment of antitumor effect resulted since 12 of 15 patients had remissions (10 complete and 2 partial). Pulmonary toxicity was practically abolished: a median dose of 675 mg per patient (range 450 to 1050) was followed by normal lung X-ray and normal or near normal functional parameters after completing treatment. Median arterial oxygen pressure was 78 mm Hg (range 62 to 89), and median Tiffeneau index was 84 (range 64 to 87). Only 2 of 15 patients had skin marks from bleomycin toxicity at the end of treatment, so that cutaneous toxicity was also very low. Oral mucosa reversible damage was prominent in 2 patients. On the contrary, alopecia was a common finding.

Alpha-2 interferon and 5-fluorouracil in advanced colorectal cancer.

A total of 21 untreated patients (5 males, 16 females; median age, 55 years; range, 28-72) with advanced measurable colorectal carcinoma were treated with an association of 5-fluorouracil (1000 mg/weekly) and alpha-2 interferon (three times a week s.c.: 6 x 10(6) U in the 1st month, 9 x 10(6) U in the 2nd month, 12 x 10(6) U in the 3rd month and then 18 x 10(6) U) until maximum response or progression of disease. Sites of disease involved liver in 10 patients, lung in 6, supraclavicular lymph nodes in 3, skin in 1, abdomen in 4, and vagina in 1 patient. Nine responses (42.8%) were documented (4 complete and 5 partial) with metastases confined to the liver, lung, nodes and skin. Median duration of response was 11 months (range, 4-17+) and median survival was 10 months (range, 2-17+). Side effects (fever, flu-like syndrome and leukopenia) required a dose reduction of 5-fluorouracil in 8 patients and interferon in 2 patients.

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.

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.

High-dose medroxyprogesterone in disseminated breast cancer. Correlation between bioavailability and clinical response.

Clinical response to high-dose medroxyprogesterone (MPA), administered following three different routes of administration (i.m., p.o. + i.m., p.o.) and monitoring drug plasma levels, was evaluated in pretreated advanced breast cancer patients. Fifty-eight of 68 eligible patients were considered evaluable for response. Age ranged between 36 years and 82 years. Fifty-six of 58 evaluable patients were postmenopausal. An overall remission rate of 48% was achieved with i.m. MPA, 50% with combined (i.m. + p.o.) modalities; only a 19% remission rate was recorded in the p.o. group. Response rate and MPA plasma concentrations were correlated, and a drug level of 80 ng/ml, by means of a GLC method, seems to identify a subset of patients with high probability of response. Only mild toxic effects were recorded.