Obesity and adverse breast cancer risk and outcome: Mechanistic insights and strategies for intervention.

Answer questions and earn CME/CNE Recent decades have seen an unprecedented rise in obesity, and the health impact thereof is increasingly evident. In 2014, worldwide, more than 1.9 billion adults were overweight (body mass index [BMI], 25-29.9 kg/m2 ), and of these, over 600 million were obese (BMI ≥30 kg/m2 ). Although the association between obesity and the risk of diabetes and coronary artery disease is widely known, the impact of obesity on cancer incidence, morbidity, and mortality is not fully appreciated. Obesity is associated both with a higher risk of developing breast cancer, particularly in postmenopausal women, and with worse disease outcome for women of all ages. The first part of this review summarizes the relationships between obesity and breast cancer development and outcomes in premenopausal and postmenopausal women and in those with hormone receptor-positive and -negative disease. The second part of this review addresses hypothesized molecular mechanistic insights that may underlie the effects of obesity to increase local and circulating proinflammatory cytokines, promote tumor angiogenesis and stimulate the most malignant cancer stem cell population to drive cancer growth, invasion, and metastasis. Finally, a review of observational studies demonstrates that increased physical activity is associated with lower breast cancer risk and better outcomes. The effects of recent lifestyle interventions to decrease sex steroids, insulin/insulin-like growth factor-1 pathway activation, and inflammatory biomarkers associated with worse breast cancer outcomes in obesity also are discussed. Although many observational studies indicate that exercise with weight loss is associated with improved breast cancer outcome, further prospective studies are needed to determine whether weight reduction will lead to improved patient outcomes. It is hoped that several ongoing lifestyle intervention trials, which are reviewed herein, will support the systematic incorporation of weight loss intervention strategies into care for patients with breast cancer. CA Cancer J Clin 2017;67:378-397. © 2017 American Cancer Society.

Viral G protein-coupled receptor up-regulates Angiopoietin-like 4 promoting angiogenesis and vascular permeability in Kaposi's sarcoma.

Kaposi's sarcoma (KS) is an enigmatic vascular tumor thought to be a consequence of dysregulated expression of the human herpesvirus-8 (HHV-8 or KSHV)-encoded G protein-coupled receptor (vGPCR). Indeed, transgenic animals expressing vGPCR manifest vascular tumors histologically identical to human KS, with expression of the viral receptor limited to a few cells, suggestive of a paracrine mechanism for vGPCR tumorigenesis. Both human and vGPCR experimental KS lesions are characterized by prominent angiogenesis and vascular permeability attributed to the release of angiogenic molecules, most notably vascular endothelial growth factor. However, the relative contribution of these paracrine mediators to the angiogenic and exudative phenotype of KS lesions remains unclear. Here we show that vGPCR up-regulation of Angiopoietin-like 4 (ANGPTL4) plays a prominent role in promoting the angiogenesis and vessel permeability observed in KS. Indeed, ANGPTL4 expression is a hallmark of vGPCR experimental and human KS lesions. Inhibition of ANGPTL4 effectively blocks vGPCR promotion of the angiogenic switch and vascular leakage in vitro and tumorigenesis in vivo. These observations suggest that ANGPTL4 is a previously unrecognized target for the treatment of patients with KS. As angiogenesis and increased vessel permeability are common themes in all solid tumors, these findings may have a broad impact on our understanding and treatment of cancer.

Disrupted abdominal laparotomy wounds in gynaecologic oncology patients: benefits of active surgical re-closure.

OBJECTIVE: To assess the outcome of active management of disrupted wounds through surgical approximation and re-closure. METHOD: A prospective, non-comparative study, on all consecutive patients with disrupted laparotomy wounds treated at a tertiary medical centre, from November 2009 to December 2011. Data on patient demographics, diagnosis, type of abdominal incision, initial closure technique, infections and results of secondary re-closure were collected from the medical files. All patients underwent bedside closure with an en bloc mass suture mattress technique, performed by two attending gynaecologic oncologists. RESULTS: Of 197 patients who underwent abdominal laparotomy during the study period, 31 (16%) had a disrupted wound. Following surgical re-closure, 26 wounds (84%) were completely healed or needed only minor additional care by follow up on day 10. Five wounds (16%) failed primary management and required re-suturing; all subsequently healed. There were no long-term complications. CONCLUSION: Active surgical re-closure of disrupted abdominal laparotomy wounds is safe and effective in patients after treatment surgically for Müllerian malignancies.

