Muscle protein anabolism in advanced cancer patients: response to protein and amino acids support, and to physical activity.

In the field of oncology, it is well recognized that a decrease in mass, density, strength, or function of skeletal muscle is associated to increased treatment toxicities and postoperative complications, as well as poor progression-free survival and overall survival. The ability of amino acids to stimulate protein synthesis in cancer patients is reduced. Considering nutritional intervention, this anabolic resistance could be in a part counteracted by increasing protein or by giving specific amino acids. In particular, Leucine might counteract this anabolic resistance not only by increasing substrate availability, but also by directly modulating the anabolic signal pathway. Few studies showed the possibility of increasing muscle protein synthesis by specific nutriments and/or by increasing amino acids or protein administration. In addition, whereas many studies provide evidence of a benefit of adapted physical activity in advanced cancer patients, it is difficult to specify the most appropriate type of exercise, and the optimum rhythm and intensity. Moreover, the benefits of physical activities and of protein support seem greater when it is started at the precachexia stage rather than at the cachexia stage, and their benefits are limited or nonexistent at the stage of refractory cachexia. Future approaches should integrate the combination of several complementary treatments in order to prevent (or improve) cachexia and/or sarcopenia in cancer patients.

Muscle protein anabolism in advanced cancer patients: response to protein and amino acids support, and to physical activity.

In the field of oncology, it is well recognized that a decrease in mass, density, strength, or function of skeletal muscle is associated to increased treatment toxicities and postoperative complications, as well as poor progression-free survival and overall survival. The ability of amino acids to stimulate protein synthesis in cancer patients is reduced. Considering nutritional intervention, this anabolic resistance could be in a part counteracted by increasing protein or by giving specific amino acids. In particular, Leucine might counteract this anabolic resistance not only by increasing substrate availability, but also by directly modulating the anabolic signal pathway. Few studies showed the possibility of increasing muscle protein synthesis by specific nutriments and/or by increasing amino acids or protein administration. In addition, whereas many studies provide evidence of a benefit of adapted physical activity in advanced cancer patients, it is difficult to specify the most appropriate type of exercise, and the optimum rhythm and intensity. Moreover, the benefits of physical activities and of protein support seem greater when it is started at the precachexia stage rather than at the cachexia stage, and their benefits are limited or nonexistent at the stage of refractory cachexia. Future approaches should integrate the combination of several complementary treatments in order to prevent (or improve) cachexia and/or sarcopenia in cancer patients.

[Pulmonary tumor thrombotic microangiopathy]. / Microangiopathie thrombotique tumorale pulmonaire.

Pulmonary tumor thrombotic microangiopathy syndrome is a rare clinicopathological entity in which tumor cell micro-emboli in the pulmonary microcirculation induced thrombotic microangiopathy. This can cause respiratory failure, and acute or sub-acute right heart failure. Histological features include micro tumor emboli in the small arteries and arterioles of the lung associated with thrombus formation and fibro-cellular and fibro-muscular intimal proliferation. The diagnosis is however extremely difficult to make before death. Thus, most of the observations reported are based on autopsy data. Very rare diagnostic observations made before death suggest the potential effectiveness of chemotherapy. Many details remain to be elucidated, interdisciplinary research is a priority with close collaboration between pathologists and clinicians to better understand this, often fatal, syndrome. It may be that the use of targeted therapies will improve the very poor prognosis allowing survival of several weeks or months after diagnosis.

Seasonal changes in the incidence of Escherichia coli bloodstream infection: variation with region and place of onset.

Previous research has shown that Escherichia coli infection rates peak in the summer; however, to date there has been no investigation as to whether this is seen in both hospital and community-onset cases, and how this differs across regions. We investigated and quantified E. coli bloodstream infection (BSI) seasonality. A generalized additive Poisson model was fitted to mandatory E. coli BSI surveillance data reported in England. There was no impact of seasonality in hospital-onset cases; however, for the community-onset cases, there was statistically significant seasonal variation over time nationally. When examined regionally, seasonality was significant in the North of England only. This variation resulted in an absolute increase of 0.06 (95% CI 0.02-0.1) cases above the mean (3.25) in each hospital trust for each week of the peak summer season, and a decrease of (-) 0.07 (95% CI -0.1 to -0.03) in the autumn. We estimate that fewer than one hospital bed-day per week per hospital is lost because of seasonal increases during the summer. Our findings highlight the need to understand the distinct community and hospital dynamics of E. coli BSI, and to explore the regional differences driving the variation in incidence, in order to design and implement effective control measures.

