Deviations in reward sensitivity and behavioral flexibility, particularly in the ability to change or stop behaviors in response to changing environmental contingencies, are important phenotypic dimensions of several neuropsychiatric disorders. Neuroimaging evidence suggests that variation in dopamine signaling through dopamine D2-like receptors may influence these phenotypes, as well as associated psychiatric conditions, but the specific neurocognitive mechanisms through which this influence is exerted are unknown. To address this question, we examined the relationship between behavioral sensitivity to reinforcement during discrimination learning and D2-like receptor availability in vervet monkeys. Monkeys were assessed for their ability to acquire, retain and reverse three-choice, visual-discrimination problems, and once behavioral performance had stabilized, they received positron emission tomography (PET) scans. D2-like receptor availability in dorsal aspects of the striatum was not related to individual differences in the ability to acquire or retain visual discriminations but did relate to the number of trials required to reach criterion in the reversal phase of the task. D2-like receptor availability was also strongly correlated with behavioral sensitivity to positive, but not negative, feedback during learning. These results go beyond electrophysiological findings by demonstrating the involvement of a striatal dopaminergic marker in individual differences in feedback sensitivity and behavioral flexibility, providing insight into the neural mechanisms that are affected in neuropsychiatric disorders that feature these deficits.

Rationale Poor cognitive control, including reversal learning deficits, has been reported in children with attention deficit hyperactivity disorder, in stimulant-dependent humans, and in animal models of these disorders; these conditions have each been associated with abnormal catecholaminergic function within the prefrontal cortex. Objectives In the current studies, we sought to explore how elevations in extracellular catecholamine levels, produced by pharmacological inhibition of catecholamine reuptake proteins, affect behavioral flexibility in rats and monkeys. Materials and methods Adult male Long-Evans rats and vervet monkeys were trained, respectively, on a fourposition discrimination task or a three-choice visual discrimination task. Following systemic administration of pharmacological inhibitors of the dopamine and/or norepinephrine membrane transporters, rats and monkeys were exposed to retention or reversal of acquired discriminations. Results In accordance with our a priori hypothesis, we found that drugs that inhibit norepinephrine transporters, such as methylphenidate, atomoxetine, and desipramine, improved reversal performance in rats and monkeys; this was mainly due to a decrease in the number of perseverative errors. Interestingly, the mixed dopamine and norepinephrine transporters inhibitor methylphenidate, if anything, impaired performance during retention in both rats and monkeys, while administration of the selective dopamine transporter inhibitor GBR-12909 increased premature responses but did not alter reversal learning performance. Conclusions Our results suggest that pharmacological inhibition of the membrane norepinephrine, but not membrane dopamine, transporter is associated with enhanced behavioral flexibility. These data, combined with earlier reports, may indicate that enhanced extracellular catecholamine levels in cortical regions, secondary to norepinephrine reuptake inhibition, improves multiple aspects of inhibitory control over responding in rats and monkeys.

Multiple long-term studies have demonstrated a propensity for breast cancer recurrences to develop near the site of the original breast cancer. Recognition of this local recurrence pattern laid the foundation for the development of accelerated partial breast irradiation (APBI) approaches designed to limit the radiation treatment field to the site of the malignancy. However, there is a paucity of data regarding the efficacy of APBI in general, and intraoperative radiotherapy (IORT), in particular, for the management of ductal carcinoma in situ (DCIS). As a result, use of APBI, remains controversial. A prospective nonrandomized trial was designed to determine if patients with pure DCIS considered eligible for concurrent IORT based on preoperative mammography and contrast-enhanced magnetic resonance imaging (CE-MRI) could be successfully treated using IORT with minimal need for additional therapy due to inadequate surgical margins or excessive tumor size. Between November 2007 and June 2014, 35 women underwent bilateral digital mammography and bilateral breast CE-MRI prior to selection for IORT. Patients were deemed eligible for IORT if their lesion was ≤4 cm in maximal diameter on both digital mammography and CE-MRI, pure DCIS on minimally invasive breast biopsy or wide local excision, and considered resectable with clear surgical margins using breast-conserving surgery (BCS). Postoperatively, the DCIS lesion size determined by imaging was compared with lesion size and surgical margin status obtained from the surgical pathology specimen. Thirty-five patients completed IORT. Median patient age was 57 years (range 42-79 years) and median histologic lesion size was 15.6 mm (2-40 mm). No invasive cancer was identified. In more than half of the patients in our study (57.1%), MRI failed to detect a corresponding lesion. Nonetheless, 30 patients met criteria for negative margins (i.e., margins ≥2 mm) whereas five patients had positive margins (<2 mm). Two of the five patients with positive margins underwent mastectomy due to extensive imaging-occult DCIS. Three of the five patients with positive margins underwent successful re-excision at a subsequent operation prior to subsequent whole breast irradiation. A total of 14.3% (5/35) of patients required some form of additional therapy. At 36 months median follow-up (range of 2-83 months, average 42 months), only two patients experienced local recurrences of cancer (DCIS only), yielding a 5.7% local recurrence rate. No deaths or distant recurrences were observed. Imaging-occult DCIS is a challenge for IORT, as it is for all forms of breast-conserving therapy. Nonetheless, 91.4% of patients with DCIS were successfully managed with BCS and IORT alone, with relatively few patients requiring additional therapy.

