Giovan Battista Doglietto

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.

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.

How can the assessment of fistula-in-ano be improved?

PURPOSE. Fistula-in-ano anatomy and its relationship with anal sphincters are important factors influencing the results of surgical management. Preoperative definition of fistulous track(s) and the internal opening play a primary role in minimizing iatrogenic damage to the sphincters and recurrence of the fistula. METHODS. Physical examination and endoanal ultrasound (performed with a 10 MHz endoprobe), either conventionally or with an injection of hydrogen peroxide, were performed in 26 consecutive patients. Results were matched with surgical features to establish their accuracy in preoperative fistula-in-ano assessment. RESULTS. Accuracy rates of clinical examination endoanal ultrasound, and hydrogen peroxide-enhanced ultrasound were 65.4, 50, and 76.9 percent for primary tracks, 73.1, 65.4, and 88.5 percent for secondary tracks, and 80.8, 80.8, and 92.3 percent for horseshoe extensions, respectively. Compared with physical examination and endoanal ultrasound, accuracy of hydrogen peroxide-enhanced ultrasound was higher for transsphincteric and intersphincteric primary tracks and horseshoe extensions. Both endoanal ultrasound and hydrogen peroxide-enhanced ultrasound displayed a significantly higher accuracy in detecting the internal openings (53.8 and 53.8 percent, respectively) compared with clinical evaluation (23.1 percent;P=0.027). CONCLUSIONS. Our data suggest that hydrogen peroxide-enhanced ultrasound can be very reliable and useful in the definition of fistula anatomy, its relationship with anal sphincters, and, hence, surgical strategy. It also improves identification of secondary extensions, particularly horseshoe tracks. This method, besides being safe, economic and reputable, both preoperatively and postoperatively, could be helpful in checking operative results and recurrence.

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.

Mesorectal Microfoci Adversely Affect the Prognosis of Patients With Rectal Cancer

AbstractPURPOSE: Mesorectal involvement is a common feature in rectal tumors. Neoplastic foci can be identified at pathologic examination of the mesorectum, but their incidence and prognostic significance remain to be defined. METHODS: A series of 77 patients with extraperitoneal rectal cancer, resected with total mesorectal excision, entered the study. After fixation, the excised specimens were submitted to serial transverse sections and staining. Direct tumor infiltration, lymph node involvement, and neoplastic microfoci in the mesorectum were investigated. Patients with mesorectal foci were compared with those without deposits with regard to clinical and pathologic parameters; different patterns of foci (endovasal, endolymphatic, perineural, isolated) were also considered. Univariate and multivariate analyses were used to evaluate the impact on survival rate. RESULTS: Neoplastic mesorectal involvement was found in 64 patients (83.1 percent). Direct tumor infiltration was detected in 66.2 percent, node involvement in 28.6 percent, microscopic foci in 44.2 percent of cases (endovasal in 11.7 percent, endolymphatic in 15.7 percent, perineural in 26 percent, isolated in 14.3 percent). In 7 cases (10.9 percent) microfoci alone (without any kind of other mesorectal involvement) were detected. Deposits were found in 18.8 percent of TNM Stage I tumors, in 46.9 percent of Stage II and in 59.3 percent of Stage III cancers. Similar incidence was found in patients treated with integrated therapies and surgery alone (43.3 vs. 44.7 percent, P = not significant). Poorer median (44.5 vs. 57 months, P = 0.04) five-year overall survival rate (43.4 vs. 63.3 percent, P = 0.016) and disease-free survival rate (43.3 vs. 57.7 percent, P = 0.048) were observed in patients with microscopic foci compared with those without deposits. Tumor configuration was found to be a independent prognostic factor for both overall and disease-free survival rates; furthermore, endolymphatic, perineural, and isolated foci significantly affected overall survival rate, while TNM staging affected disease-free survival rate. CONCLUSIONS: The incidence of neoplastic foci in the mesorectum is high, even in early staged tumors and despite aggressive preoperative treatment. They seem to affect prognosis. Such features should, therefore, be considered when local excision of the tumor is planned. Presence of mesorectal foci should modify conventional staging of the rectal tumor.

Infusional 5-fluorouracil and ZD1839 (Gefitinib-Iressa) in combination with preoperative radiotherapy in patients with locally advanced rectal cancer: a phase I and II Trial (1839IL/0092)

PURPOSE To report the final data of a Phase I and II study (1839IL/0092) on the combination of an anti-epidermal growth factor receptor drug (gefitinib), infusional 5-fluorouracil, and preoperative radiotherapy in locally advanced, resectable rectal cancer. METHODS AND MATERIALS Patients received 45 Gy in the posterior pelvis plus a boost of 5.4 Gy on the tumor and corresponding mesorectum. Infusional 5-fluorouracil (5-FU) and gefitinib (250 and 500 mg/day) were delivered during all radiotherapy course. An IORT boost of 10 Gy was allowed. The main endpoints of the study were to establish dose-limiting toxicity (DLT) and to evaluate the rate of pathologic response according to the tumor regression grade (TRG) Mandard score. RESULTS A total of 41 patients were enrolled. The DLT was not reached in the 6 patients enrolled in the dose-escalation part of the study. Of the 33 patients in the Phase II, TRG 1 was recorded in 10 patients (30.3%) and TRG 2 in 7 patients (21.2 %); overall 17 of 33 patients (51.5%) had a favorable endpoint. Overall, Grade 3+ toxicity was recorded in 16 patients (41%); these included Grade 3+ gastrointestinal toxicity in 8 patients (20.5%), Grade 3+ skin toxicity in 6 (15.3%), and Grade 3+ genitourinary toxicity in 4 (10.2%). A dose reduction of gefitinib was necessary in 24 patients (61.5%). CONCLUSIONS Gefitinib can be associated with 5-FU-based preoperative chemoradiation at the dose of 500 mg without any life-threatening toxicity and with a high pCR (30.3%). The relevant rate of Grade 3 gastrointestinal toxicity suggests that 250 mg would be more tolerable dose in a neaoadjuvant approach with radiotherapy and infusional 5-FU.