Effect of triiodothyronine on antidepressant screening tests in mice and on presynaptic 5-HT1A receptors: mediation by thyroid hormone α receptors.

Although triiodothyronine (T3) is widely used clinically, preclinical support for its antidepressant-like effects is limited, and the mechanisms are unknown. We evaluated 1) the antidepressant-like effects of T3 in the novelty suppressed feeding test (NSFT), tail suspension test (TST), and forced swim test (FST), 2) the role of presynaptic 5-HT(1A) receptors in the antidepressant-like mechanism of T3 by the hypothermic response to the 5-HT(1A) receptor agonist, 8-hydroxy-N,N-dipropyl-2-aminotetralin (8-OH-DPAT), 3) the thyroid hormone receptor type mediating the antidepressant-like effects by concurrent administration of the specific thyroid hormone α receptor (TRα) antagonist, dronedarone, and 4) the presence of these effects in both genders. Male and female BALB/c mice were administered 1) T3 (20, 50, 200, or 500 µg/kg per day) or vehicle or 2) T3 (50 µg/kg per day), dronedarone (100 µM/day), or the combination intraperitoneally for 21 days and then underwent a behavioral test battery. The NSFT showed a shortened latency to feed in males at the two lower T3 doses. The TST and FST showed decreased immobility in male mice at T3 doses >20 µg/kg per day and in females at all T3 doses. Concurrent dronedarone prevented T3 effects in males on the NSFT and in the TST and FST in both genders. Attenuation of 8-OH-DPAT-induced hypothermia was observed in males only and may be reduced by concurrent dronedarone. These findings support an antidepressant-like effect of T3. Attenuation of 8-OH-DPAT-induced hypothermia in males only suggests the need to evaluate a possible gender disparity in the role of presynaptic 5-HT(1A) receptors in T3 antidepressant mechanisms. Blockade by dronedarone of the antidepressant-like effects of T3 suggests that these effects are TRα receptor-mediated.

Modulation of dopamine tone induces frequency shifts in cortico-basal ganglia beta oscillations.

Βeta oscillatory activity (human: 13-35 Hz; primate: 8-24 Hz) is pervasive within the cortex and basal ganglia. Studies in Parkinson's disease patients and animal models suggest that beta-power increases with dopamine depletion. However, the exact relationship between oscillatory power, frequency and dopamine tone remains unclear. We recorded neural activity in the cortex and basal ganglia of healthy non-human primates while acutely and chronically up- and down-modulating dopamine levels. We assessed changes in beta oscillations in patients with Parkinson's following acute and chronic changes in dopamine tone. Here we show beta oscillation frequency is strongly coupled with dopamine tone in both monkeys and humans. Power, coherence between single-units and local field potentials (LFP), spike-LFP phase-locking, and phase-amplitude coupling are not systematically regulated by dopamine levels. These results demonstrate that beta frequency is a key property of pathological oscillations in cortical and basal ganglia networks.

Practical Aspects of Multiscale Classical and Quantum Simulations of Enzyme Reactions.

This chapter aims to present some basic multiscale approaches available for enzyme simulations, and to point out practical details and pitfalls that are not often discussed in the literature, but can greatly influence the outcome of any in silico enzyme study. We cover principle methodological steps of multiscale studies of general enzyme reactions. This includes choice of starting structures, boundary conditions, potential energy surfaces, reaction coordinates, simulation methods, as well as the choice of method for the treatment of nuclear quantum effects. Together, these and additional steps are crucial for the success of enzyme-modeling projects and should be considered prior to embarking on multiscale modeling.

Enhanced killing of chordoma cells by antibody-dependent cell-mediated cytotoxicity employing the novel anti-PD-L1 antibody avelumab.

