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Increasing pursuit of subspecialized training has quietly revolutionized physician training, but the potential impact on physician workforce estimates has not previously been recognized. The Physicians Specialty Data Reports of the Association of American Medical Colleges, derived from specialty designations in the American Medical Association (AMA) Physician Professional Data (PPD), are the reference source for US physician workforce estimates; by 2020, the report for pathologists was an undercount of 39% when compared with the PPD. Most of the difference was due to the omission of pathology subspecialty designations. The rest resulted from reliance on only the first of the AMA PPD's 2 specialty data fields. Placement of specialty designation in these 2 fields is sensitive to sequence of training and is thus affected by multiple or intercalated (between years of residency training) fellowships. Both these phenomena have become progressively more common and are not unique to pathology. Our findings demonstrate the need to update definitions and methodology underlying estimates of the US physician workforce for pathology and suggest a like need in other specialties affected by similar trends., Competing Interests: Conflicts of interest Please see ICMJE form(s) for author conflicts of interest. These have been provided as supplementary materials., (© The Author(s) 2024. Published by Oxford University Press on behalf of Project HOPE - The People-To-People Health Foundation, Inc.)

Dosimetry after 177 Lu-DOTATATE peptide receptor radionuclide therapy (PRRT) enables estimation of radiation doses absorbed by normal organs and target lesions. This process is time-consuming and requires multiple posttreatment studies on several subsequent days. In a previous study, we described a newly developed multiple-linear-regression model to predict absorbed doses (ADs) from a single-time-point (STP) posttreatment study acquired 168 h after the first infusion and 24 h after the following ones, with similar results to the standard multiple-time-point (MTP) protocol. The present study aimed to validate this model in a large patient cohort and to assess whether STP dosimetry affects patient management decisions compared with our MTP protocol. Methods: Quantitative 177 Lu-DOTATATE SPECT/CT post-PRRT data from 159 consecutive patients (172 therapies, 477 therapy cycles) were retrospectively analyzed. ADs obtained from an STP model were compared with those obtained using an MTP model. We evaluated the impact of the STP model on the decision on whether PRRT should be stopped because of an expected kidney AD exceeding the safety threshold. We hypothesized that patient management based on the STP model does not differ from that based on the MTP model in at least 90% of the cases. Results: There was no difference in management decisions between the MTP and STP models in 170 of 172 therapies (98.8%). A Fisher χ 2 test for combined probabilities produced a composite P value of 0.0003. Mean cumulative AD relative differences between the STP and MTP models were 0.8% ± 8.0%, -7.7% ± 4.8%, 0.0% ± 11.4%, -2.8% ± 6.3%, and -2.1% ± 18.4% for kidneys, bone marrow, liver, spleen, and tumors, respectively (Pearson r = 0.99 for all), for patients who underwent 4 therapy cycles. Similar results were obtained with fewer therapy cycles. Conclusion: Estimated radiation ADs and patient management decisions were similar with the STP and MTP models. The STP model can simplify the dosimetry process while also reducing scanner and staff time and improving patient comfort., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Background and Objective: The management of large mediastinal tumors requires a complex multidisciplinary approach, particularly in the perioperative setting due to increased risk of hemodynamic compromise. The utilization of extracorporeal membrane oxygenation (ECMO) provides a useful adjunct in the surgical management for biopsy and resection of these mediastinal masses. The objective of this article is to review indications and implementation of ECMO in the surgical management of mediastinal disease., Methods: A literature review of the PubMed database was completed evaluating articles discussing 'extracorporeal circulation', 'cardiopulmonary bypass', 'anesthesia', 'mediastinal disease', and 'mediastinal cancer'. These articles were evaluated for contribution to the discussion of indications and implementation of ECMO in the management of these patients., Key Content and Findings: Large mediastinal tumors place patients at risk of hemodynamic collapse on induction of anesthesia due to compression of vascular structures, tracheobronchial tree and creation of V/Q mismatch. Patients may be stratified regarding their risk of perioperative complications by evaluation of postural symptoms, cross sectional imaging findings and pulmonary function tests. Those patients at elevated perioperative risk may benefit from the utilization of ECMO, most commonly veno-arterial (V-A) ECMO. Guidewires or ECMO cannulas may be placed under local anesthesia prior to induction. Those patients with hemodynamic compromise may receive mechanical circulatory support to allow completion of the operation., Conclusions: The use of a multidisciplinary team consisting of surgeons, anesthesiologists, perfusionists and OR team is critical to the success in the use of ECMO in the resection of mediastinal masses. With diligent preparation, these high-risk patients may be optimally managed at the time of resection., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-22-1391/coif). The series “Extracorporeal Life Support in Thoracic Surgery” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare., (2023 Journal of Thoracic Disease. All rights reserved.)