Intraoperative Radiotherapy (IORT) is a form of accelerated partial breast radiation that has been shown to be equivalent to conventional whole breast external beam radiotherapy (EBRT) in terms of local cancer control. However, questions have been raised about the potential of f IORT to produce breast parenchymal changes that could interfere with mammographic surveillance of cancer recurrence. The purpose of this study was to identify, quantify, and compare the mammographic findings of patients who received IORT and EBRT in a prospective, randomized controlled clinical trial of women with early stage invasive breast cancer undergoing breast conserving therapy between July 2005 and December 2009. Treatment groups were compared with regard to the 1, 2 and 4-year incidence of 6 post-operative mammographic findings: architectural distortion, skin thickening, skin retraction, calcifications, fat necrosis, and mass density. Blinded review of 90 sets of mammograms of 15 IORT and 16 EBRT patients demonstrated a higher incidence of fat necrosis among IORT recipients at years 1, 2, and 4. However, none of the subjects were judged to have suspicious mammogram findings and fat necrosis did not interfere with mammographic interpretation.

Breast conserving surgery has been accepted as the optimal local therapy for women with early breast cancer, emphasizing the necessity to balance oncologic goals with patient satisfaction and cosmetic outcomes. In the move to enhance a surgeon's ability to achieve histologically clear margins intraoperatively at the initial surgery, the MarginProbe (Dune Medical Devices, Caesarea, Israel) has emerged as an effective tool to accomplish that task. Based on previously reported success using the device, we assessed cosmesis and tissue resection volumes among participants in a randomized-controlled trial comparing the standard of care lumpectomy performed with and without the MarginProbe. The use of the MarginProbe device resulted in a 57% reduction in reexcision rates compared to the control group with a small increase in tissue volume removed at the primary lumpectomy. When total tissue volumes removed were analyzed, the device and control groups were still very similar after normalization to bra cup size. We concluded that the MarginProbe is an effective device to assist surgeons in determining margin status intraoperatively while allowing for better patient cosmetic outcomes due to the smaller volumes of tissue resected and the reduction in patient referrals for second surgeries due to positive margins.

As part of the Accreditation Council for Graduate Medical Education requirements, residents must participate in structured didactic activities. Traditional didactics include lectures, grand rounds, simulations, case discussions, and other forms of in-person synchronous learning. The COVID-19 pandemic has made in-person activities less feasible, as many programs have been forced to transition to remote didactics. Educators must still achieve the goals and objectives of their didactic curriculum despite the new limitations on instructional strategies. There are several strategies that may be useful for organizing and creating a remote residency didactic curriculum. Educators must master new technology, be flexible and creative, and set rules of engagement for instructors and learners. Establishing best practices for remote didactics will result in successful, remote, synchronous didactics; reduce the impact of transitioning to a remote learning environment; and keep educators and learners safe as shelter-at-home orders remain in place.

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187 Background: Increasing constraints on health care resources call for implementation of breast cancer treatment strategies that preserve treatment efficacy while reducing healthcare cost. In this investigation, we model potential cost savings associated with the use of single-fraction intraoperative radiotherapy (IORT) compared to two commonly used alternative radiotherapy approaches. Methods: A database survey was performed of female subjects undergoing breast conserving surgery (BCS) with or without sentinel lymphadenectomy at HealthCare Partners, a major IPA in metropolitan Los Angeles, CA. Subjects were identified by cross-referencing ICD-9 codes (174.0-174.9) for invasive breast cancer, CPT codes for BCS (19120, 19125, or 19301), and CPT codes for sentinel node biopsy without ALND (38500, 38525, or 38740). Calculations were based on the 2011 U.S. Medicare Fee Schedule. Treatment costs and savings were modeled assuming that patients with node-negative disease who underwent BCS were eligible for accelerated partial breast irradiation based on American Society of Breast Surgeons Guidelines (age ≥45, IDCA, DCIS, size ≤3 cm, node and margin negative). Results: A sample of 1,478 women meeting criteria was evaluated to determine the average per-patient cost of breast radiotherapy comparing three modalities: single-fraction IORT ($4,402), 5-day multi-lumen balloon brachytherapy (MLBB) (e.g., MammoSite) ($12,021), and standard 6-week whole breast external beam radiotherapy followed by a tumor bed boost (WBRT) ($8,988). IORT was approximately 49% the cost of standard 6-week WBRT and 37% the cost of MLBB. Conclusions: When eligible breast cancer patients are offered IORT as an alternative to WBRT, the expenditures from this sample may be reduced from $13.3M to $6.5M, a savings of $6.8M. Compared to MLBB, IORT may reduce radiotherapy expenditures from $17.8M to $6.5M, a savings of $11.3M. [Table: see text]