Maurizio Bossola

Accurate lymph-node detection in colorectal specimens resected for cancer is of prognostic significance.

PURPOSE: Lymph-node involvement is the most important prognostic factor in colorectal cancers. Many staging systems adopted node status as a parameter of tumor classification. However, the number of identified and positive glands varies across articles, depending on specimen examination. There is a consistent risk of substaging tumors and undertreating patients. Aim of this study was to investigate the prognostic significance of different pathologic methods. METHODS: Eight hundred one patients who underwent curative resection of colorectal cancer entered the study and were divided into two groups. In Group 1 the specimen was “en bloc” fixed, and nodes were identified by sight and palpation. In Group 2 the mesentery of the excised specimen was dissected away from the bowel, stretched, and pinned to cork board. The mesenteric segment surrounding the origin of principal vessels was divided from the segment surrounding the colic vessels. All specimen segments were fixed, node identification being performed by sight and palpation. Examined and positive nodes were recorded, and metastatic rate and incidence was calculated in the two groups. Patients were classified with used of different staging systems. Survival rates were calculated, related to tumor stage, and compared statistically. Pathologic procedures were included in a multivariate analysis. RESULTS: A significantly higher number of detected and positive nodes and metastatic rate (37.5vs. 30.2 percent;P<0.05) were observed in Group 2; 45.2 percent of Group 2 and 25.3 percent of Group 1 cases had more than three positive nodes (P<0.05). In Group 2 several patients shifted from earlier to more advanced stages compared with Group 1 cases. Five-year and ten-year survival rates were significantly higher (P=p.pr) in Group 2 (81.5 and 77.2 percent) than in Group 1 (76.7 and 61.5 percent), mostly in patients with TNM Stage N0. Survival analysis related to Astler and Collers and Tangs classifications confinrmed such features. Higher rates of local recurrences and distant metastases were found in Group 1, particularly if related to node status (P<0.05). Multivariate analysis demonstrated the pathologic method is an independent prognostic factor. CONCLUSIONS: This study demonstrates the prognostic impact of specimen examination. Inaccurate methods could downstage the tumor and exclude the patient from adjuvant therapies, with detrimental effects on the outcome of the case.

Increased muscle proteasome activity correlates with disease severity in gastric cancer patients

ObjectiveTo investigate the state of activation of the ATP-ubiquitin-dependent proteolytic system in the skeletal muscle of gastric cancer patients. Summary Background DataMuscle wasting in experimental cancer cachexia is frequently associated with hyperactivation of the ATP-dependent ubiquitin-proteasome proteolytic system. Increased muscle ubiquitin mRNA levels have been previously shown in gastric cancer patients, suggesting that this proteolytic system might be modulated also in human cancer. MethodsBiopsies of the rectus abdominis muscle were obtained intraoperatively from 23 gastric cancer patients and 14 subjects undergoing surgery for benign abdominal diseases, and muscle ubiquitin mRNA expression and proteasome proteolytic activities were assessed. ResultsMuscle ubiquitin mRNA was hyperexpressed in gastric cancer patients compared to controls. In parallel, three proteasome proteolytic activities (CTL, chymotrypsin-like; TL, trypsin-like; PGP, peptidyl-glutamyl-peptidase) significantly increased in gastric cancer patients with respect to controls. Advanced tumor stage, poor nutritional status, and age more than 50 years were associated with significantly higher CTL activity but had no influence on TL and PGP activity. ConclusionsThese results confirm the involvement of the ubiquitin-proteasome proteolytic system in the pathogenesis of muscle protein hypercatabolism in cancer cachexia. The observation that perturbations of this pathway in gastric cancer patients occur even before clinical evidence of body wasting supports the thinking that specific pharmacologic and metabolic approaches aimed at counteracting the upregulation of this pathway should be undertaken as early as cancer is diagnosed.

