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The human visual system is tasked with recovering the different physical sources of optical structure that generate our retinal images. Separate research has focused on understanding how the visual system estimates (a) environmental sources of image structure and (b) blur induced by the eye’s limited focal range, but little is known about how the visual system distinguishes environmental sources from optical defocus. Here, we present evidence that this is a fundamental perceptual problem and provide insights into how and when the visual system succeeds and fails in solving it. We show that fully focused surface shading can be misperceived as defocused and that optical blur can be misattributed to the material properties and shape of surfaces. We further reveal how these misperceptions depend on the relationship between shading gradients and sharp contours, and conclude that computations of blur are inherently linked to computations of surface shape, material, and illumination.

Michael J Hall,1 Julie Innocent,2 Christina Rybak,1 Colleen Veloski,3 Walter J Scott,4 Hong Wu,5 John A Ridge,4 John P Hoffman,4 Hossein Borghaei,2 Aruna Turaka,6 Mary B Daly1 1Department of Clinical Genetics, 2Department of Medical Oncology, 3Department of Internal Medicine, 4Department of Surgical Oncology, 5Department of Pathology, 6Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA Introduction: Multiple endocrine neoplasia 1 (MEN1) is a cancer syndrome resulting from mutations of the MEN1 gene. The syndrome is characterized by neoplasia of the parathyroid and pituitary glands, and malignant tumors of the endocrine pancreas. Other manifestations include benign lipomas, angiofibromas, and carcinoid tumors commonly originating in the colon, thymus, and lung. This is the first report of MEN1 syndrome manifesting as bilateral granulosa cell ovarian tumors, and which is associated with a rare intronic mutation of the MEN1 gene. Case report: A 41-year-old woman presented with abdominal pain, increasing abdominal girth, and dysmenorrhea. Ultrasound demonstrated enlarged ovaries and uterine fibroids. After an exploratory laparotomy, she subsequently underwent bilateral salpingo–oophorectomy with hysterectomy where the pathology revealed bilateral cystic granulosa cell tumors of the ovaries. Additional workup including computed tomography imaging discovered a thymic mass, which the pathology showed was malignant, along with a pancreatic mass suspicious for a neuroendocrine tumor. Hyperparathyroidism was also discovered and was found to be secondary to a parathyroid adenoma. Genetic testing revealed an exceedingly rare mutation in the MEN1 gene (c.654 + 1 G>A). Discussion: Mutations of the menin gene leading to MEN1 syndrome are classically nonsense or missense mutations producing a dysfunctional protein product. Recently, researchers described a novel mutation of MEN1 (c.654 + 1 G>A) in a male proband meeting the criteria for clinical MEN1 syndrome. Functional analysis performed on the stable mutant protein showed selective disruption of the transforming growth factor beta signaling pathway, yet it maintained its wild-type ability to inhibit nuclear factor kappa B and to suppress JunD transcriptional activity. Conclusion: To our knowledge, this is the first report of MEN1 syndrome associated with bilateral granulosa cell malignancy. We postulate that this presentation may be due to the novel menin gene mutation recently described. Keywords: menin gene, ovarian tumors, hyperparathyroidism

STUDY OBJECTIVES: The role of radiofrequency ablation (RFA) for primary lung cancer remains poorly defined. The purpose of this 'ablate and resect' pilot study was to evaluate the safety of performing RFA in patients with primary non-small cell lung cancer (NSCLC) and to characterize the histologic changes in tumor tissue following such ablation. DESIGN: This prospective study was undertaken at a single institution, and 10 patients were accrued from June 2002 to June 2003. Eligible patients included those with clinical stage I or II disease. RFA of the tumor was performed through a standard thoracotomy followed by conventional lobectomy and lymph node dissection. Extent of cell death was determined histologically. MEASUREMENTS AND RESULTS: Following the exclusion of two patients, the treated portions of eight tumors were examined for tumor cell viability. Gross inspection and routine histologic staining could not reliably identify the 'immediately ablated' tissue. However, using a supravital staining technique, the treated areas from seven of the eight tumors (87.5%) demonstrated > 80% nonviability (100% nonviability was noted in the treated areas from three of the eight tumors). No bleeding or thermal complications were noted at the time of RFA, and none of the patients had skin burns at the electrode dispersive pad sites. CONCLUSIONS: RFA of primary NSCLC is feasible and can be performed safely in the setting of an open thoracotomy. Complete tumor cell necrosis, as determined by supravital staining, was noted in the treated areas from three of eight tumors (37.5%). Such complete ablation was observed in the treated areas from smaller tumors (< 2 cm), whereas the treated areas from larger tumors demonstrated incomplete ablation. Additional investigation with histopathologic correlation is needed to fully assess the long-term efficacy of RFA for NSCLC. [ABSTRACT FROM AUTHOR]

The prevention of tobacco-related morbidity and mortality through smoking cessation intervention is among the most vital missions of the chest clinician. This article summarizes the major findings and clinical recommendations of the US Department of Health and Human Services/Public Health Service Guideline, Treating Tobacco Use and Dependence, which is a comprehensive, evidence-based blueprint for smoking cessation. By becoming fluent in the clinical interventions and by implementing the simple institutional changes described in this article and in the guideline, chest clinicians can more effectively intervene with their patients who smoke. [ABSTRACT FROM AUTHOR]

