Simultaneous Contralateral Autologous Breast Augmentation during Unilateral Breast Reconstruction Utilizing Deep Inferior Epigastric Flaps.

It is predicted that 281,550 new cases of invasive breast cancer and 49,290 new cases of ductal carcinoma in situ will be diagnosed this year. In this study, we will detail our experience with simultaneous contralateral autologous breast augmentation during unilateral breast reconstruction utilizing bilateral deep inferior epigastric perforator (DIEP) flaps. Methods: A retrospective analysis of patients who underwent simultaneous contralateral autologous breast augmentation during unilateral breast reconstruction utilizing bilateral DIEP flaps by the senior surgeons at Beaumont Health Systems, Royal Oak, was conducted. Demographic data, operative details, complications, medical comorbidities, and patient outcomes were retrospectively analyzed. Results: Seven patients who met the inclusion criteria were identified. One patient underwent immediate reconstruction with DIEP flaps, one patient had a history of lumpectomy and underwent delayed partial breast reconstruction, three patients had delayed unilateral DIEP breast reconstruction with contralateral breast augmentation, and two patients had previous augmentations that were revised. All patients examined in this review tolerated the procedures well and had clinically viable flaps along with superior aesthetic outcomes. Conclusions: This technique can be applied to various clinical conditions, including immediate breast reconstruction, delayed breast reconstruction, and salvage for failed implant-based reconstruction, leading to optimal patient outcomes and satisfaction. Unilateral breast reconstruction with simultaneous contralateral autologous breast augmentation utilizing bilateral DIEP flaps is a surgical technique that more plastic surgeons should utilize.

Comparing Plastic Surgeon Operative Time for DIEP Flap Breast Reconstruction: 2-stage More Efficient than 1-stage?

The deep inferior epigastric perforator flap for breast reconstruction is associated with lengthy operative times that remain an issue for plastic surgeons today. The main objective of this study was to determine if a 2-stage deep inferior epigastric perforator flap reconstruction resulted in a shorter total plastic surgeon operative time compared with an immediate reconstruction. METHODS: A retrospective chart review was conducted on all patients who underwent deep inferior epigastric perforator flap breast reconstruction from February 2013 to July 2020 by the senior author. Patient demographics, medical comorbidities, mastectomy characteristics, expander placement, reconstructive procedures, operative time, and complications were tabulated. RESULTS: The study included a total of 128 patients. For immediate/1-stage flap reconstruction, average operative times for the plastic surgeon were 427.0 minutes for unilateral procedures, and 506.3 minutes for bilateral procedures. For delayed/2-stage reconstruction, average combined plastic surgeon operative times were 351.1 minutes for unilateral expander followed by flap reconstruction (75.9 minutes shorter than immediate unilateral, P = 0.007), and 464.8 minutes for bilateral reconstruction (41.5 minutes shorter than immediate bilateral, P = 0.04). Total patient time under anesthesia was longer for 2-staged bilateral reconstruction (P = 0.0001), but did not differ significantly for unilateral reconstruction. Complications between immediate and delayed groups were not significantly different. CONCLUSIONS: We found that staged reconstruction over 2 procedures resulted in a significant reduction in operative time for the plastic surgeon for both unilateral and bilateral reconstruction. With amenable breast surgeons and patients, the advantages of controlling scheduling and the operating room may encourage plastic surgeons to consider performing free flap reconstruction in a delayed fashion.

Total scrotal reconstruction following Fournier's gangrene with bilateral prelaminated superior medial thigh flaps.

The patient is a 45-year-old man diagnosed with Fournier's gangrene and underwent treatment for septic shock, broad-spectrum antibiotic therapy and extensive surgical debridement of perineum, including total scrotectomy, ischiorectal fossa, abdomen and left superior thigh and flank. The patient required multiple staged complex reconstruction of the scrotum utilising prelaminated superior medial thigh flaps with use of dermal matrix, split-thickness skin grafting and pedicled gracilis muscle flap for coverage of the ischiorectal wound. The patient had full recovery and followed up 1 year postoperatively. This report discusses our technique for total scrotal reconstruction and provides review of surgical reconstructive techniques for wounds due to Fournier's gangrene.

Intraneural Lipoma of the Digital Nerve: A Case Report and Literature Review.

Intraneural lipomas are rare soft-tissue tumors that can occur particularly within the median nerve. Even fewer cases have been reported of their occurrence within the ulnar nerve. These masses can cause compression neuropathies. In this report, we present the first documented case of an intraneural lipoma of an ulnar digital nerve.

Becker Implant Intracapsular Rupture with Contralateral Axillary Silicone Lymphadenopathy in an Asymptomatic Patient: A Case Report and Literature Review.