Total thyroidectomy for management of benign thyroid disease: review of 526 cases

Total thyroidectomy is not frequently performed in cases of benign disease because of the associated risk of postoperative hypoparathyroidism and recurrent laryngeal nerve (RLN) damage. We chose a series of patients who had undergone total thyroidectomy (TT) for benign thyroid tumors to evaluate the safety of this approach and its role in the treatment of nonmalignant lesions of the thyroid. We considered only patients with a minimum follow-up of 24 months. Records of 526 patients who underwent TT were carefully reviewed, assessing for perioperative complications and late sequelae. The mean age was 44 ± 15.7 years; 109 patients (20.7%) were male and 417 (79.3%) were female. Altogether, 65 patients (12.3%) were operated on for toxic goiter, 429 (81.6%) for bilateral nodular goiter, and 32 (6.1%) for thyroiditis. Postoperative hemorrhage requiring reoperation occurred in 8 cases (1.5%). The incidences of permanent RLN palsy (considered as a percentage of the nerves at risk) and permanent hypocalcemia were 0.4% and 3.4%, respectively. A trend toward a decrease in the complication rate was observed during the last 5 years. There were no disease recurrences during a mean follow-up of 44 months. The results of our series show that TT can be performed safely in patients, with a low incidence of lifetime disabilities. TT has the advantage of reducing/avoiding the risk of disease recurrence and reoperation and should therefore be considered a valuable option for treating benign thyroid diseases.Résumé.La thyroïdectomie total mais n’est pas réalisée fréquemment en cas de maladie bénigne en raison du risque d’hypoparathyroïde postopératoire et de lésions du nerf récurrent. Nous avons sélectionné une série de thyroïdeectomies totales (TT) pour maladie bénigne afin d’évaluer la sécurité de cette approche et son rôle dans le traitement des lésions non malignes de la thyroïde. Nous avons pris en compte seulement les patients ayant un suivi minimum de 24 mois. Les dossiers de 526 patients ayant eu une TT ont été revus pour évaluers les complications péri-opératoires et les séquelles tardives. L’âge moyen était de 44 ± 15.7 ans. Cent neuf patients (20.7%) étaient des hommes et 417 (79.3%) des femmes. Soixante=cinq patients (12.3%) ont été opérés pour goitre toxique, 429 (81.6%) pour goitre nodulaire bilatéral et 32 (6.1%) pour thyroïdite. Une hémorragie postopératoire a nécessité une ré-intervention dans 8 cas (1.5%). L’incidence de paralysie permanente du nerf récurrent (pourcentage de nerfs récurrents à risque) et d’hypocalcémie permenente ont été, respectivement, de 0.4% et de 3.4%. On a observé une tendance vers une diminution du taux de complications pendant les cinq dernières années. Aucune récidive n’a été observée avec un suivi moyen de 44 mois. Les résultats de notre série indiquent que la TT peut être réalisée avec sécurité dans cette population avec une incidence d’incapacité permenent réduite. La TT a l’avantage de réduire/éviter le risque de récidive de la maladie et de réopération et devrait être une option valable pour le traitement de maladies bénignes de la thyroïde.ResumenLa tiroidectomia total no es un procedimiento de realización frecuente en la enfermedad benigna por razón del riesgo de hipoparatiroidismo postoperatorio y de lesión del nervio laríngeo recurrente. Tomamos una serie de tiroidectomías totales (TT) practicadas por tumores benignos con el objeto de evaluar la seguridad de esta conducta y su papel en el tratamiento de lea lesiones no malignas de la tiroides. En el presente estudio sólo fueron considerados pacientes con un seguimiento mínomo de 24 meses. Se revisaron las historias de 526 pacientes que habían sido sometidos a TT para determinar las complicaciones postoperatorias y las secuelas tardías. La edad promedio fue 44 ± 15.7 años; 109 (20.7%) eran hombres y 417 (79.3%) mujeres; 65 (12.3%) fueron operados por bocio tóxico, 429 (81.6%) por bocio nodular bilateral y 32 (6.1%) por tiroiditis. Se presentó hemorragia postoperatoria que requirió reoperación en 8 casis 91.5%). La incidencia de parálisis permamente del nervio laríngeo recurrente consierada como porcentaje de los nervios en riesgo y de hipocalcemia fue 0.4% y 3.4% respectivamente. Se observó tendencia hacia la disminución de las complicaciones en el curso de los últimos 5 años. No se registró recurrencia de la enfermedad en el seguimiento de 44 meses. Los resultados del análisis de nuestra serie indican que la TT puede ser practicada con seguridad en pacientes con enfermedad benigna de la tiroides, con una baja tasa de complicaciones permenentes. La TT tiene la ventaja de reducir o abolir tanto el riesgo de recurrencia de la enfermedad como el de una reoperación, y en consecuencia, debe ser considerada Bellantone et al.: Benign Thyroid Disease and Total Thyroidectomy como una opción valiosa en el tratamiento de la enfermedad tiroidea benigna.