BACKGROUND: The surgical treatment of stage I and II non-small cell lung cancer (NSCLC) continues to evolve in the areas of intraoperative lymph node staging (specifically the issue of lymph node dissection vs sampling), the role of sublobar resections instead of lobectomy for treatment of smaller tumors, and the use of video-assisted techniques to perform anatomic lobectomy. Adjuvant therapy (both chemotherapy and radiation therapy) and the use of larger fractions of radiotherapy delivered to a smaller area for nonoperative treatment of early stage NSCLC have shown promising results. METHODS: The panel selected the following areas for review based on clinical relevance and the amount and quality of data available for analysis: surgical approaches to resecting early stage NSCLC, methods of lymph node staging at the time of surgical resection, adjuvant chemotherapy in the treatment of early stage NSCLC, and the use of radiation therapy for primary treatment of early stage NSCLC as well as in the adjuvant setting. Recommendations by the multidisciplinary writing committee were based on literature review using established methods. RESULTS AND CONCLUSIONS: Surgical resection remains the treatment of choice for stage I and II NSCLC, although surgical methods continue to evolve. Adjuvant chemotherapy for patients with stage II, but not stage I, NSCLC is well established. Radiotherapy remains an important treatment for either cases of early stage NSCLC that are medically inoperable or patients who refuse surgery. [ABSTRACT FROM AUTHOR]

Stage IIIB includes patients with T4, any N, M0, and any T, N3, M0. Surgery may be indicated only for carefully selected T4N0M0 patients with or without neoadjuvant chemotherapy or chemoradiotherapy. Patients with N3 lymph node involvement are not considered as surgical candidates. For patients with unresectable disease, good performance score, and minimal weight loss, treatment with combined chemotherapy and radiotherapy has resulted in better survival than treatment with radiotherapy alone. Multiple daily fractions of radiotherapy have not resulted in improved survival compared with standard fractionation once daily. Concurrent chemoradiotherapy appears to be associated with improved survival compared with sequential chemotherapy and radiotherapy. Treatment of stage IIIB due to malignant pleural effusion is addressed in the section that deals with stage IV disease. [ABSTRACT FROM AUTHOR]

Stage IIIA non-small cell lung cancer represents a relatively heterogeneous group of patients with metastatic disease to the ipsilateral mediastinal (N2) lymph nodes and also includes T3N1 patients. Presentations of disease range from apparently resectable tumors with occult microscopic nodal metastases to unresectable, bulky multistation nodal disease. Controversy abounds as to the optimal treatment of the various stage IIIA subsets, which is fueled by a lack of meaningful, large randomized trials. Multimodality therapy of some type appears to be preferable in stage IIIA patients. [ABSTRACT FROM AUTHOR]

Objective: To compare the efficiency of venturi and peristaltic pump phacoemulsification systems in patients undergoing routine laser cataract surgery., Design: Single center, nonrandomized clinical study., Participants: The study compared consecutive eyes with moderate nuclear sclerosis undergoing routine laser cataract surgery at the Outpatient Eye Center, Mercy Health System, Springfield, MO, USA., Methods: Each surgery used the same femtosecond laser settings. Surgeries were performed with either a venturi or peristaltic vacuum system by a single surgeon (WJS). The EFX, percent power, ultrasound time (UST), the total time that the phaco tip was in the eye (phaco tip in/out time, PIOT), and the surgery time (speculum in/out time) were recorded. Exclusions and intraoperative complications were also analyzed., Results: 995 eyes were included in the study. The EFX in the venturi eyes (1.7 ± 1.3; n = 521) compared to peristaltic eyes (2.1 ± 1.4; n = 474) was lower (p < 0.0001). Similarly, the UST in the eyes performed with the venturi system versus the peristaltic system was reduced (32.4 ± 22.3 s vs 40.7± 25.7 s; p < 0.0001). The PIOT in the venturi group compared to the peristaltic group was less (71.1 ± 31.1 sec vs 79.1 ± 36.1 s; p = 0.0002). The case time (speculum in/out time) was lower for the venturi eyes (307.2 ± 68.8 s vs. 311.6 ± 53.6 s; p = 0.268)., Conclusion: In eyes undergoing routine laser cataract surgery, the use of the venturi pump system was more efficient compared to the peristaltic pump system based on energy use and time, and there was no significant difference in complications., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate the effectiveness of feedback reports and feedback reports + external facilitation on completion of life-sustaining treatment (LST) note the template and durable medical orders. This quality improvement program supported the national roll-out of the Veterans Health Administration (VA) LST Decisions Initiative (LSTDI), which aims to ensure that seriously-ill veterans have care goals and LST decisions elicited and documented., Data Sources: Primary data from national databases for VA nursing homes (called Community Living Centers [CLCs]) from 2018 to 2020., Study Design: In one project, we distributed monthly feedback reports summarizing LST template completion rates to 12 sites as the sole implementation strategy. In the second involving five sites, we distributed similar feedback reports and provided robust external facilitation, which included coaching, education, and learning collaboratives. For each project, principal component analyses matched intervention to comparison sites, and interrupted time series/segmented regression analyses evaluated the differences in LSTDI template completion rates between intervention and comparison sites., Data Collection Methods: Data were extracted from national databases in addition to interviews and surveys in a mixed-methods process evaluation., Principal Findings: LSTDI template completion rose from 0% to about 80% throughout the study period in both projects' intervention and comparison CLCs. There were small but statistically significant differences for feedback reports alone (comparison sites performed better, coefficient estimate 3.48, standard error 0.99 for the difference between groups in change in trend) and feedback reports + external facilitation (intervention sites performed better, coefficient estimate -2.38, standard error 0.72)., Conclusions: Feedback reports + external facilitation was associated with a small but statistically significant improvement in outcomes compared with comparison sites. The large increases in completion rates are likely due to the well-planned national roll-out of the LSTDI. This finding suggests that when dissemination and support for widespread implementation are present and system-mandated, significant enhancements in the adoption of evidence-based practices may require more intensive support., (© 2022 Health Research and Educational Trust.)

