Breast cancer commonly metastasizes to bone where its growth depends on the action of bone-resorbing osteoclasts. We have previously shown that breast cancer cells secrete factors able to directly stimulate osteoclastogenesis from receptor activator of nuclear factor B ligand (RANKL)-primed precursors and that transforming growth factor-␤ (TGF␤) plays a permissive role in this process. Now, we evaluate the signaling events triggered in osteoclast precursors by soluble factors produced by MDA-MB-231 human breast carcinoma cells. In mouse bone marrow cultures and RAW 264.7 murine monocytic cells, MDA-MB-231-derived factors increased osteoclast number, size, and nucleation. These factors failed to induce Smad2 phosphorylation, and short interfering RNAs against Smad4 did not affect their ability to induce osteoclastogenesis. In contrast, MDA-MB-231 factors induced phosphorylation of p38 and ERK1/2, and pharmacological inhibitors against p38 (SB203580) and MEK1/2 (PD98059) impeded the osteoclastogenic effects of cancer-derived factors. Neutralizing antibodies against TGF␤ attenuated p38 activation, whereas activation of ERK1/2 was shortened in duration, but not decreased in amplitude. ERK1/2 phosphorylation induced by cancer-derived factors was blocked by MEK1/2 inhibitor, but not by Ras (manumycin A) or Raf (GW5074) inhibitors. Inhibition of protein kinase C␣ using Gö6976 prevented both ERK1/2 phosphorylation and osteoclast formation in response to MDA-MB-231-derived factors. Using microspectrofluorimetry of fura-2-AM-loaded osteoclast precursors, we have found that cancer-derived factors, similar to RANKL, induced sustained oscillations in cytosolic free calcium. The calcium chelator BAPTA prevented calcium elevations and osteoclast formation in response to MDA-MB-231-derived factors. Thus, we have shown that breast cancer-derived factors induce osteoclastogenesis through the activation of calcium/protein kinase C␣ and TGF␤-dependent ERK1/2 and p38 signaling pathways.Breast cancer exhibits a high propensity to metastasize to bone causing bone pain, pathological fractures, hypercalcemia, spinal cord compression, and immobility (1, 2). Breast cancer cells do not resorb bone; instead they rely on stimulation of osteoclasts, cells physiologically responsible for bone destruction (1-4). Breast cancer cells can stimulate osteoclasts indirectly, by producing factors, such as parathyroid hormone-related peptide, interleukin-1, -6, and -11, which act on bone-forming osteoblasts to increase the production of an essential osteoclast stimulator, receptor activator of nuclear factor B (RANK) 4 ligand (RANKL) (1, 5-11). We have found that soluble factors produced by human or mouse breast cancer cells can directly stimulate osteoclast formation from late human or mouse osteoclast precursors (12). These effects depended on the permissive action of TGF␤, and we observed that TGF␤ type I receptor expression (T␤RI) was up-regulated in late osteoclast precursors (12). The expression of TGF␤ and T␤RI increases at the interface between...

Osteoclasts are giant bone cells formed by fusion from monocytes and uniquely capable of a complete destruction of mineralized tissues. Previously, we have demonstrated that in energy-rich environment not only osteoclast fusion index (the number of nuclei each osteoclast contains), but also cytoplasm volume per single nucleus was increased. The goal of this study was to investigate the regulation of metabolic sensor mTOR during osteoclast differentiation in energy-rich environment simulated by addition of pyruvate. We have found that in the presence of pyruvate, the proportion of mTOR associated with raptor increased, while mTOR-rictor-mediated Akt phosphorylation decreased. Inhibition of mTOR with rapamycin (10 nM) significantly interfered with all aspects of osteoclastogenesis. However, rapamycin at 1 nM, which preferentially targets mTOR-raptor complex, was only effective in control cultures, while in the presence of pyruvate osteoclast fusion index was successfully increased. Inhibition of Akt drastically reduced osteoclast fusion, however in energy-rich environment, osteoclasts of comparable size were formed through increased cytoplasm growth. These data suggest that mTOR-rictor mediated Akt signaling regulates osteoclast fusion, while mTOR-raptor regulation of protein translation contributes to fusion-independent cytoplasm growth. We demonstrate that depending on the bioenergetics microenvironment osteoclastogenesis can adjust to occur through preferential multinucleation or through cell growth, implying that attaining large cell size is part of the osteoclast differentiation program.

