Activation of the SDF1/CXCR4 pathway retards muscle atrophy during cancer cachexia.

Cancer cachexia is a life-threatening syndrome that affects most patients with advanced cancers and causes severe body weight loss, with rapid depletion of skeletal muscle. No treatment is available. We analyzed microarray data sets to identify a subset of genes whose expression is specifically altered in cachectic muscles of Yoshida hepatoma-bearing rodents but not in those with diabetes, disuse, uremia or fasting. Ingenuity Pathways Analysis indicated that three genes belonging to the C-X-C motif chemokine receptor 4 (CXCR4) pathway were downregulated only in muscles atrophying because of cancer: stromal cell-derived factor 1 (SDF1), adenylate cyclase 7 (ADCY7), and p21 protein-activated kinase 1 (PAK1). Notably, we found that, in the Rectus Abdominis muscle of cancer patients, the expression of SDF1 and CXCR4 was inversely correlated with that of two ubiquitin ligases induced in muscle wasting, atrogin-1 and MuRF1, suggesting a possible clinical relevance of this pathway. The expression of all main SDF1 isoforms (α, ß, γ) also declined in Tibialis Anterior muscle from cachectic mice bearing murine colon adenocarcinoma or human renal cancer and drugs with anticachexia properties restored their expression. Overexpressing genes of this pathway (that is, SDF1 or CXCR4) in cachectic muscles increased the fiber area by 20%, protecting them from wasting. Similarly, atrophying myotubes treated with either SDF1α or SDF1ß had greater total protein content, resulting from reduced degradation of overall long-lived proteins. However, inhibiting CXCR4 signaling with the antagonist AMD3100 did not affect protein homeostasis in atrophying myotubes, whereas normal myotubes treated with AMD3100 showed time- and dose-dependent reductions in diameter, until a plateau, and lower total protein content. This further confirms the involvement of a saturable pathway (that is, CXCR4). Overall, these findings support the idea that activating the CXCR4 pathway in muscle suppresses the deleterious wasting associated with cancer.

[Intraoperative radiolocalization of intraductal breast carcinoma: sentinel lymph node evaluation]. / La radiolocalizzazione intraoperatoria nel carcinoma intraduttale della mammella: valutazione del linfonodo sentinella.

Sentinel lymph node biopsy and intraoperatory radiolocalization (RLI) are fast becoming the standard surgical treatment for invasive breast cancer. Actually, it seems, they have the same rule in "high risk" DCIS of the breast.

Sentinel lymphadenectomy in cutaneous melanoma.

AIMS AND BACKGROUND: In the last ten years validation of the sentinel lymph node (SLN) concept has led to modification of the surgical approach for patients with intermediate-risk cutaneous melanoma. METHODS AND STUDY DESIGN: Forty-eight patients affected by cutaneous melanoma with a Breslow thickness between 0.65 and 4 mm were enrolled in the study. Approximately 2 mCi of radiotracer and 1 mL of vital blue dye were injected in each patient around the site of the primary lesion. Lymphoscintigraphy was performed until the lymphatic basin and the respective SLN were localized. The whole surgical procedure consisted of enlargement of the surgical margins followed by localization and excision of the SLN(s) by using both radiotracer and vital dye. Whenever the SLN proved to be histologically positive for metastasis, complete regional lymphadenectomy was performed. RESULTS: Within 15 minutes of radiotracer administration the lymphatic basin was localized in all 4 patients by lymphoscintigraphy. Vital dye and radiotracer successfully allowed SLN localization and excision in 46 of 48 patients (97%); in one case the SLN was detected by radiotracer alone. The SLN proved to be metastatic in six (13%) of 46 evaluable patients; interestingly, in three of them the presence of metastatic cells was revealed only by immunohistochemistry. All patients with tumor-positive SLNs had primary lesions with a Breslow thickness = 2 mm. CONCLUSIONS: Sentinel lymphadenectomy is able to identify lymph node involvement in patients with cutaneous melanoma with a Breslow thickness > 1 mm, thus avoiding the risks associated with radical regional lymphadenectomy. Lymphoscintigraphy proved to be an important tool to obtain correct preoperative localization of the drainage basin, especially for melanomas located on the face and trunk.