Objective: The quality of care provided by the US Department of Veterans Affairs (VA) is increasingly being compared to community providers. The objective of this study was to compare the VA Community Living Centers (CLCs) to nursing homes in the community (NHs) in terms of characteristics of their post-acute populations and performance on 3 claims-based ("short-stay") quality measures., Design: Observational, cross-sectional., Setting and Participants: CLC and NH residents admitted from hospitals during July 2015-June 2016., Methods: CLC residents were compared with 3 NH populations: males, Veterans, and all NH residents. CLC and NH performance was compared on risk-adjusted claims-based measures: unplanned rehospitalizations and emergency department visits within 30 days of CLC or NH admission and successful discharge to the community within 100 days of NH admission., Results: Veterans admitted from hospitals to CLCs (n = 23,839 Veterans/135 CLCs) were less physically impaired, less likely to have anxiety, congestive heart failure, hypertension, and dementia than Veterans (n = 241,177/14,818 NHs), males (n = 661,872/15,280 NHs), and all residents (n = 1,674,578/15,395 NHs) admitted to NHs from hospitals. Emergency department and successful discharge risk-adjusted rates of CLCs were statistically significantly better than those of NHs [mean (standard deviation): 8.3% (4.6%) and 67.7% (11.5%) in CLCs vs 11.9% (5.3%) and 57.0% (10.5%) in NHs, respectively]. CLCs had slightly worse rehospitalization rates [22.5% (6.2%) in CLCs vs 21.1% (5.9%) in NHs], but lower combined emergency department and rehospitalization rates [30.8% (0.8%) in CLCs vs 33.0% (0.7%) in NHs]., Conclusions and Implications: CLCs and NHs serve different post-acute care populations. Using the same risk-adjusted NH quality metrics, CLCs provided better post-acute care than community NHs., (Published by Elsevier Inc.)

Context: As part of its Life-Sustaining Treatment (LST) Decisions Initiative, the Veterans Health Administration (VA) in January 2017 began requiring electronic documentation of goals of care and preferences for Veterans with serious illness and at high risk for life-threatening events., Objectives: To evaluate whether goals of "to be comfortable" were associated with greater palliative care (PC) use and lesser acute care use., Methods: We identified Veterans with VA inpatient or nursing home stays overlapping July 2018-January 2019, with LST templates documented by January 31, 2019, and who died by April 30, 2019 (N = 18,163). From template documentation, we identified a "to be comfortable" goal. Using VA and Medicare data, we determined PC use (consultations and hospice) and hospital, intensive care unit, and emergency department use 7 and 30 days before death. Multivariate logistic regression examined the associations of interest., Results: Sixty-four percent of the 18,163 Veterans had comfort-care goals; 80% with comfort care goals received hospice and 57% PC consultations (versus 57% and 46%, respectively, for decedents without comfort-care goals). In adjusted analyses, comfort care documented on the LST template prior to death was associated with significantly lower odds of hospital, intensive care unit, and emergency department use near the end of life. In the last 30 days of life, Veterans with a comfort care goal had 44% lower odds (adjusted odds ratio 0.57; 95% CI: 0.51, 0.63) of being hospitalized., Conclusion: Findings support the VA's commitment to honoring of Veterans' preferences post introduction of its Life Sustaining Treatment Decisions Initiative., (Published by Elsevier Inc.)

Background: User-centered design (UCD) methods are well-established techniques for creating useful artifacts, but few studies illustrate their application to clinical feedback reports. When used as an implementation strategy, the content of feedback reports depends on a foundational audit process involving performance measures and data, but these important relationships have not been adequately described. Better guidance on UCD methods for designing feedback reports is needed. Our objective is to describe the feedback report design method for refining the content of prototype reports., Methods: We propose a three-step feedback report design method (refinement of measures, data, and display). The three steps follow dependencies such that refinement of measures can require changes to data, which in turn may require changes to the display. We believe this method can be used effectively with a broad range of UCD techniques., Results: We illustrate the three-step method as used in implementation of goals of care conversations in long-term care settings in the U.S. Veterans Health Administration. Using iterative usability testing, feedback report content evolved over cycles of the three steps. Following the steps in the proposed method through 12 iterations with 13 participants, we improved the usability of the feedback reports., Conclusions: UCD methods can improve feedback report content through an iterative process. When designing feedback reports, refining measures, data, and display may enable report designers to improve the user centeredness of feedback reports.