Chordoma, a rare bone tumor derived from the notochord, has been shown to be resistant to conventional therapies. Checkpoint inhibition has shown great promise in immune-mediated therapy of diverse cancers. The anti-PD-L1 mAb avelumab is unique among checkpoint inhibitors in that it is a fully human IgG1 capable of mediating antibody-dependent cell-mediated cytotoxicity (ADCC) of PD-L1-expressing tumor cells. Here, we investigated avelumab as a potential therapy for chordoma. We examined 4 chordoma cell lines, first for expression of PD-L1, and in vitro for ADCC killing using NK cells and avelumab. PD-L1 expression was markedly upregulated by IFN-γ in all 4 chordoma cell lines, which significantly increased sensitivity to ADCC. Brachyury is a transcription factor that is uniformly expressed in chordoma. Clinical trials are ongoing in which chordoma patients are treated with brachyury-specific vaccines. Co-incubating chordoma cells with brachyury-specific CD8+ T cells resulted in significant upregulation of PD-L1 on the tumor cells, mediated by the CD8+ T cells' IFN-γ production, and increased sensitivity of chordoma cells to avelumab-mediated ADCC. Residential cancer stem cell subpopulations of chordoma cells were also killed by avelumab-mediated ADCC to the same degree as non-cancer stem cell populations. These findings suggest that as a monotherapy for chordoma, avelumab may enable endogenous NK cells, while in combination with T-cell immunotherapy, such as a vaccine, avelumab may enhance NK-cell killing of chordoma cells via ADCC.

Risk factors for recurrence after Le Fort colpocleisis for severe pelvic organ prolapse in elderly women.

INTRODUCTION: We investigated parameters associated with recurrence after partial (Le Fort) colpocleisis surgery for severe pelvic organ prolapse (POP) in elderly women. METHODS: A retrospective cohort study included all women who underwent partial colpocleisis in a single tertiary center from February 2007 through July 2013 for stage 3 or 4 triple compartment prolapse. Inclusion criteria were age over 60, sexually inactive, medical comorbidities, increased risk for comprehensive reconstructive pelvic surgery, and refusal or failure to use a pessary as a conservative non-surgical treatment. Exclusion criteria were post-menopausal bleeding, pelvic malignancy, and the desire to preserve coital function. RESULTS: The study group included 47 women of mean age 77.3 ± 8.2 (range 61-91 years). All had medical comorbidities. Fourteen patients (29.8%) had undergone previous hysterectomy. All patients underwent partial colpocleisis and perineorrhaphy. Seven women (14.9%) underwent mid-urethral sling for urinary incontinence. Mean follow-up was 14.8 ± 10.3 months (range, 2-37 months) and mean hospitalization, 3.5 ± 1.5 days (range, 2-9 days). There were no intraoperative complications. Postoperative complications comprised lower urinary tract infection (n = 2). Objective cure (according to vaginal examination) was 80.9% (38/47), and subjective (according to symptoms), 91.5% (43/47). No patient regretted the loss of sexual function. The main reasons for prolapse recurrence were statistically significant longer post-operative vaginal length and wider genital hiatus. CONCLUSIONS: Objective and subjective cure rates of Le Fort colpocleisis for the treatment of severe POP were high with low morbidity. Parameters associated with prolapse recurrence were longer postoperative vaginal length and wider genital hiatus.

Robotic blue-dye sentinel lymph node detection for endometrial cancer - Factors predicting successful mapping.