Serum tumour necrosis factor-alpha levels in cancer patients are discontinuous and correlate with weight loss.

Tumour necrosis factor‐α (TNF) has been regarded as a potential mediator of cancer cachexia. Assessment of TNF circulating levels in cancer patients and their correlation with weight loss has led to controversial results.

Expression of NF-kappaB and IkappaB proteins in skeletal muscle of gastric cancer patients

The mechanisms eliciting cancer cachexia are not well understood. Wasting of skeletal muscle is problematic because it is responsible for the clinical deterioration in cancer patients and for the ability to tolerate cancer treatment. Studies done on animals suggest that nuclear factor of kappa B (NF-kappaB) signalling is important in the progression of muscle wasting due to several types of tumours. However, there are no published studies in humans on the role of NF-kappaB in cancer cachexia. In this project, we studied the rectus abdominis muscle in patients with gastric tumours (n=14) and in age-matched control subjects (n=10) for markers of NF-kappaB activation. Nuclear levels of p65, p50 and Bcl-3 were the same in both groups of subjects. However, phospho-p65 was elevated by 25% in the muscles of cancer patients. In addition, expression of the inhibitor of kappa B alpha (IkappaBalpha) was decreased by 25% in cancer patients. Decreased expression of IkappaBalpha reflects its degradation by one of the IkappaBalpha kinases and is a marker of NF-kappaB activation. Interestingly, there was no correlation between the stage of cancer and the extent of IkappaBalpha decrease, nor was there a correlation between the degree of cachexia and decreased IkappaBalpha levels. This suggests that the activation of NF-kappaB is an early and sustained event in gastric cancer. The work implicates the NF-kappaB signalling in the initiation and progression of cancer cachexia in humans and demonstrates the need for additional study of this pathway; it also recommends NF-kappaB signalling as a therapeutic target for the amelioration of cachexia as has been suggested from studies done on rodents.

CALPAIN activity is increased in skeletal muscle from gastric cancer patients with no or minimal weight loss

The influence of cancer on skeletal muscle calpain expression and activity in humans is poorly understood. We tested the hypothesis that calpain activity is increased in skeletal muscle from gastric cancer patients with no or <5% weight loss. Muscle biopsies were obtained from rectus abdominis muscle in 15 patients who underwent surgery for gastric cancer and had <5% weight loss and also in 15 control patients. Calpain activity was determined using a calpain‐specific substrate in the absence or presence of calcium. The expression of μ‐ and m‐calpain, calpastatin, atrogin‐1, and MuRF1 was determined by real‐time polymerase chain reaction. Calpain activity was increased by 70% in cancer patients compared with controls. There were no differences in mRNA levels for μ‐ and m‐calpain, calpastatin, atrogin‐1, or MuRF1 between control and cancer patients. Calpain activity may be increased in muscle from gastric cancer patients even before changes in molecular markers of muscle wasting and significant weight loss occur. Muscle Nerve, 2011

Skeletal muscle in cancer cachexia: the ideal target of drug therapy

Cancer cachexia is a debilitating and life-threatening syndrome that accounts for at least 20% of deaths in neoplastic patients. Cancer cachexia significantly impairs quality of life and response to anti-neoplastic therapies, increasing morbidity and mortality of cancer patients. The loss of lean body mass is the main characteristic of cancer cachexia and the principal cause of function impairment, fatigue and respiratory complications. It is the result of an imbalance between protein synthesis and protein degradation, the mechanisms underlying such alteration being multiple and partially known. Current therapy of cancer cachexia continues to be extremely poor. However, in the last decade, the attention has focused just on the skeletal muscle, as a potential target of therapy, with the aim to discover drugs capable to inhibit the catabolic processes and to stimulate the anabolic pathways. The skeletal muscle has been faced at different levels such as the mediators (cytokines and tumor-derived factors), the receptors (TNF-alpha and androgen receptors), the proteolytic pathways (calpains and ubiquitin-proteasome), the intracellullar signalling pathways (NF-kB, AP-1, FOXO, PKR), and the negative modulators of muscle growth/hypertrophy (myostatin, GSK3-beta). Most of the drugs that have been tested have shown to be effective, at least in experimental models of cancer cachexia. It remains to define their safety, tolerance and efficacy in humans through large, adequate, clinical trials. However, the impression is that there is a light at the back of the tunnel.