Shailesh Agarwal

Effect of Breast Conservation Therapy vs Mastectomy on Disease-Specific Survival for Early-Stage Breast Cancer

IMPORTANCE To our knowledge, there are no recent studies that directly compare survival after breast conservation therapy (BCT) vs mastectomy. OBJECTIVE To compare the breast cancer-specific survival rates of patients undergoing BCT, mastectomy alone, or mastectomy with radiation using a contemporary cohort of patients. DESIGN, SETTING, AND PARTICIPANTS We performed univariate, multivariate logistic regression, and propensity analyses to compare the hazard of death for female patients with early-stage invasive ductal carcinoma treated with BCT, mastectomy alone, or mastectomy with radiation during the period from 1998 to 2008. The data were extracted from the Surveillance, Epidemiology, and End Results database. Early-stage breast cancer was defined as having a tumor size of 4 cm or smaller with 3 or less positive lymph nodes. EXPOSURE Breast conservation therapy, mastectomy alone, or mastectomy with radiation. MAIN OUTCOMES AND MEASURES Hazard of death due to breast cancer for patients undergoing BCT, mastectomy alone, or mastectomy with radiation. RESULTS A total of 132,149 patients were included in this analysis. Breast conservation therapy was used to treat 70% of patients, mastectomy alone was used to treat 27% of patients, and mastectomy with radiation was used to treat 3% of patients. The 5-year breast cancer-specific survival rates of patients who underwent BCT, a mastectomy alone, or a mastectomy with radiation were 97%, 94%, and 90%, respectively (P < .001); the 10-year breast cancer-specific survival rates were 94%, 90%, and 83%, respectively (P < .001). Multivariate analysis showed that women undergoing BCT had a higher survival rate than those undergoing mastectomy alone (hazard ratio, 1.31; P < .001) or mastectomy with radiation (hazard ratio, 1.47; P < .001). When propensity score stratification was used, the effect of treatment method on survival was similar. CONCLUSIONS AND RELEVANCE Patients who underwent BCT have a higher breast cancer-specific survival rate compared with those treated with mastectomy alone or mastectomy with radiation for early-stage invasive ductal carcinoma. Further investigation is warranted to understand what may be contributing to this effect.

Treatment of heterotopic ossification through remote ATP hydrolysis.

Heterotopic ossification induced by injuries and burns is mediated by signaling through the SMAD pathway and can be targeted with topical apyrase. No Bones About It Heterotopic ossification is a painful side effect that can complicate burns, trauma, and some types of surgery. In patients with this condition, small amounts of bone form in abnormal locations throughout the body, causing pain and complicating recovery. Now, Peterson et al. have developed a mouse model of heterotopic ossification, investigated the mechanism of this disorder, and then used their animal model to demonstrate a potential therapeutic intervention: topical application of apyrase. Although apyrase was only applied to the injury site, it decreased the abnormal formation of bone throughout the body. Other therapies, such as celecoxib and a drug called LDN-193189, were effective as well, suggesting the possibility of multiple therapeutic options for preventing heterotopic ossification in injured patients. Heterotopic ossification (HO) is the pathologic development of ectopic bone in soft tissues because of a local or systemic inflammatory insult, such as burn injury or trauma. In HO, mesenchymal stem cells (MSCs) are inappropriately activated to undergo osteogenic differentiation. Through the correlation of in vitro assays and in vivo studies (dorsal scald burn with Achilles tenotomy), we have shown that burn injury enhances the osteogenic potential of MSCs and causes ectopic endochondral heterotopic bone formation and functional contractures through bone morphogenetic protein–mediated canonical SMAD signaling. We further demonstrated a prevention strategy for HO through adenosine triphosphate (ATP) hydrolysis at the burn site using apyrase. Burn site apyrase treatment decreased ATP, increased adenosine 3′,5′-monophosphate, and decreased phosphorylation of SMAD1/5/8 in MSCs in vitro. This ATP hydrolysis also decreased HO formation and mitigated functional impairment in vivo. Similarly, selective inhibition of SMAD1/5/8 phosphorylation with LDN-193189 decreased HO formation and increased range of motion at the injury site in our burn model in vivo. Our results suggest that burn injury–exacerbated HO formation can be treated through therapeutics that target burn site ATP hydrolysis and modulation of SMAD1/5/8 phosphorylation.

Heterotopic Ossification: Basic-science Principles and Clinical Correlates.

➤ Heterotopic ossification occurs most commonly after joint arthroplasty, spinal cord injury, traumatic brain injury, blast trauma, elbow and acetabular fractures, and thermal injury.➤ The conversion of progenitor cells to osteogenic precursor cells as a result of cell-mediated interactions with the local tissue environment is affected by oxygen tension, pH, availability of micronutrients, and mechanical stimuli, and leads to heterotopic ossification.➤ Radiation and certain nonsteroidal anti-inflammatory medications are important methods of prophylaxis against heterotopic ossification.➤ Well-planned surgical excision can improve patient outcomes regardless of the joint involved or the initial cause of injury.➤ Future therapeutic strategies are focused on targeted inhibition of local factors and signaling pathways that catalyze ectopic bone formation.