Radioguided-surgery of early breast lesions.

BACKGROUND: Radioguided-surgery has been recently proposed in patients with clinically occult breast lesions. This study aimed to evaluate the feasibility of correctly locating and eradicating, by a single intralesional injection of a radiotracer, any breast lesion and, in the case of malignancy, to perform simultaneous sentinel lymph node (SLN) biopsy procedure. PATIENTS AND METHODS: Sixty-three women with early breast lesions were enrolled: 42 were invasive carcinomas, 16 in situ ductal carcinomas (DCIS) and 5 fibroadenomas. RESULTS: Scintigraphic images clearly identified the lesions in all patients while SLN/s were evident in 88% of them. At surgery all the breast lesions were easily radiolocalized and eradicated with minimum surgical trauma and, for those patients with invasive carcinomas, the SLN technique was performed in 86% of them. No skip metastases were found. CONCLUSION: A single intralesional administration of radiotracer is an easy and reliable procedure to simultaneously locate and remove both the non-palpable breast lesion and the SLN when primary malignancy was intraoperatively confirmed.

Efficacy and safety of pentoxifylline in geriatric patients with intermittent claudication.

The effects of pentoxifylline on intermittent claudication were evaluated at a dose of 1200 mg/day in an open-label twelve-week study on geriatric patients with chronic occlusive arterial disease (COAD). Standardized treadmill testing and clinical signs and symptoms of COAD were followed up before and during drug administration. Twenty-four subjects with a mean age of 73.5 years, capable of walking between 20 and 200 meters on the treadmill, were entered into the trial; 22 participated for eight weeks and 19 completed the study in terms of treadmill walking distance measurements at 12 weeks. The mean walking distance for all patients was increased 111% over baseline at week 12. Thirteen subjects were considered drug responders (greater than or equal to 50% increase in treadmill walking distance) and 9 were considered nonresponders (less than 50% increase). Improvements in clinical signs and symptoms of COAD were noted. Decreases in elevated systemic systolic pressures (but not diastolic) were unexpectedly observed in many drug responders. Seven of 19 males reported sexual function improvements while receiving pentoxifylline. Fourteen (58%) of the 24 subjects reported mild side effects of dyspepsia, nausea, vomiting, dizziness, headache, or insomnia; no subjects were withdrawn from the study because of side effects. In summary, pentoxifylline improved function and symptoms in 13 of 22 geriatric patients with intermittent claudication; the drug was safe and well tolerated at the usual dosage in this geriatric patient population.

Medical and industrial hygiene characterization of the cotton waste utilization industry.

We studied 260 workers in the cotton waste utilization industry and 310 "blue-collar" control workers from nondusty industries in the same geographic area of the United States by respiratory symptom questionnaire and by pre- and postshift spirometry. We excluded 75 cotton workers and 75 control workers from statistical analysis because of prior hazardous occupational exposures. Plant-wide, 8-hour time-weighted average exposures ranged from 0.28 mg/m3 to 7.80 mg/m3. The overall prevalence of symptoms compatible with byssinosis was 5.9% in cotton workers and 4.7% in the controls. Cotton workers with less than 2 years of employment had a significantly greater prevalence of bronchitis than their control counterparts. The cotton workers with 2 years or more of employment had significantly greater prevalences of bronchitis, shift decrement in forced expiratory volume in 1 second (FEV1) of greater than or equal to 10%, and FEV1/FEV1-predicted less than 80%, than their control counterparts. Regression analysis showed that for matched cotton and control workers, the percentage decrement in FEV1 over the shift was significantly greater for cotton workers; and that in all cotton workers, longevity in industry had a negative effect on the before-shift forced vital capacity (FVC). This study suggests that there are both acute and chronic effects of cotton exposure in the cotton waste utilization industry.