Background: Enhanced recovery after thoracic surgery (ERATS) protocols use a combination of analgesics for pain control. We investigated the effect of non-steroidal analgesic drugs (NSAIDs) on pain control by comparing patient levels and opioid requirements after robotic pulmonary resections., Methods: We retrospectively analyzed our prospectively maintained institutional database for elective, opioid-naïve robotic thoracoscopic pulmonary resections. All patients received postoperative NSAIDs unless contraindicated or at the discretion of the attending surgeons. Our original protocol (ERATS-V1) was modified to optimize opioid-sparing effect without affecting pain control (ERATS-V2). Demographics, operative outcomes, and postoperative opioid dispensed [morphine milligram equivalent (MME)] were collected., Results: A total of 491 patients (147 ERATS-V1; 344 ERATS-V2) were included in this study. There was no difference in patient characteristics or operative outcomes between ERATS cohorts. Protocol optimization was associated with a 2- to 10-fold reduction of postoperative opioid use without compromising pain control. In ERATS-V1 cohort, there was no difference in pain levels and opioid requirements with NSAID usage. In ERATS-V2 cohort, while pain levels were similar, higher in-hospital opioid consumption was observed in no-NSAID subgroup {MME: 20.5 [interquartile range (IQR), 4.8-40.5] vs. 12.0 (IQR, 2.0-32.2), P=0.0096, schedule II: 14.2 (IQR, 3.0-36.4) vs. 6.8 (IQR, 1.4-24.0), P=0.012} as well as total postoperative schedule II opioid requirement [17.8 (IQR, 3.0-43.5) vs. 8.8 (IQR, 1.5-30), P=0.032]., Conclusions: The opioid-sparing effect of NSAIDs was observed only in optimized ERATS patients. Modifications of our pre-existing ERATS was associated with a significant reduction of opioid consumption without affecting pain levels. This revealed the role of NSAIDs in postoperative pain management otherwise masked by excessive opioids use., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-709/coif). The authors have no conflicts of interest to declare., (2023 Journal of Thoracic Disease. All rights reserved.)

Objective: Implementation and continuing optimization of enhanced recovery protocol after thoracic surgery results in significant improvement of postoperative outcomes. We observed a 10-fold increase in the rate of postoperative day (POD) 1 discharges following robotic thoracoscopic anatomic resections over time. We aimed to determine factors associated with safe POD1 discharges., Methods: We performed a retrospective analysis of a prospectively maintained database of robotic anatomic pulmonary resections between July 1, 2012, and June 30, 2022, with patients of the last 2.5 years forming the basis of this study. Data collected included demographics, insurance types, Area Deprivation Index (indicator of poverty), and operative and postoperative variables including length of stay, opioid use, daily pain levels, readmissions, and outpatient interventions. Factors associated with POD1 were analyzed using a logistic regression module., Result: In total, 279 patients met inclusion criteria (91 POD1 discharges, 32.6%; none discharged with a pleural catheter). There was neither an increase of postdischarge interventions for pleural complications nor readmission in early discharge patients. After adjusting for relevant factors, younger age, right middle lobectomy, lower opioid use on POD1, operating room finish before 4 PM, and low Area Deprivation Index were significantly associated with POD1 discharge. A subanalysis of 49 patients, who could have been discharged on POD1, identified hypoxemia requiring home oxygen, atrial fibrillation, and poorly controlled pain being common mitigatable clinical factors delaying POD1 discharge., Conclusions: Safe POD1 discharge following robotic thoracoscopic anatomic resection was achieved in 32% of cases. Identification of positive and negative factors affecting early discharge provides guidance for further modifications to increase the number of POD1 discharges., Competing Interests: The authors reported no conflicts of interest. The authors discuss the off-label use of liposomal bupivacaine (EXPAREL; Pacira Pharmaceuticals Inc) for intercostal nerve block, used with institutional approval. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest., (© 2023 The Author(s).)