OBJECTIVE: Sentinel lymph node (SLN) mapping has emerged as a viable option for the treatment of patients with endometrial cancer. We report our initial experience with SLN mapping algorithm, and examine the factors predicting successful SLN mapping. METHODS: We analyzed all data recorded in our institute on robotic blue-dye SLN detection mapping from the time it was first introduced to our department in January 2012-December 2014. Data included patient demographics, SLN allocation, operating room times, and pathology results. RESULTS: During the study period, 74 patients had robotic assisted surgery for endometrial cancer with attempted SLN mapping. SLN was found overall in 46 patients (62.1%). At first, SLN was detected in only 50% of cases, but after performing 30 cases, detection rates rose to 84.6% (OR = 3.34, CI 1.28-8.71; p = 0.003). Univariate analysis showed a higher detection rate with methylene blue than patent blue dye, 74.3% vs. 52.3% (OR = 2.744, 95% CI 1.026-7.344; p = 0.042). In multivariate analysis, high body mass index (BMI) was associated with failed mapping (OR = 0.899; 95% CI 0.808-1.00), as was the presence of lymph-vascular space invasion (LVSI) (OR = 0.126; 95% CI 0.24-0.658) and few cases per surgeon (OR = 1.083, 95% CI 1.032-1.118). Factors related to uterine pathology itself, including tumor histology, grade, method of diagnosis, the presence of an endometrial polyp, and lower uterine segment involvement were not found to be associated with successful mapping. CONCLUSIONS: Surgeon experience, BMI and LVSI may affect the success rate of SLN mapping for endometrial cancer. These factors should be investigated further in future studies.

Puerperal adrenal abscess complicating chorioamnionitis.

BACKGROUND: An abscess in the adrenal gland is a rare finding described only a few times in the literature. We present a case report of chorioamnionitis complicated by a puerperal adrenal abscess diagnosed and drained percutaneously using ultrasound and computed tomography. CASE: A 22-year-old woman delivered prematurely because of chorioamnionitis. Amoxicillin clavulanate was administered, and her fever defervesced. Six days later, the patient presented with a temperature of 40C and right flank pain. Workup revealed an abscess in the right adrenal gland, which was diagnosed by computed tomography scan, and then drained percutaneously. Follow-up revealed regression of the abscess to complete recovery. CONCLUSION: Adrenal abscess has not been described in the past as a possible complication of choriamnionitis. It is important to assess the entire abdominal cavity by ultrasound or computed tomography in febrile patients who do not respond to medical therapy.

Lymphangioma-Like Kaposi's Sarcoma Presenting as Gangrene.

Kaposi's sarcoma (KS) is a multicentric vascular neoplasm associated with the Kaposi's sarcoma-associated herpes virus (KSHV). KS can occur in immunocompromised patients as well as certain populations in Africa or in the Mediterranean. Less than 5% of KS cases can present with lymphangioma-like kaposi sarcoma (LLKS), which can occur in all KS variants. KS presents with characteristic skin lesions that appear as brown, red, blue, or purple plaques and nodules. The lesions are initially flat and if untreated will become raised. LLKS presents similarly to KS but is associated with severe lymphedema and soft tissue swelling as well as bulla-like vascular lesions. We present the case of an 85-year-old Lebanese, HIV negative, man who presented with a swollen and painful right lower extremity accompanied by necrotic lesions. Wound cultures were positive, and we began the work-up for secondarily infected gangrene. However, skin biopsy results revealed that he in fact had lymphangioma-like Kaposi sarcoma, which allowed us to shift our management. Advanced Kaposi's sarcoma can present similar to gangrene. It is important to recognize the typical skin lesions of KS and not to overlook Kaposi's sarcoma or LLKS within the differential.

Can parametrectomy be avoided in early cervical cancer? An algorithm for the identification of patients at low risk for parametrial involvement.

AIMS: To assess the rate of parametrial involvement in a large cohort of patients who underwent radical hysterectomy for cervical cancer and to suggest an algorithm for the triage of patients to simple hysterectomy or simple trachelectomy. METHODS: Multicenter retrospective study of patients with cervical cancer stage I through IIA who underwent radical hysterectomy and pelvic lymphadenectomy. The patients were divided into 2 groups according to whether or not the parametrium was involved. The two groups were compared with regard to the clinical and histopathological variables. Logistic regression of the variables potentially assessable prior to definitive hysterectomy such as age, tumor size, lymph-vascular space invasion (LVSI) and nodal involvement was performed. RESULTS: Five hundred and thirty patients had specific histological data on parametrial involvement and in 58 (10.9%) patients, parametria was involved. Parametrial involvement was significantly associated with older age, tumors larger than 2 cm, deeper invasion, LVSI, involved surgical margins, and the presence of nodal metastasis. By triaging patients with a tumor ≤ 2 cm and no LVSI, the parametrial involvement rate was 1.8% (2/112 patients). With further triage of patients with negative nodes, the rate of parametrial involvement was 0% (0/107 patients). CONCLUSION: Using a pre-operative triage algorithm, patients with early small lesions, no LVSI and no nodal involvement may be spared radical surgical procedures and parametrectomy. Further prospective data are urgently needed.