Purpose: To evaluate the frequency of anterior capsule tears and capsule edge irregularities in femtosecond laser anterior capsulotomy, including the effect of optimized vertical spacing settings., Methods: Three thousand eight hundred thirty-four cases were examined and grouped according to the femtosecond laser capsulotomy settings using manufacturer default settings with a vertical spacing of 10, 15, and 20 µm. Capsulotomy edge irregularities and anterior capsule tears were recorded intraoperatively., Results: The anterior capsule tear rates for the 10, 15, and 20 µm groups were 0.79%, 0.35%, and 0.09%, respectively. The capsule edge irregularity rates for the 10, 15, and 20 µm groups were 6.25%, 1.13%, and 1.15%, respectively. The treatment times for the 10, 15, and 20 µm groups were 1.6, 0.7, and 0.8 second, respectively. The risk reduction of anterior capsule tears positively correlated with the 15 and 20 µm group settings. The anterior capsule tear rate difference between the 10 and 20 µm group settings was statistically significant. Capsule edge irregularity rates were reduced in the 15 and 20 µm group settings. Eye movement was monitored in the 20 µm group and was observed in 9 of 13 patients with capsule edge irregularities., Conclusions: Anterior capsule tear rates are low with femtosecond laser cataract surgery. The rate can be further reduced with optimization of the settings, including an increase in vertical spacing. [J Refract Surg. 2019;35(5):280-284.]., (Copyright 2019, SLACK Incorporated.)

Objective: To identify existing evidence on interagency collaboration between law enforcement, emergency services, statutory services and third sector agencies regarding people with mental ill health., Design: Systematic scoping review. Scoping reviews map particular research areas to identify research gaps., Data Sources and Eligibility: ASSIA, CENTRAL, the Cochrane Library databases, Criminal Justice Abstracts, ERIC, Embase, MEDLINE, PsycINFO, PROSPERO and Social Care Online and Social Sciences Citation Index were searched up to 2017, as were grey literature and hand searches. Eligible articles were empirical evaluations or descriptions of models of interagency collaboration between the police and other agencies., Study Appraisal and Synthesis: Screening and data extraction were undertaken independently by two researchers. Arksey's framework was used to collate and map included studies., Results: One hundred and twenty-five studies were included. The majority of articles were of descriptions of models (28%), mixed methods evaluations of models (18%) and single service evaluations (14%). The most frequently reported outcomes (52%) were 'organisational or service level outcomes' (eg, arrest rates). Most articles (53%) focused on adults with mental ill health, whereas others focused on adult offenders with mental ill health (17.4%). Thirteen models of interagency collaboration were described, each involving between 2 and 13 agencies. Frequently reported models were 'prearrest diversion' of people with mental ill health (34%), 'coresponse' involving joint response by police officers paired with mental health professionals (28.6%) and 'jail diversion' following arrest (23.8%)., Conclusions: We identified 13 different interagency collaboration models catering for a range of mental health-related interactions. All but one of these models involved the police and mental health services or professionals. Several models have sufficient literature to warrant full systematic reviews of their effectiveness, whereas others need robust evaluation, by randomised controlled trial where appropriate. Future evaluations should focus on health-related outcomes and the impact on key stakeholders., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Pulmonary resection after pneumonectomy is a reasonable option in selected patients. Wedge resection for single peripheral metachronous disease has the best outcome with 5-year survival as high as 63%. Current and predicted postoperative cardiopulmonary reserve should be evaluated carefully. Stereotactic body radiotherapy is a promising alternative for inoperable patients., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: There has been an increased drive towards Evidence Based Policing in recent years. Unlike in other public sector services, such as health and education, randomised controlled trials in the police setting are relatively rare. This paper discusses some of the methodological and practical challenges of conducting a randomised controlled trial in the police setting in the UK, based on our experience of the Connect trial. This pragmatic, cluster-randomised controlled trial investigated the effectiveness of a face-to-face training intervention for frontline officers in comparison to routine training. The primary outcome was the number of incidents which resulted in a police response reported to North Yorkshire Police control room in a 1-month period up to 6 months after delivery of training., Main Text: The methodological and practical challenges that we experienced whilst conducting the Connect trial are discussed under six headings: establishing the unit of randomisation; population of interest and sample size; co-production of evidence; time frame; outcomes; and organisational issues., Conclusion: Recommendations on the conduct of future randomised controlled trials in the police setting are made. To understand the context in which research is undertaken, collaboration between police and academia is needed and police officers should be embedded within trial management groups. Engagement with police data analysts to understand what data is available and facilitate obtaining trial data is also recommended. Police forces may wish to review their IT systems and recording practices. Pragmatic trials are encouraged and time frames need to allow for trial set-up and obtaining relevant ethical approvals., Trial Registration: ISRCTN Registry, ID: ISRCTN11685602 . Retrospectively registered on 13 May 2016.