Muscle myostatin signalling is enhanced in experimental cancer cachexia

Background/Aims   Myostatin belongs to the transforming growth factor‐β superfamily and negatively regulates skeletal muscle mass. Its deletion induces muscle overgrowth, while, on the contrary, its overexpression or systemic administration cause muscle atrophy. The present study was aimed at investigating whether muscle depletion as occurring in an experimental model of cancer cachexia, the rat bearing the Yoshida AH‐130 hepatoma, is associated with modulations of myostatin signalling and whether the cytokine tumour necrosis factor‐α may be relevant in this regard.

Mitochondrial pathways in sarcopenia of aging and disuse muscle atrophy.

Abstract Muscle loss during aging and disuse is a highly prevalent and disabling condition, but knowledge about cellular pathways mediating muscle atrophy is still limited. Given the postmitotic nature of skeletal myocytes, the maintenance of cellular homeostasis relies on the efficiency of cellular quality control mechanisms. In this scenario, alterations in mitochondrial function are considered a major factor underlying sarcopenia and muscle atrophy. Damaged mitochondria are not only less bioenergetically efficient, but also generate increased amounts of reactive oxygen species, interfere with cellular quality control mechanisms, and display a greater propensity to trigger apoptosis. Thus, mitochondria stand at the crossroad of signaling pathways that regulate skeletal myocyte function and viability. Studies on these pathways have sometimes provided unexpected and counterintuitive results, which suggests that they are organized into a complex, heterarchical network that is currently insufficiently understood. Untangling the complexity of such a network will likely provide clinicians with novel and highly effective therapeutics to counter the muscle loss associated with aging and disuse. In this review, we summarize the current knowledge on the mechanisms whereby mitochondrial dysfunction intervenes in the pathogenesis of sarcopenia and disuse atrophy, and highlight the prospect of targeting specific processes to treat these conditions.

Is malnutrition still a risk factor of postoperative complications in gastric cancer surgery

OBJECTIVE & AIMS The present study aimed at retrospectively evaluating the incidence of mortality and major and minor postoperative complications in patients who underwent surgery for gastric cancer between 2000 and 2006 stratified according to the preoperative percentage weight loss, serum albumin levels and body mass index (BMI). METHODS One hundred and ninety-six patients affected by gastric cancer admitted to the Division of Digestive Surgery of the Catholic University of Rome between January 2000 and December 2006 were considered eligible and were included in the study. According to the weight loss, patients were divided into three groups: (1) 0-5%; (2) 5.1-10%; (3) >10%. On the basis of serum albumin levels, were divided into three groups: (1) <3.0 g/dl; (2) 3.0-3.4 g/dl; (3) >3.5 g/dl. According to BMI, were divided into four groups: (1) <18.5 kg/m(2); (2) 18.5-24.9 kg/m(2); (3) 25.0-29.9 kg/m(2); (4) >30.0 kg/m(2). Postoperative complications and mortality were reported. Complications were classified by objective criteria as major or minor, and as infectious or non-infectious. RESULTS The postoperative mortality was 0%. Major infectious complications occurred in 20 patients (10.2%), major non-infectious in 18 (9.2%), minor infectious in 21 (10.7%), whereas minor non-infectious complications were absent. The rate of major infectious, major non-infectious and minor infectious postoperative complications was similar in patients with absent or light weight loss (8.8%, 8.8%, 10.6%, respectively), mild weight loss (15.3%, 11.5%, 9.6%, respectively), or severe weight loss (6.4%, 6.4%, 12.9%, respectively). Similarly, the rate of postoperative complications did not differ between patients with serum albumin <3.0 g/dl (10.8%, 8.1%, 8.1%, respectively); between 3.0 and 3.4 (8.8%, 13.3%, 17.7%, respectively) or > or =3.5 g/dl (10.5%, 7.9%, 8,7%, respectively). According to BMI, the rate of postoperative complications was: 11.7%, 5.8%, and 5.8% for BMI <18.5 kg/m(2); 9.4%, 8.2%, and 11.7% for BMI between 18.5 and 24.9 kg/m(2); 10.7%, 10.7%, and 9.2% for BMI between 25 and 29.9 kg/m(2); 10.3%, 10.3% and 13.7% for BMI >30 kg/m(2). Then, we evaluated the postoperative morbidity only in patients who underwent total gastrectomy or distal subtotal gastrectomy associated with extended lymphadenectomy. In this group of patients, the rate of postoperative complications was comparable in patients with 0-5% (8.8%, 7.7%, 10%, respectively), 5.1-10% (14.6%, 9.7%, 9.7%, respectively), and >10% (7.1%, 7.1%, 14.3%, respectively) weight loss. Also stratifying the patients according to the serum albumin levels, the rate of postoperative complications did not differ significantly (serum albumin <3.0 g/dl: 14.8%, 11.1%, 14.8%, respectively; serum albumin between 3.0 and 3.4 g/dl: 6.2%, 12.5%, 15.6%, respectively; serum albumin > or =3.5 g/dl: 10.4%, 5.8%, 7.0%, respectively). According to BMI, the rate of postoperative complications was: 7.6%, 0%, and 7.6% for BMI <18.5 kg/m(2); 9.5%, 9.5%, and 11.1% for BMI between 18.5 and 24.9 kg/m(2); 12.5%, 8.3%, and 10.4% for BMI between 25 and 29.9 kg/m(2); 9.5%, 9.5% and 9.5% for BMI >30 kg/m(2). CONCLUSION The present study suggests that weight loss and hypoalbuminemia are not associated with an increased risk of mortality and morbidity in patients who underwent surgery for gastric cancer. This study may represent a stimulus for further studies aiming at evaluating the actual role of malnutrition in the development of postoperative complications in major abdominal surgery.

