Osama Hussein

Laparoscopic Assisted Cystectomy and Lymphadenectomy for Bladder Cancer: Initial Experience

Abstract. 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.

Breast Cancer-derived Factors Stimulate Osteoclastogenesis through the Ca2+/Protein Kinase C and Transforming Growth Factor-β/MAPK Signaling Pathways

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 κB ligand (RANKL)-primed precursors and that transforming growth factor-β (TGFβ) 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 TGFβ 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 Cα 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 Cα and TGFβ-dependent ERK1/2 and p38 signaling pathways.

Rapamycin inhibits osteolysis and improves survival in a model of experimental bone metastases

Breast cancer metastasis to bone results in pain, pathological fractures and hypercalcemia. Activation of osteoclasts is critical for the formation of osteolytic lesions by metastasizing tumors. Although the potent drugs, zoledronic acid and Denosumab were introduced, the presence of resistant or intolerant cases necessitated the continued search of osteoclast-targeting treatments. Rapamycin acts through the mTOR pathway, which is important for osteoclast formation. Mouse mammary carcinoma 4T1 cells were injected into the tibia of balb/c mice. Rapamycin treatment significantly decreased the osteoclast population and osteolysis associated with experimental metastases. Our data indicate the benefit of rapamycin in treating metastases-associated osteolytic disease.

Breast cancer at bone metastatic sites: recent discoveries and treatment targets

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.

Breast cancer cells inhibit spontaneous and bisphosphonate-induced osteoclast apoptosis

Breast cancer metastasizes to bone where it stimulates formation of bone-resorbing osteoclasts. Bisphosphonates constitute an important treatment for osteolytic metastases. The goal of this study was to assess the effects of soluble factors produced by breast cancer cells on osteoclast survival and responsiveness to bisphosphonates. Osteoclasts derived from the murine monocytic cell line RAW264.7 or from primary mouse bone marrow were cultured for 24-48 h untreated, with 10% conditioned media (CM) from human (MDA-MB-231) or mouse (4T1) metastatic breast carcinoma cells, or with a pro-survival factor RANKL. Cancer-derived factors maintained osteoclast survival at the levels comparable to those observed with RANKL. Alendronate (10⁻⁴M) or pamidronate (10⁻⁷M) induced osteoclast apoptosis in untreated and, to a smaller extent, in RANKL-treated cultures, resulting in a significant decrease in osteoclast number and size, induction of caspase-3 cleavage and up-regulation of BIM. In the presence of cancer-derived factors, bisphosphonates were ineffective in inducing osteoclast apoptosis, resulting in only modest decrease in osteoclast numbers and not in size. MDA-MB-231 CM prevented bisphosphonate-induced cleavage of caspase-3 and up-regulation of BIM. MCSF-neutralizing antibody attenuated the effect of MDA-MB-231 CM by ~50%, but could not fully restore osteoclast responsiveness to alendronate. Inhibition of phospholipase C (PLC)-γ interfered with MDA-MB-231-induced down-regulation of BIM and prevented anti-apoptotic action of cancer-derived factors on osteoclasts. Our data suggest that factors produced by the metastatic breast cancer cells promote osteoclast survival and block the apoptotic effect of bisphosphonates in MCSF and PLC-dependent manner, potentially compromising bisphosphonate effectiveness in the bone metastasis setting.

Skin-Sparing Mastectomy with Immediate Breast Reconstruction by a New Modification of Extended Latissimus Dorsi Myocutaneous Flap