Low skeletal muscle is associated with toxicity in patients included in phase I trials.

BACKGROUND: Low muscle mass has been associated with chemotherapy toxicity. We conducted this prospective study to evaluate the effects of body composition on the occurrence of toxicity in phase I trials. PATIENTS AND METHODS: Patients were consecutively enrolled irrespective of the type of tumor or the type of drug. The Skeletal Muscle Index (SMIndex) and visceral and subcutaneous adipose tissue were assessed with computed tomography imaging by measuring cross-sectional areas of the tissues (cm(2)/m(2)). Dose-limiting toxicity (DLT) corresponded to toxicities occurring during the 1(st) cycle that necessitated dose reduction, postponement or interruption of drug administration and severe toxicity events (STE) corresponded to DLT or permanent treatment withdrawal due to toxicity. RESULTS: 93 patients were evaluated. Ten percent of patients experienced DLT and had a lower SMIndex: 40.8 ± 4.6 vs. 48.1 ± 9.6 cm(2)/m(2) (p = 0.01). STE occurred in 14 % of the patients. The only factor associated with STE was a low SMIndex: 42.4 ± 5.8 vs. 48.4 ± 9.7 cm(2)/m(2) (p = 0.02). STE were observed in 25.5 % of the patients when the SMIndex was below the median value compared to 6.5 % of patients with a high SMIndex (p = 0.02). CONCLUSION: Muscle mass is a critical predictor of severe toxicity events in phase I patients, suggesting that sarcopenia may be considered in assessing patients for eligibility of phase-1 studies.

[Managing nutritional support in thoracic oncology]. / Spécificités de la prise en charge nutritionnelle en oncologie thoracique.

INTRODUCTION: Cancer treatments are based on specific anticancer chemotherapy. However, there is increasing interest in general aspects of care, which are increasingly evidence based. STATE OF THE ART: The importance of muscle mass is becoming increasingly evident. Its role is not only limited to the maintenance of physical performance and quality of life. In oncology, recent studies have shown a close link between sarcopenia (low muscle mass) and mortality as well as between sarcopenia and chemotherapy toxicity. To treat malnutrition and the lack of energy intake, nutritional support is considered, whether through the prescription of oral nutritional supplements, enteral nutrition or even parenteral nutrition. Scientific arguments are often absent and few studies have been carried out in patients with lung cancer. PERSPECTIVES: There are many experimental arguments and a few clinical trials that support using omega 3 fatty acids to modulate inflammatory reaction and to reduce its consequences on muscular proteolysis. The benefit of regular physical activity has already been proven in chronic respiratory disease and its use in association with nutritional support must be recommended in oncologic care. CONCLUSION: Given the increasing recognition of the role of muscle mass in cancer, the purpose of any nutritional support must be focused on increasing muscle anabolism and decreasing proteolysis.

Impact of Caesarean section on subsequent fertility: a systematic review and meta-analysis.