Background: Standard treatment for locally advanced esophageal cancer includes neoadjuvant therapy followed by surgical resection. However, many patients experience a period of decreased oral intake during neoadjuvant treatment and are at risk for malnutrition. We hypothesize that use of jejunostomy tube (j-tube) feedings during neoadjuvant therapy in selected patients may be associated with better perioperative outcomes., Methods: A prospectively collected database at a single institution was retrospectively analyzed. The study period was from 2005 to 2015. Patients who underwent j-tube placement before neoadjuvant therapy before definitive resection for esophageal cancer were included in the analysis. Perioperative outcomes were compared between patients who adhered to recommended tube feeds during neoadjuvant therapy (users) and patients who did not adhere (nonusers)., Results: During the study period, 94/301 patients received a j-tube before or during neoadjuvant therapy for esophageal cancer. Seventy-three patients utilized tube feeds regularly during the neoadjuvant phase, while 21 patients did not. The groups did not differ significantly with respect to clinical factors such as dysphagia on presentation, postneoadjuvant therapy performance status, or Charlson Comorbidity Index. Perioperative pneumonia rates were lower in j-tube users compared to nonusers (6.8% [5 of 73] versus 23.8% [5 of 21]), respectively, P = .036); this difference remained significant with adjustment for type of surgery (odds ratio = 0.16, P = .018)., Conclusions: j-Tube users had a significantly lower incidence of pneumonia within 30 days of curative resection when compared to nonusers. j-Tube feedings during neoadjuvant therapy for selected patients with locally advanced esophageal cancer should be encouraged.

Introduction: Police officers frequently come into contact with individuals with mental health problems. Specialist training in this area for police officers may improve how they respond to individuals with mental health problems; however, evidence to support this is sparse. This study evaluated the effectiveness of one bespoke mental health training package for frontline police officers relative to routine training., Design: Pragmatic, two-armed cluster randomised controlled trial in one police force in England. Police stations in North Yorkshire were randomised with frontline police officers receiving either a bespoke mental health training package or routine training. The primary outcome was the number of incidents which resulted in a police response reported to the North Yorkshire Police control room up to six months after delivery of training. Secondary outcomes included: likelihood of incidents using Section 136 of the Mental Health Act; likelihood of incidents having a mental health tag applied; and number of individuals with a mental health warning marker involved in incidents. The appropriateness of mental health tags applied to a random sample of incidents was checked by an independent mental health professional. Routinely collected data were used., Results: Twelve police stations were recruited and randomised (Intervention group n = 6; Control group n = 6), and 249 officers received the bespoke mental health training intervention. At follow-up, a median of 397 incidents were assigned to trial stations in the intervention group, and 498 in the control group. There was no evidence of a difference in the number of incidents with a police response (adjusted incidence rate ratio (IRR) 0.92, 95% CI 0.61 to 1.38, p = 0.69), or in the number of people with mental health warning markers involved in incidents (adjusted IRR 1.39, 95% CI 0.91 to 2.10, p = 0.13) between the intervention and control groups up to six months following the intervention; however, incidents assigned to stations in the intervention group were more likely to have a mental health tag applied to them than incidents assigned to control stations (adjusted odds ratio 1.41, 95% CI 1.16 to 1.71, p = 0.001). The review of 100 incidents suggests that there may be incidents involving individuals with mental health issues that are not being recorded as such (Kappa coefficient 0.65). There was no statistically significant difference in the likelihood of Section 136 of the Mental Health Act being applied to an incident., Conclusions: The bespoke one day mental health training delivered to frontline officers by mental health professionals did not reduce the number of incidents reported to the police control room up to six months after its delivery; however training may have a positive effect on how the police record incidents involving individuals with mental health problems. Our trial has shown that conducting pragmatic trials within the police setting is feasible and acceptable. There is a wealth of routinely collected police data that can be utilised for research and further collaboration between police forces and academia is encouraged., Trial Registration: ISRCTN (ISRCTN11685602). The authors confirm that all ongoing and related trials for this drug/intervention are registered.

Objectives: Preoperative chemotherapy and radiation for localized esophageal cancer produces cure rates near 30% when combined with surgical resection. Vandetanib, a small molecule receptor tyrosine kinase inhibitor of VEGFR-2, VEGFR-3, RET, and EGFR, demonstrated synergy with radiation and chemotherapy in preclinical models. We conducted a phase I study to assess the safety and tolerability of vandetanib when combined with preoperative chemoradiation in patients with localized esophageal carcinoma who were surgical candidates., Methods: Patients with stage II-III esophageal and gastroesophageal junction carcinoma without prior therapy were enrolled in a 3+3 phase I design. Patients received once-daily vandetanib (planned dosing levels of 100, 200, and 300 mg) with concomitant daily radiotherapy (1.8 Gy/d, 45 Gy total) and chemotherapy, consisting of infusional 5-FU (225 mg/m/d over 96 h, weekly), paclitaxel (50 mg/m, days 1, 8, 15, 22, 29) and carboplatin (AUC of 5, days 1, 29)., Results: A total 9 patients were enrolled with 8 having either distal esophageal or gastroesophageal junction carcinomas. All patients completed the planned preoperative chemoradiation and underwent esophagectomy. Nausea (44%) and anorexia (44%) were the most common acute toxicities of any grade. One grade 4 nonhematologic toxicity was observed (gastrobronchial fistula). One additional patient suffered a late complication, a fatal aortoenteric hemorrhage, not definitively related to the investigational regimen. Five (56%) patients achieved a pathologic complete response. Three (33%) additional patients had only microscopic residual disease. Five (56%) patients remain alive and disease free with a median follow-up of 3.7 years and median overall survival of 3.2 years. The maximum tolerated dose was vandetanib 100 mg/d., Conclusions: Vandetanib at 100 mg daily is tolerable in combination with preoperative chemotherapy (5-FU, paclitaxel, carboplatin) and radiation therapy with encouraging efficacy worthy of future study.