Silicone gel implants are widely used for cosmetic and reconstructive breast surgery. There has been a paradigm shift with increased utilization of implant-based breast reconstruction compared to autologous reconstruction in the United States over the past couple of decades. Implant rupture is a known complication of silicone gel implants with variable incidence and increased propensity with the age of the implant. Usually, the clinical findings suggestive of implant rupture are not obvious to the patient and surgeon. Intracapsular implant rupture, when the shell of the implant ruptures but the fibrous capsule formed by the breast remains intact, occurs in the majority of cases. While extracapsular rupture, which denotes silicone leakage extending beyond the capsule, is less common. In rare cases, silicone migrates beyond the capsule to distant sites, regional sites, and lymph nodes, leading to a variety of symptoms. Following mastectomy with lymph node dissection, the disruption of normal breast lymphatic drainage may result in aberrant drainage to internal mammary nodes and contralateral axillary lymph nodes. We present a unique case of axillary silicone lymphadenopathy due to contralateral breast intracapsular implant rupture in a patient with no previous ipsilateral breast surgery. The condition was found during a routine breast cancer screening. We also engage in a review of the relevant literature.

Natural IAP inhibitor Embelin enhances therapeutic efficacy of ionizing radiation in prostate cancer.

Embelin is an active ingredient of traditional herbal medicine that exhibits anti-tumor effects in human prostate cancer cells. However, therapeutic effect of embelin in combination with conventional radiation therapy is not yet determined. In this study, we evaluate the sensitizing potential of embelin on ionizing radiation (IR) in a human prostate cancer model. In vitro, embelin combined with radiation potently suppressed prostate cancer PC-3 cell proliferation that was associated with S and G2/M arrest in cell cycle. Moreover, the combination treatment promoted caspase-independent apoptosis, as evidenced by the increased apoptotic cell death without caspase-3 activation, but not autophagy. Clonogenic survival assay showed that S-phase arrest was required for embelin-mediated radiosensitization. In vivo, embelin significantly improved tumor response to X-ray radiation in the PC-3 xenograft model. Combination therapy produced enhanced tumor growth delay and prolonged time to progression, with minimal systemic toxicity. Immunohistochemistry studies showed that embelin plus IR significantly inhibited cell proliferation, induced apoptosis, and decreased microvessel density in tumors as compared with either treatment alone, suggesting an enhanced combinatory inhibition on tumor suppression and angiogenesis. Our results demonstrate that embelin significantly facilitates tumor suppression by radiation therapy both in vitro and in vivo in the prostate cancer model. This finding warrants embelin as a novel adjuvant therapeutic candidate for the treatment of hormone-refractory prostate cancer that is resistant to radiation therapy.

Natural proteasome inhibitor celastrol suppresses androgen-independent prostate cancer progression by modulating apoptotic proteins and NF-kappaB.

BACKGROUND: Celastrol is a natural proteasome inhibitor that exhibits promising anti-tumor effects in human malignancies, especially the androgen-independent prostate cancer (AIPC) with constitutive NF-κB activation. Celastrol induces apoptosis by means of proteasome inhibition and suppresses prostate tumor growth. However, the detailed mechanism of action remains elusive. In the current study, we aim to test the hypothesis that celastrol suppresses AIPC progression via inhibiting the constitutive NF-κB activity as well as modulating the Bcl-2 family proteins. METHODOLOGY/PRINCIPAL FINDINGS: We examined the efficacy of celastrol both in vitro and in vivo, and evaluated the role of NF-κB in celastrol-mediated AIPC regression. We found that celastrol inhibited cell proliferation in all three AIPC cell lines (PC-3, DU145 and CL1), with IC50 in the range of 1-2 µM. Celastrol also suppressed cell migration and invasion. Celastrol significantly induced apoptosis as evidenced by increased sub-G1 population, caspase activation and PARP cleavage. Moreover, celastrol promoted cleavage of the anti-apoptotic protein Mcl-1 and activated the pro-apoptotic protein Noxa. In addition, celastrol rapidly blocked cytosolic IκBα degradation and nuclear translocation of RelA. Likewise, celastrol inhibited the expression of multiple NF-κB target genes that are involved in proliferation, invasion and anti-apoptosis. Celastrol suppressed AIPC tumor progression by inhibiting proliferation, increasing apoptosis and decreasing angiogenesis, in PC-3 xenograft model in nude mouse. Furthermore, increased cellular IκBα and inhibited expression of various NF-κB target genes were observed in tumor tissues. CONCLUSIONS/SIGNIFICANCE: Our data suggest that, via targeting the proteasome, celastrol suppresses proliferation, invasion and angiogenesis by inducing the apoptotic machinery and attenuating constitutive NF-κB activity in AIPC both in vitro and in vivo. Celastrol as an active ingredient of traditional herbal medicine could thus be developed as a new therapeutic agent for hormone-refractory prostate cancer.