This study discusses our initial experience in the field of laparoscopic management of bladder carcinoma. Ten patients with invasive bladder tumors of variable histology and ranging from stage T2 to T3b were submitted to this procedure. Intraoperative assessment, lateral dissection, posterior dissection, anterior dissection, and urethral transection were achieved laparoscopically. The specimen retrieval and continent pouch construction was performed through a limited abdominal incision. This new regimen allows precise radical lymphadenectomy, early postoperative mobility, fewer wound complications, and shorter hospital stay. The early postoperative results of this procedure are encouraging. Modification and continuous refinement of the technique is still ongoing.

Minimal access surgery in the thyroid compartment has evolved considerably over the past 10 years and now takes many forms. This study examined the feasibility and reliability of minimally invasive thyroid surgery for the management of small benign thyroid lesions. A total of 68 patients with small thyroid nodules admitted to the Oncology Center of Mansoura University, Egypt, were enrolled in this prospective randomized trial. Patients were allotted to one of two procedures: minimally invasive video-assisted thyroidectomy (MIVAT) or minimally invasive open thyroidectomy using the Sofferman technique of strap muscle transection. Exclusion criteria were nodules > 4 cm, presence of thyroiditis, and thyroid gland volume > 20 ml. Preoperative diagnosis, operating time, blood loss, postoperative pain, complications, and cosmetic outcome were all evaluated. The MIVAT group included 35 patients, and the Sofferman group included 33 patients. The main preoperative pathology was a benign follicular lesion (70.5%), and the main postoperative final pathology was follicular adenoma (54.4%). The two groups were comparable regarding age, sex, and extent of thyroid surgery. Operating time was significantly longer in the MIVAT group (115.4 +/- 33.5 minutes) compared to the Sofferman group (65.6 +/- 23.7 minutes). The postoperative course was significantly less painful in the MIVAT group (p < 0.05). Although patients in the MIVAT group had smaller incisions (p < 0.05), the cosmetic outcome in the two groups was comparable. No long-term complication was encountered in either group. Two distinct approaches of minimally invasive thyroidectomy are now available and can be performed safely in selected patients. Despite some MIVAT advantages of less postoperative pain and slightly better cosmesis, minimally invasive open thyroidectomy offers an advantage of less operating time with comparable cosmetic results.

BackgroundThe aim of this study is to define an algorithm for the choice of reconstructive method for defects after laryngo-pharyngo-esophagectomy for hypopharyngeal carcinoma.MethodsOne hundred and forty two cases of hypopharyngeal carcinoma were included and operated on by either partial pharyngectomy, total pharyngectomy or esophagectomy. The reconstructive method was tailored according to the resected segment.ResultsPectoralis flap was used in 48 cases, free jejunal flap in 28 cases, augmented colon bypass in 4 cases, gastric pull up in 32 cases and gastric tube in 30 cases. Mean hospital stay was 12 days. Mortality rate was 10.6% and morbidity rate was 31.7%. Total flap failure occurred in 3 cases of free flap and one case of pectoralis flap. There were 23 cases of early fistula. Late stricture occurred in 19 cases, being highest with myocutaneous flap (early fistula 12/50 and late stricture 13/50).ConclusionFree jejunal flap was the flap of choice for reconstruction when the safety margin is still above the clavicle. In cases with added esophagectomy, we recommend gastric tube as a method of choice for reconstruction.

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Breast carcinoma is the most common cancer of women. Bones are often involved with breast carcinoma metastases with the resulting morbidity and reduced quality of life. Breast cancer cells arriving at bone tissues mount supportive microenvironment by recruiting and modulating the activity of several host tissue cell types including the specialized bone cells osteoblasts and osteoclasts. Pathologically activated osteoclasts produce osteolytic lesions associated with bone pain, pathological fractures, cord compression and other complications of metastatic breast carcinoma at bone. Over the last decade there has been enormous growth of knowledge in the field of osteoclasts biology both in the physiological state and in the tumor microenvironment. This knowledge allowed the development and implementation of several targeted therapeutics that expanded the armamentarium of the oncologists dealing with the metastases-associated osteolytic disease. While the interactions of cancer cells with resident bone cells at the established metastatic gross lesions are well-studied, the preclinical events that underlie the progression of disseminated tumor cells into micrometastases and then into clinically-overt macrometastases are just starting to be uncovered. In this review, we discuss the established information and the most recent discoveries in the pathogenesis of osteolytic metastases of breast cancer, as well as the corresponding investigational drugs that have been introduced into clinical development.

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