Objectives: Enhanced recovery after thoracic surgery (ERATS) protocols use a combination of analgesics for pain control and have been associated with decreased opioid requirements. We investigated the impact of continual ERATS refinement on the incidence of opioid-free discharge., Methods: We retrospectively analyzed our prospectively maintained institutional database for elective, opioid-naive robotic thoracoscopic procedures. Demographics, operative outcomes, postoperative opioid dispensed (morphine milligram equivalent), and opioid discharge status were collected. Our primary outcome of interest was factors associated with opioid-free discharge; our secondary objective was to determine the incidence of new persistent opioid users., Results: In total, 466 patients from our optimized ERATS protocol were included; 309 (66%) were discharged without opioids. However, 34 (11%) of patients discharged without opioids required a prescription postdischarge. Conversely, 7 of 157 patients (11%), never filled their opioid prescriptions given at discharge. Factors associated with opioid-free discharges were nonanatomic resections, mediastinal procedures, minimal pain, and lack of opioid usage on the day of discharge. More importantly, 3.2% of opioid-free discharge patients became new persistent opioid users versus 10.8% of patients filling opioid prescriptions after discharges ( P  = .0013). Finally, only 2.3% of opioid-naive patients of the entire cohort became chronic opioid users; there was no difference in the incidence of chronic use by opioid discharge status., Conclusions: Optimized opioid-sparing ERATS protocols are highly effective in reducing opioid prescription on the day of discharge. We observed a very low rate of new persistent or chronic opioid use in our cohort, further highlighting the role ERATS protocols in combating the opioid epidemic., (© 2023 The Author(s).)

We conducted a retrospective/prospective worldwide study on patients with neuroendocrine neoplasms (NENs) and a molecularly proven SARS-CoV-2 positivity. Preliminary results regarding 85 patients of the INTENSIVE study have been published in 2021. Now we are reporting the 2-year analysis.Here, we are reporting data from consecutive patients enrolled between 1 June 2020, and 31 May 2022. Among the 118 contacted centers, 25 were active to enroll and 19 actively recruiting at the time of data cut-off for a total of 280 patients enrolled. SARS-CoV-2 positivity occurred in 47.5% of patients in 2020, 35.1% in 2021, and 17.4% in 2022. The median age for COVID-19 diagnosis was 60 years. Well-differentiated tumors, non-functioning, metastatic stage, and gastroenteropancreatic (GEP) primary sites represented most of the NENs. COVID-19-related pneumonia occurred in 22.8% of the total, with 61.3% of them requiring hospitalization; 11 patients (3.9%) needed sub-intensive or intensive care unit therapies and 14 patients died (5%), in 11 cases (3.9%) directly related to COVID-19. Diabetes mellitus and age at COVID-19 diagnosis > 70 years were significantly associated with COVID-19 mortality, whereas thoracic primary site with COVID-19 morbidity. A significant decrease in both hospitalization and pneumonia occurred in 2022 vs 2020. In our largest series of NEN patients with COVID-19, the NEN population is similar to the general population of patients with NEN regardless of COVID-19. However, older age, non-GEP primary sites and diabetes mellitus should be carefully considered for increased COVID-19 morbidity and mortality. Relevant information could be derived by integrating our results with NENs patients included in other cancer patients with COVID-19 registries.