STUDY QUESTION: Is there an association between a Caesarean section and subsequent fertility? SUMMARY ANSWER: Most studies report that fertility is reduced after Caesarean section compared with vaginal delivery. However, studies with a more robust design show smaller effects and it is uncertain whether the association is causal. WHAT IS KNOWN ALREADY: A previous systematic review published in 1996 summarizing six studies including 85 728 women suggested that Caesarean section reduces subsequent fertility. The included studies suffer from severe methodological limitations. STUDY DESIGN, SIZE, DURATION: Systematic review and meta-analysis of cohort studies comparing subsequent reproductive outcomes of women who had a Caesarean section with those who delivered vaginally. PARTICIPANTS/MATERIALS, SETTING, METHODS: Searches of Cochrane Library, Medline, Embase, CINAHL Plus and Maternity and Infant Care databases were conducted in December 2011 to identify randomized and non-randomized studies that compared the subsequent fertility outcomes after a Caesarean section and after a vaginal delivery. Eighteen cohort studies including 591 850 women matched the inclusion criteria. Risk of bias was assessed by the Newcastle-Ottawa scale (NOS). Data extraction was done independently by two reviewers. The meta-analysis was based on a random-effects model. Subgroup analyses were performed to assess whether the estimated effect was influenced by parity, risk adjustment, maternal choice, cohort period, and study quality and size. MAIN RESULTS AND THE ROLE OF CHANCE: The impact of Caesarean section on subsequent pregnancies could be analysed in 10 studies and on subsequent births in 16 studies. A meta-analysis suggests that patients who had undergone a Caesarean section had a 9% lower subsequent pregnancy rate [risk ratio (RR) 0.91, 95% confidence interval (CI) (0.87, 0.95)] and 11% lower birth rate [RR 0.89, 95% CI (0.87, 0.92)], compared with patients who had delivered vaginally. Studies that controlled for maternal age or specifically analysed primary elective Caesarean section for breech delivery, and those that were least prone to bias according to the NOS reported smaller effects. LIMITATIONS, REASONS FOR CAUTION: There is significant variation in the design and methods of included studies. Residual bias in the adjusted results is likely as no study was able to control for a number of important maternal characteristics, such as a history of infertility or maternal obesity. WIDER IMPLICATIONS OF THE FINDINGS: Further research is needed to reduce the impact of selection bias by indication through creating more comparable patient groups and applying risk adjustment.

Poor prognosis nonseminomatous germ-cell tumours (NSGCTs): should chemotherapy doses be reduced at first cycle to prevent acute respiratory distress syndrome in patients with multiple lung metastases?

BACKGROUND: Patients with extensive lung metastases from nonseminomatous germ-cell tumours (NSGCTs) and dyspnoea at presentation are at high risk of acute respiratory distress syndrome (ARDS) and death within the first weeks after chemotherapy induction. This syndrome is linked to acute intra-alveolar haemorrhage related to early tumour necrosis, which in turn, can be complicated by pulmonary infection promoted by neutropenia. The management of these patients was modified at Institut Gustave Roussy in 1997 to try to avoid this complication. PATIENTS AND METHODS: Data concerning all patients with lung metastases from NSGCT and dyspnoea or a partial pressure of oxygen (pO(2)) <80 mmHg treated from 1980 to 2006 in our institution were collected. Patients were treated in a specialised intensive care unit. From 1980 to 1997, the first chemotherapy cycle consisted in a full-dose regimen. After 1997, a 3-day reduced induction regimen of EP (cisplatin 20 mg/m(2)/day and etoposide 100 mg/m(2)/day) was used, with bleomycin and two additional days of EP being postponed to day 15, with the regular BEP regimen being started at day 21. RESULTS: Twenty-five patients with poor-risk disseminated NSGCT according to the International Germ Cell Consensus Classification Group had extensive lung metastases plus dyspnoea at presentation (n = 6), a pO(2) <80 mmHg (n = 2), or both criteria (n = 17). Median human chorionic gonadotrophin was 200 000 UI (range 11-8 920 000), and 18 of 25 (72%) patients also had nonpulmonary visceral metastases. During the 1980-1997 period, 13 of 15 patients (87%) developed ARDS, 10 of whom died, and only 4 of 15 (27%) patients were long-term survivors. In contrast, during the 1997-2006 period, only 3 of 10 patients (30%) developed ARDS (P = 0.01), 2 of whom died, and 4 of 10 (40%) eventually survived. CONCLUSION: Initial reduction of chemotherapy doses during the first cycle of chemotherapy for poor prognosis NSGCT with extensive lung metastases seems to prevent the risk of early death due to ARDS.

Prevalence, risk factors and clinical implications of malnutrition in French Comprehensive Cancer Centres.