Circulating Bacterial-Derived DNA Fragments and Markers of Inflammation in Chronic Hemodialysis Patients

BACKGROUND AND OBJECTIVES Bacterial-derived DNA fragments (BDNAs) have been shown to be present in dialysis fluid, to pass through dialyzer membranes, and to induce IL-6 (IL-6) in mononuclear cells. The present study aimed at assessing the eventual presence of BDNAs in the blood of hemodialysis (HD) patients and if this is associated with markers of chronic inflammation. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Fifty-eight HD patients and 30 controls were included in the study. A blood sample was collected from a peripheral vein and from the central venous catheter (CVC) or the arteriovenous fistula (AVF) and examined for presence of BDNAs by 16S rRNA gene PCR amplification, bacterial growth, and measurement of C-reactive protein and IL-6. Thirty minutes after the start of HD, a sample of dialysis fluid was collected before the entry into and at the exit of the dialyzer and examined for presence of BDNAs. RESULTS Controls had negative blood cultures and absence of blood BDNAs. All HD patients had negative blood cultures, but in 12 (20.7%), BDNAs were present in the whole blood. In five of the latter, BDNAs were also found in the dialysis fluid. C-reactive protein serum levels (mg/L) were significantly higher in patients with than in those without BDNAs. Likewise, IL-6 serum levels (pg/ml) were significantly higher in patients with BDNA than in those without. CONCLUSIONS Circulating BDNAs are associated with higher levels of C-reactive protein and IL-6 in HD patients.

Cancer Cachexia: It’s Time for More Clinical Trials

Cancer cachexia (CC) is a multifactorial paraneoplastic syndrome characterized by anorexia, body weight loss, loss of adipose tissue and skeletal muscle, accounting for at least 20% of deaths in neoplastic patients. CC significantly impairs quality of life and response to anti-neoplastic therapies, increasing morbidity and mortality of cancer patients. Muscle wasting is the most important phenotypic feature of CC and the principal cause of function impairment, fatigue and respiratory complications, mainly related to a hyperactivation of muscle proteolytic pathways. Most current therapeutic strategies to counteract CC have proven to be only partially effective. In the last decade, the correction of anorexia, the inhibition of catabolic processes and the stimulation of anabolic pathways in muscle have been attempted pharmacologically with encouraging results in animal models and through preliminary clinical trials. However, data in the clinical setting are still scanty and non definitive. It is time to start prospective, randomized, controlled trials to evaluate which drugs are effective in counteracting the loss of lean of muscle mass and in improving nutritional status and quality of life in patients affected by cancer-related cachexia.