Amplification of the angiogenic signal through the activation of the TSC/mTOR/HIF axis by the KSHV vGPCR in Kaposi's sarcoma.

BACKGROUND: Kaposi's sarcoma (KS) is a vascular neoplasm characterized by the dysregulated expression of angiogenic and inflammatory cytokines. The driving force of the KS lesion, the KSHV-infected spindle cell, secretes elevated levels of vascular endothelial growth factor (VEGF), essential for KS development. However, the origin of VEGF in this tumor remains unclear. METHODOLOGY/PRINCIPAL FINDINGS: Here we report that the KSHV G protein-coupled receptor (vGPCR) upregulates VEGF in KS through an intricate paracrine mechanism. The cytokines secreted by the few vGPCR-expressing tumor cells activate in neighboring cells multiple pathways (including AKT, ERK, p38 and IKKß) that, in turn, converge on TSC1/2, promoting mTOR activation, HIF upregulation, and VEGF secretion. Conditioned media from vGPCR-expressing cells lead to an mTOR-dependent increase in HIF-1α and HIF-2α protein levels and VEGF upregulation. In a mouse allograft model for KS, specific inhibition of the paracrine activation of mTOR in non-vGPCR-expressing cells was sufficient to inhibit HIF upregulation in these cells, and abolished the ability of the vGPCR-expressing cells to promote tumor formation in vivo. Similarly, pharmacologic inhibition of HIF in this model blocked VEGF secretion and also lead to tumor regression. CONCLUSIONS/SIGNIFICANCE: Our findings provide a compelling explanation for how the few tumor cells expressing vGPCR can contribute to the dramatic amplification of VEGF secretion in KS, and further provide a molecular mechanism for how cytokine dysregulation in KS fuels angiogenesis and tumor development. These data further suggest that activation of HIF by vGPCR may be a vulnerable target for the treatment of patients with KS.

Angiopoietin-like 4: a novel molecular hallmark in oral Kaposi's sarcoma.

Kaposi's sarcoma (KS) remains among the most common causes of oral cancer in HIV-infected individuals. Infection with the KS-associated herpesvirus (KSHV/HHV8) is a necessary event for disease development. Emerging evidence suggests that KSHV infects vascular endothelial (or endothelial progenitor) cells promoting the formation of the KS tumor (or spindle) cell. These cells elaborate angiogenic growth factors and cytokines that promote the dysregulated angiogenesis and profuse edema that characterizes this unusual vascular tumor. Central among these secreted factors is the potent endothelial cell mitogen, vascular endothelial growth factor (VEGF). Indeed, VEGF has proven to be a key player in KSHV pathogenesis and is a molecular hallmark of KS lesions. We have recently shown that a second angiogenic factor, Angiopoietin-like 4 (ANGPTL4), may also play a critical role in KS development. Here we demonstrate that ANGPTL4 is upregulated both directly and indirectly by the KSHV oncogene, vGPCR. We further show that ANGPTL4 is a molecular hallmark of oral KS lesions. Indeed, expression of this protein was observed in more tumor cells and in more biopsies specimens than expression of VEGF (23/25 or 92% vs. 19/25 or 76%, respectively) in oral KS. These surprising results support a key role for ANGPTL4 in Kaposi's sarcomagenesis and further suggest that this angiogenic factor may provide a novel diagnostic and therapeutic marker for oral KS patients.

Separate necdin domains bind ARNT2 and HIF1alpha and repress transcription.