An analysis of immediate postmastectomy breast reconstruction frequency using the surveillance, epidemiology, and end results database

Abstract:  Mastectomy is used to treat one third of the nearly 180,000 women diagnosed with breast cancer in the United States annually. In this study, we use population‐level data from multiple years of the Surveillance, Epidemiology, End Results (SEER) database to further define patient, tumor, and geographic characteristics associated with immediate and early‐delayed breast reconstruction. Population level de‐identified data for the years 1998 to 2002 were extracted from the National Cancer Institute’s (NCI) SEER cancer database. All female patients who were treated with mastectomy for a diagnosis of ductal and/or lobular breast cancer (including Paget disease) were included. The primary end point of interest was odds of reconstruction. Multivariate analysis was performed to control for patient demographic and oncologic characteristics. A total of 52,249 patients met the inclusion criteria. Reconstruction was performed in 8,446 patients (16.2%). Odds of reconstruction varied by region from 0.60 (Seattle) to 2.81 (Atlanta). African Americans were noted to have a significantly lower likelihood of reconstruction when compared with Caucasian patients (OR 0.60 versus 1.00). Patients living in nonmetropolitan regions were also significantly less likely to undergo reconstruction. Receipt of radiation therapy was also negatively correlated with likelihood of reconstruction. In this multicenter, multiyear analysis of factors associated with immediate or early‐delayed reconstruction after mastectomy, we demonstrate that younger age, white race, metropolitan locale, and lower stage disease were all independently associated with higher likelihood of reconstruction. This information provides insight into breast reconstruction utilization and will help guide future studies to understand how these factors affect patient and physician decision‐making.

Inhibition of Hif1α prevents both trauma-induced and genetic heterotopic ossification

Significance Heterotopic ossification (HO) is a debilitating condition in which bone forms inappropriately within soft tissues. Two vastly different patient populations are at risk for developing HO: those with musculoskeletal trauma or severe burns and those with a genetic mutation in the bone morphogenetic protein receptor ACVR1 (Activin type 1 receptor). In this study, we demonstrate that both forms of HO share a common signaling pathway through hypoxia inducible factor-1α, and that pharmacologic inhibition or genetic knockout of this signaling pathway can mitigate and even abolish HO formation. These findings pave the way for pharmacologic inhibitors of hypoxia inducible factor-1α as therapeutic options for heterotopic ossification. Pathologic extraskeletal bone formation, or heterotopic ossification (HO), occurs following mechanical trauma, burns, orthopedic operations, and in patients with hyperactivating mutations of the type I bone morphogenetic protein receptor ACVR1 (Activin type 1 receptor). Extraskeletal bone forms through an endochondral process with a cartilage intermediary prompting the hypothesis that hypoxic signaling present during cartilage formation drives HO development and that HO precursor cells derive from a mesenchymal lineage as defined by Paired related homeobox 1 (Prx). Here we demonstrate that Hypoxia inducible factor-1α (Hif1α), a key mediator of cellular adaptation to hypoxia, is highly expressed and active in three separate mouse models: trauma-induced, genetic, and a hybrid model of genetic and trauma-induced HO. In each of these models, Hif1α expression coincides with the expression of master transcription factor of cartilage, Sox9 [(sex determining region Y)-box 9]. Pharmacologic inhibition of Hif1α using PX-478 or rapamycin significantly decreased or inhibited extraskeletal bone formation. Importantly, de novo soft-tissue HO was eliminated or significantly diminished in treated mice. Lineage-tracing mice demonstrate that cells forming HO belong to the Prx lineage. Burn/tenotomy performed in lineage-specific Hif1α knockout mice (Prx-Cre/Hif1αfl:fl) resulted in substantially decreased HO, and again lack of de novo soft-tissue HO. Genetic loss of Hif1α in mesenchymal cells marked by Prx-cre prevents the formation of the mesenchymal condensations as shown by routine histology and immunostaining for Sox9 and PDGFRα. Pharmacologic inhibition of Hif1α had a similar effect on mesenchymal condensation development. Our findings indicate that Hif1α represents a promising target to prevent and treat pathologic extraskeletal bone.

Use of resorbable implants for mandibular fixation: a systematic review.