Background and Objective: Bronchogenic cysts represent a rare form of cystic malformation of the respiratory tract. Primarily located in the mediastinum if occurring early in gestation as opposed to the thoracic cavity if arising later in development. However, they can arise from any site along the foregut. They exhibit a variety of clinical and radiologic presentations, representing a diagnostic challenge, especially in areas with endemic hydatid disease. Endoscopic drainage has emerged as a diagnostic and potentially therapeutic option but has been complicated by reports of infection. Surgical excision remains the standard of care allowing for symptomatic resolution and definitive diagnosis via pathologic examination; minimally invasive approaches such as robotic and thoracoscopic approaches aiding treatment. Following complete resection, prognosis is excellent with essentially no recurrence., Methods: A review of the available electronic literature was performed from 1975 through 2022, using PubMed and Google Scholar, with an emphasis on more recent series. We included all retrospective series and case reports. A single author identified the studies, and all authors reviewed the selection until there was a consensus on which studies to include., Key Content and Findings: The literature consisted of relatively small series, mixed between adult and pediatric patients, and the consensus remains that all symptomatic lesions should be excised via minimally invasive approach where feasible., Conclusions: Surgical excision of symptomatic bronchogenic cysts remains the gold standard, with endoscopic drainage being reserved for diagnosis or as a temporizing measure in clinically unstable patients., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://med.amegroups.com/article/view/10.21037/med-22-46/coif). The series “Mediastinal Cysts” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare., (2023 Mediastinum. All rights reserved.)

Context.—: There has long been debate about whether and when there may be a shortage of pathologists in the United States. One way to assess this is to survey the hiring experiences of pathology practices. A 2018 survey revealed a strong demand for pathologists, with expectations of continued strength. This study updates that prior analysis using data from a 2021 survey of pathology practice leaders., Objective.—: To assess the US pathologist job market and examine implications., Design.—: We analyzed data from the 2021 College of American Pathologists Practice Leader Survey. This survey queried practice leaders, including regarding the hiring of pathologists, the level of experience being sought, success in filling positions, and expectations for hiring in the next 3 years., Results.—: Among the 375 surveyed practice leaders (about one-third of all US pathology practices), 282 provided information about pathologist hiring in 2021. A total of 157 of these 282 practices (55.7%) sought to hire at least 1 pathologist in 2021, up from 116 of 256 practices (45.3%) in 2017; the mean number of pathologists hired per practice also increased. In 2021, a total of 175 of 385 positions (45.5%) were to fill new positions, compared with 95 of 249 positions (38.2%) in 2017. Most practice leaders were comfortable hiring pathologists with less than 2 years of posttraining experience. Practice leaders anticipated continued strong demand for hiring pathologists during the next 3 years., Conclusions.—: Our analysis confirms that the demand in pathologist hiring is strong and much increased from 2017. We believe, in combination with other job market indicators, that demand may outstrip the supply of pathologists, which is limited by the number of trainees and has remained constant during the past 20 years., (© 2023 College of American Pathologists.)

Background: Cases of variations in anterior belly of the digastric muscle must be carefully identified to avoid misinterpretations and assist in the correct surgical or aesthetic procedure and help in the teaching of anatomy. The aim of this study was to describe the anatomical variations of anterior belly of digastric muscle in Brazilian cadavers., Materials and Methods: Thirty-one human heads were selected, from adult cadavers (18-80 years, 29 males and 2 females). The morphology of the anterior belly of the digastric muscle was observed, identifying the possible anatomical variations that were characterised and classified according to the amount of muscle bellies, fibre direction and place of origin and insertion. The morphometric measurements were performed using a digital calliper. To analyse the data obtained, photographic documentation, anatomical description and individual morphometric description of each muscle belly were performed. The incidence of anatomical variation was obtained in percentage (%)., Results: The anatomical variation of the anterior belly of the digastric muscle was present in 6 cadavers (19.31%; 1 female and 5 male). All anatomical variations presented an accessory belly to the anterior belly. However, these accessory bellies were configured differently in the location, direction of muscle fibres and in their dimensions (length and width)., Conclusions: The gross anatomy of the anterior belly of the digastric muscle and their variations is important to assist in surgical procedures, pathological or diagnostic function. In addition, asymmetrical variations in the submental region must be carefully identified to avoid misinterpretations.