Anorexia and Serum Leptin Levels in Hemodialysis Patients

Background and Aims: Hyperleptinemia is a common feature in hemodialysis (HD) patients. However, the role of increased serum leptin levels in the pathogenesis of HD-related anorexia is still controversial. The purpose of the present prospective study was to ascertain whether hyperleptinemia is causally implicated in the pathogenesis of HD-related anorexia. Methods: We measured the serum leptin levels and the serum leptin/body mass index (BMI) ratio in 24 healthy subjects and in 49 end-stage renal disease patients on maintenance HD. HD patients were subdivided into anorexic (14/49, 28.5%) and non-anorexic (35/49, 71.5%) according to a questionnaire discriminating for the presence of anorexia-related symptoms. Results: Calorie (kcal/kg/day) and protein (g/ kg/day) intakes were significantly lower in anorexic than in non-anorexic patients (20.1 ± 1.1 vs. 27.9 ± 1.3, p = 0.004, and 0.82 ± 0.05 vs. 1.19 ± 0.05, p = 0.001, respectively). Accordingly, serum albumin, total lymphocyte count, mid-arm muscle circumference, and the protein equivalence of nitrogen appearance (PNA) were significantly lower in anorexic patients. The serum leptin concentration (ng/ml) was significantly higher in HD patients than in controls, in males (15.33 ± 3.4 vs. 3.7 ± 0.3, p = 0.003) and in females (42.3 ± 7.2 vs. 10.5 ± 1.3, p = 0.03). Similarly, serum leptin/BMI ratio was significantly higher in HD patients than in controls, in males (0.56 ± 0.1 vs. 0.16 ± 0.02, p = 0.0028) and in females (1.8 ± 0.2 vs. 0.4 ± 0.04, p < 0.0001). However, serum leptin levels were similar in anorexic and in non-anorexic patients, in males (15.3 ± 5.6 vs. 16.9 ± 4.2, p = 0.85) and in females (46.6 ± 12.9 vs. 47.4 ± 9.4, p = 0.96). No differences were observed between the 2 groups in the serum leptin/BMI ratio, in males (0.59 ± 0.2 vs. 0.58 ± 0.14, p = 0.92) and in females (1.5 ± 0.4 vs. 1.8 ± 0.3, p = 0.94). Similarly, no statistically significant differences in terms of serum leptin levels and leptin/BMI ratio were observed between patients with dietary energy intake of <30 or ≧30 kcal/kg/day and between those with a dietary protein intake of <1.2 or ≧1.2 g/kg/day. No significant correlations were found between serum leptin levels and PNA, albumin, cholesterol, total lymphocytes number, weight change, C-reactive protein, fibrinogen, ferritin, and complement. Conclusion: The present results indicate that mechanisms other than increases in serum leptin levels might be involved in the pathogenesis of HD-related anorexia.

Correlates of symptoms of depression and anxiety in chronic hemodialysis patients

OBJECTIVE Little is known about the demographic, clinical and laboratory variables which may be correlated with symptoms of depression and anxiety in hemodialysis (HD) patients. The present study aimed at evaluating such correlation in HD patients treated at a single HD center in a Mediterranean country. METHODS Eighty HD patients were assessed for depression and anxiety with the Beck Depression Inventory (BDI) and the Hamilton Anxiety Rating Scale (HARS). The scores of BDI and HARS were correlated with demographic, clinical and laboratory variables. RESULTS Based on the Beck Depression Inventory, 38 patients had no symptoms of depression and 42 had symptoms of depression. Based on the HARS, three patients had no symptoms of anxiety and 38 had mild symptoms of anxiety, whereas moderate or severe symptoms of anxiety were present in 39 patients. In univariate analysis, BDI score correlated significantly with age, the Charlson Comorbidity Index, SF-36 Vitality Subscale, Mini-Mental Status Examination, creatinine, albumin, plasma 25-hydroxy vitamin D and interleukin-6 (IL-6) levels. HARS score correlated significantly with age, Charlson Comorbidity Index, SF-36 Vitality Subscale and parathyroid hormone (PTH) levels. In the multivariate analysis, a direct and an inverse correlation between BDI and IL-6 [P=.042, OR=1.31 (95% CI=1.01-1.71)] and creatinine [P=.050, OR=0.73 (95% CI=0.54-1.00)] was observed. With regard to HARS, only a direct correlation with Charlson Comorbidity Index [P<.001, OR=1.55 (95% CI=1.22-1.96)] was found. CONCLUSION Although numerous demographic, clinical and laboratory variables correlated with BDI and HARS in univariate analysis, the multivariate regression analysis showed only a direct correlation between BDI and IL-6 [P=.042, OR=1.31 (95% CI=1.01-1.71)] and an inverse correlation between BDI and creatinine [P=.050, OR=0.73 (95% CI=0.54-1.00)] and a direct correlation between HARS and the Charlson Comorbidity Index [P<.001, OR=1.55 (95% CI=1.22-1.96)].