BackgroundThe introduction of skin-sparing mastectomy has revolutionized both breast cancer surgery and breast reconstruction. Latissimus dorsi myocutaneous flap is a versatile flap that is gaining renewed popularity with the development of flap modifications and the continued recognition of its reliability and safety. We report our results with a new modification of the extended latissimus dorsi flap after skin-sparing mastectomy for breast cancer.MethodsFrom January 2002 to January 2006, 140 patients of breast carcinoma had unilateral skin-sparing mastectomy and immediate breast reconstruction. A total of 132 cases of invasive duct carcinoma and eight cases of invasive lobular carcinoma are included. Age ranged from 27 to 53 (median, 40.5) years. Tumor stage was stage I in 22 cases, stage II in 100 cases, and stage III in 18 cases. We performed a new modification to the standard extended latissimus dorsi flap, which allowed us to obtain enough autologous tissue to reconstruct the relatively large breast of the Egyptian women without implant. The postoperative aesthetic results and donor side morbidity, including contour deformity and scaring, were examined.ResultsWe applied both an objective and subjective aesthetic result monitoring. Aesthetic grading results of breast reconstruction were excellent in 85, good in 42, fair in ten and poor in three cases. Both flap and donor site complications were minor. Patients were followed for a median of 32.4 (range, 12-48) months. During this period of follow-up, no episode of local or distant failure was observed.ConclusionsSkin-sparing mastectomy with immediate breast reconstruction using our new modification of extended latissimus dorsi flap allows single-stage, totally autologous reconstruction with satisfactory aesthetic results and low morbidity.

Pharyngoesophageal reconstruction after resection of hypopharyngeal carcinoma: a new algorithm after analysis of 142 cases

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.

Therapeutic reduction mammoplasty in large- breasted women with cancer using superior and superomedial pedicles

BACKGROUND Surgical management of breast cancer in large-breasted women presents a real challenge. This study aims to evaluate the outcome of therapeutic reduction mammoplasty in large-breasted women with breast cancer using superior and superomedial pedicles, situated at any breast quadrant except for the central and upper medial quadrants. METHODS Fifty women with breast cancer and large breasts underwent simultaneous bilateral reduction mammoplasty. The weight of the tissue removed ranged from 550 g to 1050 g and the tumor-free safety margins by frozen section were in the range of 4 cm to 12 cm. RESULTS The age of the patients ranged from 36 to 58 (median 43) years and tumor size ranged from 1 cm to 4 cm. The cosmetic outcomes were excellent in 32 patients (64%), good in 15 (30%) patients, and fair in three patients (6%). The follow-up period was 8-36 (mean 20) months, with no local recurrence or systemic metastasis. CONCLUSION Therapeutic reduction mammoplasty using superior and superomedial pedicles was shown to be oncologically safer than traditional conservative surgery. This oncoplastic procedure yields a satisfactory esthetic outcome with lower morbidity in large-breasted women with breast cancer.

Hormone Receptors and Age Distribution in Breast Cancer Patients at a University Hospital in Northern Egypt

Introduction Breast cancer is the most common cancer among Egyptian women. The disease is often advanced at diagnosis. Since molecular profiling is not feasible in routine practice, we sought to examine the association of age distribution with hormone receptor profile, disease stage and outcome among Egyptian women. Patients and Methods We conducted a retrospective review of breast cancer patients treated at Mansoura University Cancer Center in the Nile Delta from 2006 through 2011. Age groups were examined in relation to hormone receptors status and tumor clinicopathological criteria. Additionally, the effect of receptor status on disease relapse and disease-free survival was examined with logistic regression and Kaplan–Meier analysis. Results A total of 263 patients were included in the current analysis. About 66.9% (n = 176) of patients were hormone receptor positive, 14.1% (n = 37) were Her2/neu positive, and 19.0% (n = 50) were triple negative. Median age of the patients was 52 years and was equal across all receptor status types. Triple negative status correlated with increased risk of disease relapse (odds ratio = 1.8, P = 0.03) and with shortened disease-free survival (hazards ratio = 2.6, P < 0.01). Conclusion The age distribution and receptor status pattern in the Nile Delta region does not explain the aggressive behavior of the disease. The age of the patients at diagnosis is older than patients in earlier studies from Egypt emphasizing the importance of implementing mammographic screening programs.

Regulation of Osteoclast Growth and Fusion by mTOR/raptor and mTOR/rictor/Akt

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.