BACKGROUND: This epidemiological observational study aimed at determining the prevalence of malnutrition in non-selected adults with cancer, to identify risk factors of malnutrition and correlate the results with length of stay and 2-month mortality. METHODS: This prospective multicentre 1-day study conducted in 17 French Comprehensive Cancer Centres included 1545 patients. Body mass index (BMI), weight loss (WL) in the past 6 months and age were routinely recorded according to the French national recommendations for hospitalised patients; malnutrition was rated as absent, moderate or severe according to the level of WL and BMI. Age, sex, tumour site, type of hospitalisation and treatment, disease stage, World Health Organisation performance status (PS) and antibiotic therapy were the potential malnutrition risk factors tested. Follow-up at 2 months allowed to determine the correlation with length of stay and mortality. RESULTS: Malnutrition was reported in 30.9% of patients, and was rated as severe in 12.2%. In multivariate analysis, only pre-existing obesity (BMI> or =30), PS > or =2 and head-and-neck or upper digestive cancers were associated with increased risk of malnutrition. Antibiotics use was significantly higher in malnourished patients (35.5 vs 22.8%; P<0.001). Severe malnutrition was independently associated with mortality. The median length of stay was 19.3+/-19.4 days for malnourished patients vs 13.3+/-19.4 days for others (P<0.0001). CONCLUSION: In French Comprehensive Cancer Centres, one out of three cancer patients are malnourished and this was associated with a longer length of stay. Pre-existing obesity could be identified as a new risk factor for malnutrition in our cancer patient population perhaps because of a misidentification or a delay in nutrition support in this category of patients.

Low body mass index and sarcopenia associated with dose-limiting toxicity of sorafenib in patients with renal cell carcinoma.

BACKGROUND: Patients with severe depletion of skeletal muscle (sarcopenia) are prone to dose-limiting toxicity (DLT) during fluoropyrimidine therapy. We hypothesized that sarcopenia may also predict toxicity of targeted therapy drugs. MATERIALS AND METHODS: Metastatic renal cell cancer (RCC) patients (n = 55) received sorafenib 400 mg b.i.d. Weight, height and skeletal muscle cross-sectional area at the third lumbar vertebra were measured by computed tomography (CT). Toxicity was assessed. RESULTS: DLT occurred in 22% of patients overall, of which three-quarters were dose reductions to 400 mg and the remainder entailed termination of treatment. DLT was most common (41%) in sarcopenic patients whose body mass index (BMI) was <25 kg/m(2) and least common (13%) in patients who were not sarcopenic and/or overweight or obese (P = 0.03). Toxicity was especially prevalent in sarcopenic male patients with BMI < 25, with 71% of men with these characteristics being unable to continue treatment at 800 mg/day. By contrast, only 5% of male patients whose muscle index was above the cut-off for sarcopenia and only 11% of male patients whose BMI was >25 experienced a DLT. CONCLUSION: BMI < 25 kg/m(2) with diminished muscle mass is a significant predictor of toxicity in metastatic RCC patients treated with sorafenib.

[Setting up supportive care in oncology: reflexions and suggestions.]. / A propos de la mise en place des soins de support en cancérologie : pistes de réflexions et propositions.

A group of 19 health professionals implicated in supportive care wanted to suggest some reflexions for organization, setting and evaluation of the supportive care in institutions and health territories. The suggested organization must be applicable to any cancer patient and the place of the care whatever the age, the stage of the disease; in the future, must be applicable to any patient with serious chronic illness. This organization must allow to optimize the accompaniment and the care of the patients and their close relations by 1) precise and regular analysis of their needs; 2) the respect of the continuity of the health care; 3) the setting of collaborative practice and transversality in the care. It is not a new medical speciality but a coordination of competences for patients and their families.

[Malnutrition in cancer patient: when to have a specialized consultation?]. / Dénutrition en cancérologie: quand demander un avis spécialisé?

Nutritional management of the cancer patient cannot be ignored, given the well-established links between malnutrition and mortality, postoperative complications, toxicity of radiation and chemotherapy, and quality of life. The expertise of a medical specialist in nutrition is often required given the diversity of the clinical presentation of malnutrition in cancer patients and in certain areas lacking evidence in the literature. In at least some situations, such as for malnourished patients requiring surgery, preoperative nutrition (normally enteral nutrition if possible), is indicated and is also the subject of international recommendations/clinical practice guidelines. The role of the specialist in nutrition is to disseminate such information. There are some situations where the literature offers useful approaches, even if there are no guidelines/recommendations. For example, in disease for which there are not curative therapies but the patient is not yet in a terminal stage, it is legitimate to propose parenteral nutrition in the case of partial bowel obstruction, without waiting for advice from a nutrition specialist. By contrast, his advice is of interest in the ethical discussion which sometimes surrounds decisions to initiate artificial nutrition in patients in the terminal phase. Nutritional recommendations are difficult to formulate for patients with solid tumors on chemotherapy, because there are few data in the literature. The expertise of the specialist in nutrition in this case is most effectively deployed when active treatment of the disease is planned (earlier rather than later in the disease trajectory, in patients responding to treatment for whom further treatment is planned, participants in phase I studies). For cancers of the head and neck preoperative enteral nutrition is recommended for malnourished patients. The literature also provides some practical solutions, even in the absence of well-defined recommendations in some instances. Enteral nutrition is also indicated, without consulting a specialist in nutrition, during radiotherapy when intake falls, to prevent the development of malnutrition. Given the high frequency and important consequences of malnutrition in patients receiving combined radiation and chemotherapy, it is appropriate to initiate enteral nutrition at the 3rd week of treatment. The role of the specialist in nutrition is to interpret the literature and to develop procedures for specific cases.