There has been little rigorous assessment of burnout among pathologists and pathology trainees. Given this relative dearth of relevant literature on pathologist burnout, this report aims to raise awareness of the issue among those working in and around this specialty. Our results are based on a survey given in conjunction with the American Board of Pathology's (ABPath) biennial Continuing Certification (CC) reporting of activities required of diplomates to maintain certification. The survey was voluntary, open to all diplomates participating in CC, and conducted over two consecutive years (2019 and 2020), with alternate years comprising different sets of diplomates. The data are based on 1256 respondents (820 from 2019 to 436 from 2020). The three highest aggregate reported rates of burnout (reported as experienced nearly all of the time, most of the time, or part of the time) occurred when respondents were in their first year of residency training (41.1%) and when they were in (47.6%) and beyond (46.6%) their first three years of practice. We considered this high-low-high, or U-shaped distribution in recollected burnout over time among pathologists a notable finding and investigated its distribution among respondents. Conversely at every point in their training and practice, from half to three-quarters of respondents reported never or infrequently experiencing burnout. This study represents the largest pathologist cohort survey to date about pathologists' burnout. Importantly, especially for those considering pathology as a career, these data are on the low end of the distribution of burnout among specialties for those in practice., Competing Interests: None of the authors have declared any conflicting financial interests related to this manuscript., (© 2022 The Authors.)

Context: Adrenocortical carcinoma (ACC) is a rare malignancy with poor prognosis for both locally advanced and metastatic disease. Standard treatment with combination etoposide-doxorubicin-cisplatin-mitotane (EDP-M) is highly toxic and some patients benefit from mitotane monotherapy. However, identification of these patients remains challenging., Objective: We present a summary of the Israeli national referral center's 20 years of experience in treating advanced ACC, with the aim of identifying prognostic factors and assisting in treatment decision making., Methods: We conducted a retrospective multivariate analysis of patients treated for metastatic or locally advanced ACC at Hadassah Medical Center between 2000 and 2020 to determine clinical, pathological, and treatment factors correlated with overall survival (OS)., Results: In our cohort of 37 patients, a combination of modified European Network for the study of Adrenal Tumors (mENSAT) staging with either grade and R status, or age and symptoms was validated to stratify prognosis ( P  = .01 and P  = .03, respectively). Patients who underwent R0 resection followed by radiotherapy or metastasectomy for oligometastatic disease had longer OS than patients with residual disease: median OS of 55 months vs 14 months, respectively, hazard ratio 3.1 (CI 1.4-6.7, P  = .005). Patients treated with mitotane monotherapy had a significantly better prognosis, yet this result was attenuated in a multivariate analysis controlling for mENSAT and R status. Of patients treated with EDP-M, 41.4% experienced grade 3 or higher adverse events., Conclusion: Patients with advanced ACC achieving R0 status have a better prognosis and might benefit from mitotane monotherapy., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)