MicroRNA regulation of cancer stem cells and therapeutic implications.

MicroRNAs (miRNAs) are a class of endogenous non-protein-coding RNAs that function as important regulatory molecules by negatively regulating gene and protein expression via the RNA interference (RNAi) machinery. MiRNAs have been implicated to control a variety of cellular, physiological, and developmental processes. Aberrant expressions of miRNAs are connected to human diseases such as cancer. Cancer stem cells are a small subpopulation of cells identified in a variety of tumors that are capable of self-renewal and differentiation. Dysregulation of stem cell self-renewal is a likely requirement for the initiation and formation of cancer. Furthermore, cancer stem cells are a very likely cause of resistance to current cancer treatments, as well as relapse in cancer patients. Understanding the biology and pathways involved with cancer stem cells offers great promise for developing better cancer therapies, and might one day even provide a cure for cancer. Emerging evidence demonstrates that miRNAs are involved in cancer stem cell dysregulation. Recent studies also suggest that miRNAs play a critical role in carcinogenesis and oncogenesis by regulating cell proliferation and apoptosis as oncogenes or tumor suppressors, respectively. Therefore, molecularly targeted miRNA therapy could be a powerful tool to correct the cancer stem cell dysregulation.

MicroRNA miR-34 inhibits human pancreatic cancer tumor-initiating cells.

BACKGROUND: MicroRNAs (miRNAs) have been implicated in cancer initiation and progression via their ability to affect expression of genes and proteins that regulate cell proliferation and/or cell death. Transcription of the three miRNA miR-34 family members was recently found to be directly regulated by p53. Among the target proteins regulated by miR-34 are Notch pathway proteins and Bcl-2, suggesting the possibility of a role for miR-34 in the maintenance and survival of cancer stem cells. METHODOLOGY/PRINCIPAL FINDINGS: We examined the roles of miR-34 in p53-mutant human pancreatic cancer cell lines MiaPaCa2 and BxPC3, and the potential link to pancreatic cancer stem cells. Restoration of miR-34 expression in the pancreatic cancer cells by either transfection of miR-34 mimics or infection with lentiviral miR-34-MIF downregulated Bcl-2 and Notch1/2. miR-34 restoration significantly inhibited clonogenic cell growth and invasion, induced apoptosis and G1 and G2/M arrest in cell cycle, and sensitized the cells to chemotherapy and radiation. We identified that CD44+/CD133+ MiaPaCa2 cells are enriched with tumorsphere-forming and tumor-initiating cells or cancer stem/progenitor cells with high levels of Notch/Bcl-2 and loss of miR-34. More significantly, miR-34 restoration led to an 87% reduction of the tumor-initiating cell population, accompanied by significant inhibition of tumorsphere growth in vitro and tumor formation in vivo. CONCLUSIONS/SIGNIFICANCE: Our results demonstrate that miR-34 may restore, at least in part, the tumor suppressing function of the p53 in p53-deficient human pancreatic cancer cells. Our data support the view that miR-34 may be involved in pancreatic cancer stem cell self-renewal, potentially via the direct modulation of downstream targets Bcl-2 and Notch, implying that miR-34 may play an important role in pancreatic cancer stem cell self-renewal and/or cell fate determination. Restoration of miR-34 may hold significant promise as a novel molecular therapy for human pancreatic cancer with loss of p53-miR34, potentially via inhibiting pancreatic cancer stem cells.

Celastrol potentiates radiotherapy by impairment of DNA damage processing in human prostate cancer.

PURPOSE: Celastrol is an active ingredient of traditional herbal medicine and has recently been identified as a potent natural proteasome inhibitor. In the present study, we evaluated the radiosensitizing potential of celastrol in the human prostate cancer PC-3 model. METHODS AND MATERIALS: Clonogenic assays were performed to determine the radiosensitizing effect of celastrol. Apoptosis was examined by flow cytometry using Annexin V and propidium iodide staining and by a caspase-3 activation assay. DNA damage processing was examined by immunofluorescent staining and Western blot for phosphorylated H2AX (gammaH2AX). The PC-3 xenograft model in the athymic nude mouse was used for the determination of the in vivo efficacy of celastrol combined with radiotherapy. The tumor samples were also analyzed for apoptosis and angiogenesis. RESULTS: Celastrol sensitized PC-3 cells to ionizing radiation (IR) in a dose- and schedule-dependent manner, in which pretreatment with celastrol for 1 h followed by IR achieved maximal radiosensitization. Celastrol significantly prolonged the presence of IR-induced gammaH2AX and increased IR-induced apoptosis. Celastrol, combined with fractionated radiation, significantly inhibited PC-3 tumor growth in vivo without obvious systemic toxicity. The combination treatment increased gammaH2AX levels and apoptosis, induced cleavage of poly(adenosine diphosphate-ribose)polymerase and Mcl-1, and reduced angiogenesis in vivo compared with either treatment alone. CONCLUSION: Celastrol sensitized PC-3 cells to radiation both in vitro and in vivo by impairing DNA damage processing and augmenting apoptosis. Celastrol might represent a promising new adjuvant regimen for the treatment of hormone-refractory prostate cancer.