[Two cases of Bacillus infection and immunodepression]. / Infections à Bacillus et immunodépression, à propos de deux cas.

OBJECTIVE: Members of the genus Bacillus are Gram-positive bacilli, ubiquitous in the environment. When isolated in clinical practice, it is frequently considered as due to environmental contamination. Bacillus cereus is the most frequent species isolated in clinical practice, nevertheless other Bacillus spp. are sometimes isolated. Bacillus bacteremia is uncommon, the affected patients are severely ill and frequently immunocompromised with hematological malignancies. STUDY DESIGN: Two cases of bloodstream infection due to Bacillus species rarely described before are described, one due to Bacillus macerans and the other to Bacillus pumilus. Both patients presented with severe bacteremia and were immunodepressed after recent chemotherapy. They died a few days after admission to our ICU. CONCLUSION: The initial report of Bacillus spp. isolated in blood culture in oncohematological patients indicates a potentially severe infection.

[Evaluating the nutritional status of a lung cancer patient is an important element in patient management]. / L'évaluation du statut nutritionnel du patient suivi pour un cancer bronchique est un élément important de la prise en charge.

Nutritional status assessment during the comprehensive management of patients treated for cancer is becoming increasingly necessary. Various data are currently available which show a relationship between the nutritional status and certain morbidity-mortality parameters. In contrast, there is a paucity of data concerning lung cancer. A relationship between survival and the nutritional status has been found in the literature, exclusively in advanced stages of lung cancer. Unlike that observed in oncological digestive tract surgery, where artificial nutrition is recommended preoperatively in severely malnourished patients, no link has been evidenced between postoperative morbidity and mortality and the preoperative nutritional status in lung surgery. The scientific nutritional societies simply recommend preoperative nutritional assessment. Reflection on management of malnourished patients receiving chemotherapy is still "archaic" and recent studies and recommendations are lacking. Although largely prescribed, oral nutritional supplements have not proven efficient and patient compliance will probably have to be improved. According to "good nutrition practice" rules, the digestive tube should be used when it is functional and in theory, enteral nutrition is indicated in this situation. In addition to the lack of clinical studies, one of the obstacles to its use is cultural with the need to obtain not only patient approval but also that of the prescriber. Parenteral nutrition was discredited in earlier studies. It should probably be reevaluated in the context of new chemotherapeutic molecules and a different way of handling nutrition care. The physiological concept of omega-3 fatty acid modulation of inflammation is of interest in animal studies but the clinical modalities of use remain to be defined and determined. The role of nutrition in the management of lung cancer is still very limited but there are major expectations and many solutions are awaited in the coming years.

[Fever and infectious complications in patient with lung cancer]. / Fièvre et complications infectieuses chez un patient porteur d'un cancer bronchique.

The respiratory infections are very frequent during lung cancer. Their diagnosis is often difficult because of the various etiologies (cancer, chemotherapy, radiotherapy) and this complexity can make discuss a preliminary bronchial exploration before any therapeutics. When it is about a located infection, germs in cause are often the same that in the community respiratory infections, in particular bacilli Gram negative, and it is thus logical to treat by the penicillin A. In front of an interstitial syndrome, it is necessary to evoke the opportunist infections, which are increasing in patients with cancer because of the multimodality therapeutic and the elongation of the survival. The neutropenic patient must be distinguished because of its specificities. The pulmonary infections lead to an important mortality. According to the patient (advanced age, underlying chronic obstructive pulmonary disease [COPD]) and to the treatment (chemotherapy, pneumonectomy), prevention must be discussed as the pneumococcal and Haemophilus influenzae vaccination.