Titanium plating is recognized as the criterion standard for the treatment of mandibular fractures and osteotomies. Use of resorbable implants is well documented in the literature for a range of craniofacial fractures. However, no clear review exists of the use of resorbable implants on the mandible. In this systematic review, we searched MEDLINE/PubMed and the Cochrane Database for studies of resorbable mandibular fixation. Two independent reviewers analyzed the search results using specific inclusion/exclusion criteria. Twenty-two articles detailing 19 studies, including 1 randomized controlled trial were analyzed in this study. These studies included fixation of mandibular fractures at various locations or fixation of bilateral sagittal split osteotomies. Overall, we found a total of 326 patients treated with resorbable plates and screws and 112 patients treated with resorbable screws alone. Analysis of these studies indicates that several material types are used in resorbable mandibular implants, including poly-l-lactic acid (PLLA) and 70% poly-l-lactic acid/30% poly-d,l-lactic acid (PLLA 70/PDLLA 30), coming from at least 10 different manufacturers. Mean follow-up ranged from 3 to 348 weeks. Based on the reported data, we found a total of 14 to 15 infections, 2 foreign body reactions, 7 malocclusions, 8 malunions, and 8 to 10 premature removals in the plate group and 1 foreign body reaction and 2 malocclusions in the screws-only group. These results should be interpreted in the context of the patient selection criteria in the studies. This systematic review demonstrates the need for further randomized controlled trials in this area and concludes with such a study design.

Therapeutic nipple-sparing mastectomy: trends based on a national cancer database.

BACKGROUND Current reports on nipple-sparing mastectomy (NSM) are limited to single-institution series. We use the National Cancer Institutes Surveillance, Epidemiology, and End Results database to report on the national experience with NSM. METHODS Population-level deidentified data were extracted from the Surveillance, Epidemiology, and End Results database. All female breast cancer patients treated with NSM from 2005 to 2009 were included. Case analysis was performed with respect to demographic and oncologic characteristics. RESULTS Four hundred forty-nine patients underwent therapeutic NSM; this number increased from 66 patients in 2005 to 133 in 2009. Patients were distributed across 16 regions, although nearly 50% were from a region of California. Tumor diameter was <2 cm in 224 patients (50%). Lymph nodes were positive in 59 patients (13%), while radiation was delivered to 74 patients (16%). CONCLUSIONS NSM use has been increasing over the past several years. A majority of patients have tumor size <2 cm, although the number of patients with tumor size ≥2 cm has increased over time. Further population-based studies of NSM may benefit from collection of oncologic data such as tumor-to-nipple distance and tumor location.

A Population-Based Study of Breast Cancer-Specific Survival Following Mastectomy and Immediate or Early-Delayed Breast Reconstruction

Abstract:  Immediate breast reconstruction allows for improved patient psychosocial outcomes after mastectomy. We used the Surveillance, Epidemiology, and End Results (SEER) database to study the breast cancer‐specific survival of patients treated with immediate or early‐delayed breast reconstruction after mastectomy. Population‐level de‐identified data was abstracted from the SEER database. All female patients treated with mastectomy for a diagnosis of ductal and/or lobular breast cancer between 1998 and 2002 were included. Breast cancer‐specific survival was reported as hazard ratios using multivariate analysis to control for patient demographic and oncologic covariates. Demographic covariates included age, race, marital status, income, education, and county metropolitan status; oncologic covariates included tumor stage, histology, grade, lymph node status, hormone receptor status, receipt of radiation therapy, and unilateral or bilateral mastectomy. A total of 52,249 patients were included in the study. Patients treated with mastectomy and reconstruction had a significantly lower hazard of death (HR 0.73, p < 0.0001) compared with patients treated with mastectomy only. Black patients had a significantly increased hazard of death (HR 1.42, p < 0.0001) compared with white patients. Receipt of radiotherapy did not significantly associate with hazard of death (HR 1.03, p = 0.3494). Additionally, bilateral mastectomy did not significantly associate with hazard of death (HR 0.98, p = 0.763). Our analysis shows that patients who undergo breast reconstruction after mastectomy have a higher breast cancer‐specific survival than those undergoing mastectomy alone, when controlling for demographic and oncologic covariates. Further research is required to understand the nature of this relationship.

Cost Analysis of Near-Infrared Spectroscopy Tissue Oximetry for Monitoring Autologous Free Tissue Breast Reconstruction

Free flap monitoring typically requires specialized nursing that can increase medical costs. This study uses near-infrared spectroscopy (NIRS) tissue oximetry to monitor free tissue breast reconstruction. We hypothesize this practice will reduce medical costs by eliminating the need for specialized nursing. From August 2006 to January 2010, women undergoing unilateral free tissue breast reconstruction were enrolled and admitted postoperatively to either the surgical intensive care unit (ICU) or floor. Each underwent continuous monitoring using NIRS tissue oximetry and intermittent clinical examination with surface Doppler ultrasonography. Patient demographics, comorbidities, perioperative details, and financial data were recorded. There were 50 patients studied, all with abdominal-based flaps (25 per group). There were no statistically significant differences in patient demographics, comorbidities, mean flap weight, ischemia time, or length of stay between the ICU and floor groups. Four flaps had vascular complications, all detected by NIRS tissue oximetry. Comparison of hospital costs showed an average reduction of

Bariatric Surgery: A History of Empiricism, a Future in Science

1937 per patient when monitored on the surgical floor (P = 0.036). NIRS tissue oximetry is a sensitive and reliable monitoring tool, eliminating the need for specialized nursing care. The effect is decreased cost structure and increased hospital contribution margin for autologous free tissue breast reconstruction.