Background: The Veterans Choice Program (VCP), enacted by Congress after concerns surfaced about access, enables veterans to receive care outside Veterans Health Administration (VHA) facilities. Veterans who face long wait times, large driving distances, or particular hardships are eligible for VCP. Prior purchased care programs were comparatively limited in scope., Objectives: We sought to describe utilization of VHA-provided and purchased outpatient care by veterans eligible for VCP before and after VCP implementation. We focused on veterans recently eligible for VHA as they are of particular policy relevance and might have less established care patterns., Research Design: We identified all Iraq and Afghanistan veterans who were eligible for VCP in 2015. We tabulated their use of VHA and purchased outpatient care for 3 years before (FY2012-2014) and 1 year after VCP implementation (FY2015)., Subjects: Our study population consisted of 214,449 Iraq and Afghanistan veterans who were eligible for VCP due to wait-time, distance, or hardship issues., Results: In the first year of the program, 3821 (2%) of these Iraq and Afghanistan veterans used non-VHA services through VCP. Per capita VHA utilization tended to decline slightly after VCP implementation, but these changes varied by type of outpatient care., Conclusions: There was low uptake of VCP services in the first year of the program. Data from additional years are needed to better understand the impact of this policy.

The PI3K-AKT-mTOR signaling cascade is activated in the majority of human cancers, and its activation also plays a key role in resistance to chemo and targeted therapeutics. In particular, in both breast and prostate cancer, increased AKT pathway activity is associated with cancer progression, treatment resistance and poor disease outcome. Here, we evaluated the activity of a novel allosteric AKT1/2 inhibitor, BAY 1125976, in biochemical, cellular mechanistic, functional and in vivo efficacy studies in a variety of tumor models. In in vitro kinase activity assays, BAY 1125976 potently and selectively inhibited the activity of full-length AKT1 and AKT2 by binding into an allosteric binding pocket formed by kinase and PH domain. In accordance with this proposed allosteric binding mode, BAY 1125976 bound to inactive AKT1 and inhibited T308 phosphorylation by PDK1, while the activity of truncated AKT proteins lacking the pleckstrin homology domain was not inhibited. In vitro, BAY 1125976 inhibited cell proliferation in a broad panel of human cancer cell lines. Particularly high activity was observed in breast and prostate cancer cell lines expressing estrogen or androgen receptors. Furthermore, BAY 1125976 exhibited strong in vivo efficacy in both cell line and patient-derived xenograft models such as the KPL4 breast cancer model (PIK3CA H1074R mutant), the MCF7 and HBCx-2 breast cancer models and the AKT E17K mutant driven prostate cancer (LAPC-4) and anal cancer (AXF 984) models. These findings indicate that BAY 1125976 is a potent and highly selective allosteric AKT1/2 inhibitor that targets tumors displaying PI3K/AKT/mTOR pathway activation, providing opportunities for the clinical development of new, effective treatments., (© 2016 UICC.)

Objectives: To identify the associations of lymph node metastases (pN+), number of positive nodes, and pN subclassification with cancer, treatment, patient, geographic, and institutional variables, and to recommend extent of lymphadenectomy needed to accurately detect pN+ for esophageal cancer., Summary Background Data: Limited data and traditional analytic techniques have precluded identifying intricate associations of pN+ with other cancer, treatment, and patient characteristics., Methods: Data on 5806 esophagectomy patients from the Worldwide Esophageal Cancer Collaboration were analyzed by Random Forest machine learning techniques., Results: pN+, number of positive nodes, and pN subclassification were associated with increasing depth of cancer invasion (pT), increasing cancer length, decreasing cancer differentiation (G), and more regional lymph nodes resected. Lymphadenectomy necessary to accurately detect pN+ is 60 for shorter, well-differentiated cancers (<2.5 cm) and 20 for longer, poorly differentiated ones., Conclusions: In esophageal cancer, pN+, increasing number of positive nodes, and increasing pN classification are associated with deeper invading, longer, and poorly differentiated cancers. Consequently, if the goal of lymphadenectomy is to accurately define pN+ status of such cancers, few nodes need to be removed. Conversely, superficial, shorter, and well-differentiated cancers require a more extensive lymphadenectomy to accurately define pN+ status.