Incidence and clinical significance of anaerobic bacteraemia in cancer patients: a 6-year retrospective study.

Recent studies have shown that anaerobes account for 0.5-9% of all episodes of bacteraemia in hospitalised patients, with variations according to geographical location and demographic characteristics, most notably age, but few data are available for cancer patients. This study investigated retrospectively the incidence of anaerobic bacteraemia in cancer patients who received non-surgical treatment over a 6-year period at a tertiary oncology centre. Gastrointestinal (27%) and haematological (29%) malignancies were the most common underlying diseases. Among 45 isolates of anaerobic bacteria recovered from 45 patients, Bacteroides spp. and Clostridium spp. were the most frequent pathogens (60% and 22%, respectively). Twenty episodes of bacteraemia were polymicrobial, most frequently with aerobic Gram-negative bacilli (18 cases). The mortality rate for patients with adequate antimicrobial therapy from the outset was 14%, compared with 63% for patients who were not treated adequately at any time.

[Usefulness of panfungal PCR for the diagnosis of fungal infection in immunocompromised patients]. / Intérêt de l'amplification génique à l'aide d'amorces universelles dans le diagnostic des infections fongiques chez le patient immunodéprimé.

The diagnostic of invasive fungal infection is often difficult because of the low sensitivity of fungal culture from infected tissues. Here we have assessed the ability of a panfungal PCR targeted on the DNA region encoding the RNA genes followed by sequencing of the amplification products to detect and identify fungi from tissue biopsies. This assay allowed us to identify the microorganism responsible for an invasive fungal infection in three of our patients. In two cases, hepatosplenic candidiasis was suspected and Candida albicans DNA was detected from liver biopsies. The third patient was cared for a thymome and developed a manubrium osteitis caused by Scedosporium apiospermum.

Human pharmacokinetic study of heated intraperitoneal oxaliplatin in increasingly hypotonic solutions after complete resection of peritoneal carcinomatosis.

PURPOSE: We studied the pharmacokinetics of heated intraoperative intraperitoneal (i.p.) oxaliplatin (LOHP) solution and its safety profile in increasingly hypotonic solutions. This is the first clinical study of i.p. chemohyperthermia with hypotonic solutions. METHODS: Patients with peritoneal carcinomatosis (PC) underwent complete cytoreductive surgery followed by intraoperative i.p. chemohyperthermia (IPCH) with successive dextrose solutions of 300, 200, 150 and 100 mosm/l. LOHP (460 mg/m(2)) was administered in 2 liters of solution/m(2) at an i.p. temperature of 42-44 degrees C for 30 min. IPCH was performed using an open procedure (skin pulled upwards) with a continuous closed circuit. Patients received intravenous leucovorin (20 mg/m(2)) and 5-fluorouracil (400 mg/m(2)) just before IPCH to maximize the effect of LOHP. i.p. plasma and tissue samples were analyzed by means of atomic absorption spectrophotometry. Sixteen consecutive patients with PC of either gastrointestinal or peritoneal origin were treated. The safety of the procedure was studied. RESULTS: Pharmacokinetics: The mean duration of the entire procedure was 7.7 +/- 2.6 h. Half the LOHP dose was absorbed within 30 min at all dose levels. Absorption was not higher with hypotonic solutions than with isotonic solutions. The area under the curve of LOHP in plasma did not increase with decreasing osmolarity of the i.p. solutions. Intratumoral LOHP penetration was high; it was similar to that at the peritoneal surface, and about 18 times higher than that in nonbathed tissues. LOHP penetration was not significantly increased by using hypotonic solutions. SAFETY: There was a very high incidence of unexplained postoperative peritoneal bleeding (50%) and unusually severe thrombocytopenia in the 150 and 100 mosm/l groups. CONCLUSION: Contrary to experimental studies, this clinical study showed no increase in tumoral or systemic penetration of LOHP with i.p. hypotonic solutions (200, 150 or 100 mosm/l) during IPCH. A high incidence of i.p. hemorrhage and thrombocytopenia was observed.