The purpose of this study was to assess the efficacy and safety of 177 Lu-DOTATATE in patients with somatostatin receptor (SSR)-positive lung neuroendocrine tumors (NETs). Methods: This is a retrospective review of the outcome of patients with typical carcinoid (TC) and atypical carcinoid (AC), treated with 177 Lu-DOTATATE at 2 ENETS Centers of Excellence. Morphologic imaging (RECIST 1.1) and 68 Ga-DOTATATE PET/CT responses were assessed at 3 mo after completion of 177 Lu-DOTATATE. Concordance between 2 response assessment methods was evaluated by κ statistics. Progression-free survival (PFS) and overall survival (OS) were estimated by Kaplan-Meier analysis and compared by Log-rank test. Treatment-related adverse events (AEs) were graded based on Common Terminology Criteria for Adverse Events, version 5. Results: Of 48 patients (median age, 63 y; 13 women), 43 (90%) had AC and 5 (10%) TC. Almost all patients (47, 98%) were treated due to progression. Most patients (40, 83%) received somatostatin analogs, and 10 patients (20%) had prior everolimus, chemotherapy, or both. All patients had high SSR expression (≥ modified Krenning score 3) on pretreatment 68 Ga-DOTATATE PET/CT. Patients received a median 4 (range, 1-4) cycles of 177 Lu-DOTATATE (33% with concurrent radiosensitizing chemotherapy) to a median cumulative activity of 27 GBq (range, 6-43GBq). At a median follow-up of 42 mo, the median PFS and OS were 23 mo (95% CI, 18-28 mo) and 59 mo (95% CI, 50-not reached [NR]), respectively. Of 40 patients with RECIST-measurable disease and 39 patients with available 68 Ga-DOTATATE PET/CT, response categories were partial response, 20% (95% CI, 10%-35%) and 44% (95% CI, 30%-59%); stable disease, 68% (95% CI, 52%-80%) and 44% (95% CI, 30%-59%); and progressive disease, 12% (95% CI, 5%-27%) by both, respectively. There was a moderate concordance between response categories by RECIST and 68 Ga-DOTATATE PET/CT, weighted κ of 0.51 (95% CI, 0.21-0.68). Of patients with stable disease by RECIST, those with partial response on 68 Ga-DOTATATE PET/CT had a longer OS than those with no response, NR versus 52 mo (95% CI, 28-64), hazard ratio 0.2 (95% CI, 0.1-0.6), P  < 0.001. Most grade 3/4 AEs were reversible and the most common was lymphopenia (14%) with no incidence of myelodysplasia or leukemia. Conclusion: In patients with advanced progressive lung NET and satisfactory SSR expression, 177 Lu-DOTATATE is effective and safe with a high disease control rate and encouraging PFS and OS., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

Introduction: Telotristat ethyl is indicated for use in combination with somatostatin analogs (SSAs) to treat carcinoid syndrome (CS) diarrhea uncontrolled by SSAs alone in adults, but long-term safety and efficacy data beyond 48 weeks are needed., Objectives: The aims of the study were to evaluate the long-term safety and tolerability of telotristat ethyl and its effect on quality of life (QOL) in patients with CS., Methods: In this phase 3, nonrandomized, multicenter, open-label, long-term extension study (TELEPATH), patients who participated in phase 2 or 3 trials of telotristat ethyl continued treatment at their present dose level (250 or 500 mg thrice daily) for 84 weeks. Safety and tolerability, the primary endpoint, were assessed by monitoring adverse events (AEs), serious AEs, AEs of special interest (AESIs; including liver-related AEs, depression, and gastrointestinal AEs), and deaths. The secondary objective was to evaluate changes in patients' QOL using validated cancer questionnaires and a subjective global assessment of CS symptoms., Results: In 124 patients exposed to telotristat ethyl for a mean of 102.6 ± 53.2 weeks, the type and frequency of AEs were consistent with those reported in previous trials. The occurrence of AESIs was not related to dosage or duration of therapy. Most AEs were mild to moderate in severity, and no deaths were related to telotristat ethyl. QOL scores remained stable, and the majority of patients reported adequate symptom relief throughout the study., Conclusions: Safety results of TELEPATH support the long-term use of telotristat ethyl in patients with CS diarrhea. Telotristat ethyl was well-tolerated and associated with sustained improvement in QOL scores (NCT02026063)., (© 2021 The Author(s) Published by S. Karger AG, Basel.)