Purpose: There are limited data regarding clinical and treatment factors associated with radiation pneumonitis (RP) in patients receiving taxane-based trimodality therapy for esophageal cancer. The purpose of this study was to identify predictors of RP in patients undergoing trimodality therapy., Methods and Materials: We retrospectively reviewed patients undergoing chemoradiation followed by esophagectomy between 2006 and 2011. The association between clinical and dosimetric factors with RP was assessed using χ 2 test and Mann-Whitney U test. Multivariable regression was used to assess the relationship between grade 2+ RP and clinical/dosimetric factors. Receiver operator curves were generated to identify threshold doses for RP., Results: A total of 139 patients were included; 19 (13.7%) patients experienced grade 2+ RP. Patients with upper/middle thoracic tumors (P = .038) and receiving higher radiation doses (P = .038) were more likely to develop grade 2+ RP. There was no association between taxane-based therapy and grade 2+ RP (P = .728). The percent volume of lung receiving 5 Gy (V5; P < .001), 10 Gy (P < .001), 20 Gy (V20; P < .001), and 30 Gy (P < .001) was associated with an increased risk of grade 2+ RP. On multivariable regression, the lung V5 (odds ratio, 1.101; 95% confidence interval, 1.1014-1.195) and V20 (odds ratio, 1.149; 95% confidence interval, 1.1015-1.301) remained associated with grade 2+ RP. A V5 ≤65% and V20 ≤25% were identified as optimal thresholds for increased grade 2+ RP., Conclusions: Dosimetric parameters are strong predictors of symptomatic RP in patients undergoing trimodality therapy for esophageal cancer. Mitigating the risk of RP in these patients should be an important consideration during treatment planning., Competing Interests: Statement: None to declare, (Copyright © 2016 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

To address uncertainty of whether pathologic stage groupings after neoadjuvant therapy (ypTNM) for esophageal cancer share prognostic implications with pathologic groupings after esophagectomy alone (pTNM), we report data-simple descriptions of patient characteristics, cancer categories, and non-risk-adjusted survival-for pathologically staged cancers after neoadjuvant therapy from the Worldwide Esophageal Cancer Collaboration (WECC). Thirty-three institutions from six continents submitted data using variables with standard definitions: demographics, comorbidities, clinical cancer categories, and all-cause mortality from first management decision. Of 7,773 pathologically staged neoadjuvant patients, 2,045 had squamous cell carcinoma, 5,686 adenocarcinoma, 31 adenosquamous carcinoma, and 11 undifferentiated carcinoma. Patients were older (61 years) men (83%) with normal (40%) or overweight (35%) body mass index, 0-1 Eastern Cooperative Oncology Group performance status (96%), and a history of smoking (69%). Cancers were ypT0 (20%), ypT1 (13%), ypT2 (18%), ypT3 (44%), ypN0 (55%), ypM0 (94%), and G2-G3 (72%); most involved the distal esophagus (80%). Non-risk-adjusted survival for yp categories was unequally depressed, more for earlier categories than later, compared with equivalent categories from prior WECC data for esophagectomy-alone patients. Thus, survival of patients with ypT0-2N0M0 cancers was intermediate and similar regardless of ypT; survival for ypN+ cancers was poor. Because prognoses for ypTNM and pTNM categories are dissimilar, prognostication should be based on separate ypTNM categories and groupings. These data will be the basis for the 8th edition cancer staging manuals following risk adjustment for patient, cancer, and treatment characteristics and should direct 9th edition data collection., (© 2016 International Society for Diseases of the Esophagus.)

To address uncertainty of whether clinical stage groupings (cTNM) for esophageal cancer share prognostic implications with pathologic groupings after esophagectomy alone (pTNM), we report data-simple descriptions of patient characteristics, cancer categories, and non-risk-adjusted survival-for clinically staged patients from the Worldwide Esophageal Cancer Collaboration (WECC). Thirty-three institutions from six continents submitted data using variables with standard definitions: demographics, comorbidities, clinical cancer categories, and all-cause mortality from first management decision. Of 22,123 clinically staged patients, 8,156 had squamous cell carcinoma, 13,814 adenocarcinoma, 116 adenosquamous carcinoma, and 37 undifferentiated carcinoma. Patients were older (62 years) men (80%) with normal body mass index (18.5-25 mg/kg 2 , 47%), little weight loss (2.4 ± 7.8 kg), 0-1 ECOG performance status (67%), and history of smoking (67%). Cancers were cT1 (12%), cT2 (22%), cT3 (56%), cN0 (44%), cM0 (95%), and cG2-G3 (89%); most involved the distal esophagus (73%). Non-risk-adjusted survival for squamous cell carcinoma was not distinctive for early cT or cN; for adenocarcinoma, it was distinctive for early versus advanced cT and for cN0 versus cN+. Patients with early cancers had worse survival and those with advanced cancers better survival than expected from equivalent pathologic categories based on prior WECC pathologic data. Thus, clinical and pathologic categories do not share prognostic implications. This makes clinically based treatment decisions difficult and pre-treatment prognostication inaccurate. These data will be the basis for the 8th edition cancer staging manuals following risk adjustment for patient characteristics, cancer categories, and treatment characteristics and should direct 9th edition data collection., (© 2016 International Society for Diseases of the Esophagus.)