Molecularly targeted radiosensitization of human prostate cancer by modulating inhibitor of apoptosis.

PURPOSE: The inhibitor of apoptosis proteins (IAP) are overexpressed in hormone-refractory prostate cancer, rendering the cancer cells resistant to radiation. This study aims to investigate the radiosensitizing effect of small-molecule IAP inhibitor both in vitro and in vivo in androgen-independent prostate cancer and the possible mechanism of radiosensitization. EXPERIMENTAL DESIGN: Radiosensitization of SH-130 in human prostate cancer DU-145 cells was determined by clonogenic survival assay. Combination effect of SH-130 and ionizing radiation was evaluated by apoptosis assays. Pull-down and immunoprecipitation assays were employed to investigate the interaction between SH-130 and IAPs. DU-145 xenografts in nude mice were treated with SH-130, radiation, or combination, and tumor suppression effect was determined by caliper measurement or bioluminescence imaging. Nuclear factor-kappaB activation was detected by luciferase reporter assay and quantitative real-time PCR. RESULTS: SH-130 potently enhanced radiation-induced caspase activation and apoptosis in DU-145 cells. Both X-linked IAP and cIAP-1 can be pulled down by SH-130 but not by inactive SH-123. Moreover, SH-130 interrupted interaction between X-linked IAP/cIAP-1 and Smac. In a nude mouse xenograft model, SH-130 potently sensitized the DU-145 tumors to X-ray radiation without increasing systemic toxicity. The combination therapy suppressed tumor growth more significantly than either treatment alone, with over 80% of complete tumor regression. Furthermore, SH-130 partially blocked tumor necrosis factor-alpha- and radiation-induced nuclear factor-kappaB activation in DU-145 cells. CONCLUSIONS: Our results show that small-molecule inhibitors of IAPs can overcome apoptosis resistance and radiosensitize human prostate cancer with high levels of IAPs. Molecular modulation of IAPs may improve the outcome of prostate cancer radiotherapy.

Restoration of tumor suppressor miR-34 inhibits human p53-mutant gastric cancer tumorspheres.

BACKGROUND: MicroRNAs (miRNAs), some of which function as oncogenes or tumor suppressor genes, are involved in carcinogenesis via regulating cell proliferation and/or cell death. MicroRNA miR-34 was recently found to be a direct target of p53, functioning downstream of the p53 pathway as a tumor suppressor. miR-34 targets Notch, HMGA2, and Bcl-2, genes involved in the self-renewal and survival of cancer stem cells. The role of miR-34 in gastric cancer has not been reported previously. In this study, we examined the effects of miR-34 restoration on p53-mutant human gastric cancer cells and potential target gene expression. METHODS: Human gastric cancer cells were transfected with miR-34 mimics or infected with the lentiviral miR-34-MIF expression system, and validated by miR-34 reporter assay using Bcl-2 3'UTR reporter. Potential target gene expression was assessed by Western blot for proteins, and by quantitative real-time RT-PCR for mRNAs. The effects of miR-34 restoration were assessed by cell growth assay, cell cycle analysis, caspase-3 activation, and cytotoxicity assay, as well as by tumorsphere formation and growth. RESULTS: Human gastric cancer Kato III cells with miR-34 restoration reduced the expression of target genes Bcl-2, Notch, and HMGA2. Bcl-2 3'UTR reporter assay showed that the transfected miR-34s were functional and confirmed that Bcl-2 is a direct target of miR-34. Restoration of miR-34 chemosensitized Kato III cells with a high level of Bcl-2, but not MKN-45 cells with a low level of Bcl-2. miR-34 impaired cell growth, accumulated the cells in G1 phase, increased caspase-3 activation, and, more significantly, inhibited tumorsphere formation and growth. CONCLUSION: Our results demonstrate that in p53-deficient human gastric cancer cells, restoration of functional miR-34 inhibits cell growth and induces chemosensitization and apoptosis, indicating that miR-34 may restore p53 function. Restoration of miR-34 inhibits tumorsphere formation and growth, which is reported to be correlated to the self-renewal of cancer stem cells. The mechanism of miR-34-mediated suppression of self-renewal appears to be related to the direct modulation of downstream targets Bcl-2, Notch, and HMGA2, indicating that miR-34 may be involved in gastric cancer stem cell self-renewal/differentiation decision-making. Our study suggests that restoration of the tumor suppressor miR-34 may provide a novel molecular therapy for p53-mutant gastric cancer.