Introduction: Patients with stage II to III lung adenocarcinomas are treated with adjuvant chemotherapy (ACT) to target the premetastatic niche that persists after curative-intent resection. We hypothesized that the premetastatic niche is a scion of resected lung tumor microenvironment and that analysis of tumor microenvironment can stratify survival benefit from ACT., Methods: Using tumor and tumoral stroma from 475 treatment-naive patients with stage II to III lung adenocarcinomas, we constructed a tissue microarray and performed multiplex immunofluorescent staining for immune markers (programmed death-ligand 1 [PD-L1], tumor-associated macrophages [TAMs], and myeloid-derived suppressor cells) and derived myeloid-lymphoid ratio. The association between immune markers and survival was evaluated using Cox models adjusted for pathologic stage., Results: Patients with high PD-L1 expression on TAMs or tumor cells in resected tumors had improved survival with ACT (TAMs: hazard ratio [HR] = 1.79, 95% confidence interval [CI]: 1.12-2.85; tumor cells: HR = 3.02, 95% CI: 1.69-5.40). Among patients with high PD-L1 expression on TAMs alone or TAMs and tumor cells, ACT survival benefit is pronounced with high myeloid-lymphoid ratio (TAMs: HR = 3.87, 95% CI: 1.79-8.37; TAMs and tumor cells: HR = 2.19, 95% CI: 1.02-4.71) or with high stromal myeloid-derived suppressor cell ratio (TAMs: HR = 2.53, 95% CI: 1.29-4.96; TAMs and tumor cells: HR = 3.21, 95% CI: 1.23-8.35). Patients with low or no PD-L1 expression on TAMs or tumor cells had no survival benefit from ACT., Conclusions: Our observation that PD-L1 expression on TAMs or tumor cells is associated with improved survival with ACT provides rationale for prospective investigation and developing chemoimmunotherapy strategies for patients with lung adenocarcinoma., (Copyright © 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

(1) Background: Neuroendocrine neoplasms of the lung (LNENs, lung carcinoids) are often diagnosed at an advanced stage when they are not surgically curable, and treatment options are limited. One of the approved options for treating inoperable tumors is everolimus-an mTOR inhibitor (mTORi). Activation of mTOR, among many other effects, inhibits autophagy, which is a cell survival mechanism in general, and in tumor cells in particular. Everolimus may paradoxically encourage cancer cell survival. In practice, the drug inhibits tumor development. Chloroquine (CQ) is a known antimalarial compound that inhibits autophagy. Our research is focused on the hypothesis that autophagy plays a key role in the development of tumor resistance to mTORi, and that the addition of autophagy inhibitors to mTORi exerts a synergistic effect on suppressing tumor cell proliferation. We have recently demonstrated that the combination of CQ with different mTORi increases their potency compared with mTORi alone in both in vitro and in vivo models of pancreatic NENs. In this study, we examined the effects of CQ and mTORi on in vitro and in vivo LNEN models. Aims: Testing the effects of CQ together with mTORi on cell proliferation, apoptosis, and autophagy in in vitro and in vivo LNEN models. (2) Methods: The NCI-H727 LNEN cells were treated with CQ ± mTORi. Cells' viability and proliferation were measured using XTT and Ki-67 FACS staining. The effects of the treatments on the mTOR pathway and autophagy were examined using Western blotting. Cytotoxicity was measured using a cytotoxicity kit; apoptosis was measured by PI FACS staining and Western blotting. We further established an LNEN subcutaneous murine xenograft model and evaluated the effects of the drugs on tumor growth. (3) Results: CQ alone suppressed LNEN cells' viability and proliferation and increased their cytotoxicity and apoptosis; these effects were augmented when CQ was added to an mTORi. We also showed the possible mechanisms for these results: on the one hand we could see a decrease in P62 levels and the absence of LC3-II (both inversely related to autophagy) following treatment with the mTORi, and on the other hand we could demonstrate an increase in their levels when CQ was added. The effect was less apparent in the murine xenograft model. (4) Conclusions: By inhibiting autophagy and inducing apoptosis, CQ suppresses tumor cell growth in LNENs. CQ potentiates mTORi effects, implying that further studies are needed in order to elucidate its possible role in tumor inhibition in patients with LNENs.