We report data-simple descriptions of patient characteristics, cancer categories, and non-risk-adjusted survival-for patients with pathologically staged cancer of the esophagus and esophagogastric junction after resection or ablation with no preoperative therapy from the Worldwide Esophageal Cancer Collaboration (WECC). Thirty-three institutions from six continents submitted de-identified data using standard definitions: demographics, comorbidities, clinical cancer categories, and all-cause mortality from first management decision. Of 13,300 patients, 5,631 had squamous cell carcinoma, 7,558 adenocarcinoma, 85 adenosquamous carcinoma, and 26 undifferentiated carcinoma. Patients were older (62 years) men (80%) with normal body mass index (51%), little weight loss (1.8 kg), 0-2 ECOG performance status (83%), and a history of smoking (70%). Cancers were pT1 (24%), pT2 (15%), pT3 (50%), pN0 (52%), pM0 (93%), and pG2-G3 (78%); most involved distal esophagus (71%). Non-risk-adjusted survival for both squamous cell carcinoma and adenocarcinoma was monotonic and distinctive across pTNM. Survival was more distinctive for adenocarcinoma than squamous cell carcinoma when pT was ordered by pN. Survival for pTis-1 adenocarcinoma was better than for squamous cell carcinoma, although monotonic and distinctive for both. WECC pathologic staging data is improved over that of the 7th edition, with more patients studied and patient and cancer variables collected. These data will be the basis for the 8th edition cancer staging manuals following risk adjustment for patient, cancer, and treatment characteristics, and should direct 9th edition data collection. However, the role of pure pathologic staging as the principal point of reference for esophageal cancer staging is waning., (© 2016 International Society for Diseases of the Esophagus.)

Gastric cancer is the fifth most frequently diagnosed cancer and the third leading cause of death from cancer in the world. Several advances have been made in the staging procedures, imaging techniques, and treatment approaches. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Gastric Cancer provide an evidence- and consensus-based treatment approach for the management of patients with gastric cancer. This manuscript discusses the recommendations outlined in the NCCN Guidelines for staging, assessment of HER2 overexpression, systemic therapy for locally advanced or metastatic disease, and best supportive care for the prevention and management of symptoms due to advanced disease., (Copyright © 2016 by the National Comprehensive Cancer Network.)

The phosphoinositide 3-kinase (PI3K) pathway is aberrantly activated in many disease states, including tumor cells, either by growth factor receptor tyrosine kinases or by the genetic mutation and amplification of key pathway components. A variety of PI3K isoforms play differential roles in cancers. As such, the development of PI3K inhibitors from novel compound classes should lead to differential pharmacological and pharmacokinetic profiles and allow exploration in various indications, combinations, and dosing regimens. A screening effort aimed at the identification of PI3Kγ inhibitors for the treatment of inflammatory diseases led to the discovery of the novel 2,3-dihydroimidazo[1,2-c]quinazoline class of PI3K inhibitors. A subsequent lead optimization program targeting cancer therapy focused on inhibition of PI3Kα and PI3Kβ. Herein, initial structure-activity relationship findings for this class and the optimization that led to the identification of copanlisib (BAY 80-6946) as a clinical candidate for the treatment of solid and hematological tumors are described., (© 2016 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.)

Purpose: To compare the vitreous loss complication rate of manual phacoemulsification cataract surgery with that of femtosecond laser-assisted cataract surgery., Setting: Mercy Eye Specialists, Springfield, Missouri, USA., Design: Retrospective single-center case series., Methods: Cataract surgeries from 2010 to 2014 performed by 4 surgeons were audited for rates of vitreous loss. Vitreous loss data were statistically analyzed with and without exclusions., Results: Of the total 7155 cases from 2010 to 2014, 3784 were consecutively performed using manual phacoemulsification from 2010 to 2012 and 3371 were performed using femtosecond laser-assisted cataract surgery from 2013 to 2014. The rate of vitreous loss with exclusions was 1.17% in the manual phacoemulsification group and versus 0.65% femtosecond laser-assisted group; without exclusions, the rate was 1.40% versus 0.77%. In absolute terms, the rate decreased for every surgeon in the study. The chi-square test showed a statistically significant association between the date of surgery, and thus technique, and vitrectomy cases (P < .05). Odds ratio analysis with exclusions versus without exclusions indicated that surgeries performed from 2010 to 2012 using manual phacoemulsification were 1.6 times and 1.8 times, respectively, more likely to have vitreous loss than surgeries performed from 2013 to 2014 using the femtosecond laser-assisted cataract surgery technique., Conclusions: Conversion from manual phacoemulsification to femtosecond laser-assisted cataract surgery resulted in a statistically significant decrease in vitreous loss. Because vitreous loss increases the risk for other serious complications of cataract surgery, this new finding has important implications for the safety of cataract surgery., Financial Disclosure: Proprietary or commercial disclosures are listed after the references., (Copyright © 2016 ASCRS and ESCRS. Published by Elsevier Inc. All rights reserved.)