PWS is caused by the loss of expression of a set of maternally imprinted genes including NECDIN (NDN). NDN is expressed in post-mitotic neurons and plays an essential role in PWS as mouse models lacking only the Ndn gene mimic aspects of this disease. Patients haploid for SIM1 develop a PW-like syndrome. Here, we report that NDN directly interacts with ARNT2, a bHLH-PAS protein and dimer partner for SIM1. We also found that NDN can interact with HIF1alpha. We showed that NDN can repress transcriptional activation mediated by ARNT2:SIM1 as well as ARNT2:HIF1alpha. The N-terminal 115 residues of NDN are sufficient for interaction with the bHLH domains of ARNT2 or HIF1alpha but not for transcriptional repression. Using GAL4-NDN fusion proteins, we determined that NDN possesses multiple repression domains. We thus propose that NDN regulates neuronal function and hypoxic response by regulating the activities of the ARNT2:SIM1 and ARNT2:HIF1alpha dimers, respectively.

Placental shelf - a common, typically transient and benign finding on early second-trimester sonography.

OBJECTIVE: Placental shelves are believed to represent circumvallate placentae. It is thought that circumvallate placenta may be associated with adverse perinatal outcome when present at delivery. The objective of this study was to determine the prevalence, persistence and significance of placental shelves detected in the early second trimester. METHODS: In 152 consecutive anomaly scans performed between 13 and 16 weeks of gestation, special attention was directed to placental structure and the presence of a placental shelf. When present, a mid-gestation scan was performed to verify if the finding persisted. If so, a third-trimester scan was performed. Delivery charts were reviewed for all cases initially diagnosed with a placental shelf, recording any placenta-related complications. RESULTS: In 17 of 152 (11.2%) early second-trimester scans a placental shelf was detected. In three of these 17 cases the shelf persisted to the 20-22-week scan. In the two cases that presented for the third-trimester scan the shelf was no longer present. In all 17 cases the perinatal outcome was good. CONCLUSIONS: In our study group early second-trimester placental shelves rarely persisted to mid-gestation and never to the third trimester. There were no placenta-related perinatal problems. Early second-trimester placental shelf appears to be a common, benign and transient sonographic finding.

Prenatal diagnosis of intestinal pseudo-obstruction.

The appearance of polyhydramnios and dilated bowel loops on prenatal sonographic examination usually implies mechanical obstruction. The prognosis is variable, depending on the etiology. Congenital pseudo-obstruction, a potentially lethal disease, comprises a group of disorders characterized by intestinal obstruction in the absence of an anatomic lesion. This report focuses on the prenatal diagnosis of intestinal pseudo-obstruction, and two cases of transient congenital intestinal pseudo-obstruction in one family are described. In both, the prenatal sonographic presentation was of small bowel obstruction. In one case there was postnatal suspicion of neurogenic bladder, and in the other there was unilateral hydronephrosis. The sonographic appearance of intestinal pseudo-obstruction is similar to that of mechanical obstruction. The clues to the prenatal diagnosis of pseudo-obstruction include associated urinary tract abnormalities and a family history of pseudo-obstruction.

Maternal and umbilical cord serum leptin concentrations in small-for-gestational-age and in appropriate-for-gestational-age neonates: a maternal, fetal, or placental contribution?

Leptin is secreted during pregnancy by the placenta and by the maternal and fetal adipose tissues. The leptin levels mainly reflect the amount of fat stored and thus are indicative of the energy balance, i.e., small-for-gestational-age (SGA) neonates represent the negative metabolic balance of in utero starved babies. We chose to compare maternal and umbilical cord leptin levels in pregnancies complicated by asymmetrical SGA versus those with appropriate-for-gestational-age (AGA) neonates as well as a model of multifetal growth concordant gestations in order to establish through the 'leptin link' the relative contributions of mother, fetus, and placenta to fetal weight. We found that the maternal leptin levels at delivery correlated poorly with the maternal weight gain/body mass index and with neonatal birth weight. Furthermore, the umbilical cord leptin levels correlated well with neonatal and placental weights in the AGA group but not in the SGA group. As in AGA singleton pregnancies, in multifetal uncomplicated pregnancies, the umbilical cord leptin levels correlated well with the birth weight of individuals, regardless of the status of the twin or triplet in the set. Thus, we speculated that in SGA neonates the birth weight represents the lean body weight and the low adipose tissue content (as opposed to the AGA neonates who have a substantial adipose tissue content) and, therefore, reflects mainly the basic placental contribution.