Tumor spread through air spaces (STAS) is associated with locoregional recurrence in patients undergoing limited resection (LR) for non-small cell lung carcinoma (NSCLC). We hypothesized that the observation of STAS in both the initial LR specimen and the additional resection specimen from the same patient, processed using different knives, would provide evidence that STAS is an in vivo phenomenon contributing to locoregional recurrence. We retrospectively identified patients with NSCLC (9 adenocarcinoma, 1 squamous cell carcinoma) who underwent LR, had STAS in the LR specimen, and underwent additional resection (lobectomy or LR). The LR and additional resection specimens from each patient were processed at different times using different tissue-processing knives. All specimens were analyzed for STAS. All 10 patients underwent LR with negative margins (R0). All additional resection specimens had STAS: 8 patients had STAS clusters in their completion lobectomy specimens, and 2 had STAS in their additional LR specimens. In 2 patients, STAS was found in the completion lobectomy specimen only after extensive sampling (>10 sections) from the staple line adjacent to the initial LR. The presence of STAS in both the LR and the additional resection specimen processed using different knives supports the concept that STAS is an in vivo phenomenon, rather than an artifact from tissue processing. This observation indicates that occult STAS tumor cells can be present in the lung tissue of the remaining unresected lobe after LR and supports the concept that STAS is a contributing factor for locoregional recurrence following LR., Competing Interests: Conflicts of Interest and Source of Funding: P.S.A.’s laboratory work is supported by grants from the National Institutes of Health (P30 CA008748, R01 CA236615-01, and R01 CA235667), the U.S. Department of Defense (BC132124, LC160212, CA170630, and CA180889), the Comedy versus Cancer Foundation, the Dalle Pezze Foundation, the Derfner Foundation, the Geoffrey Beene Foundation, the Memorial Sloan Kettering Technology Development Fund, the Miner Fund for Mesothelioma Research, the Mr. William H. Goodwin and Alice Goodwin, the Commonwealth Foundation for Cancer Research, and the Experimental Therapeutics Center of Memorial Sloan Kettering Cancer Center. D.R.J.’s laboratory work is supported by grants from the National Institutes of Health (R01 CA217169 and R01 CA240472). D.J.G. is supported, in part, by the National Institutes of Health (T32CA009501). For the remaining authors none were declared., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Following each cycle of peptide receptor radionuclide therapy (PRRT), absorbed doses by tumors and normal organs are typically calculated from three quantitative single-photon emission computed tomography (SPECT)/computed tomography (CT) studies acquired at t 1  = 24 h, t 2  = 96 h, t 3  = 168 h after the first cycle of treatment and from a single study at t 1 after the subsequent cycles. In the present study, we have assessed the feasibility of a single SPECT/CT study after each PRRT cycle using a trained multiple linear regression (MLR) model for absorbed dose calculation and have evaluated its impact on patient management. Quantitative [ 177 Lu]-DOTA-TATE SPECT/CT data after PRRT of seventy-two consecutive metastatic neuroendocrine tumors patients were retrospectively evaluated. A set of 40 consecutive studies was used to train the MLR model. The two independent variables of the model included the time of imaging after administration of the treatment and the radiopharmaceutical activity concentration in a given  organ/tumor. The dependent variable was the dose absorbed by the organ/tumor obtained with the standard protocol. For bone marrow dosimetry, the independent variables included the time of imaging, and the blood and remainder of the body activity concentration. The model was evaluated in 32 consecutive patients. Absorbed doses were assessed for kidneys, bone marrow, liver, spleen and tumor sites., Results: There was no difference in management decisions, whether PRRT can be safely continued or not because unsafe absorbed dose to risk organs between the standard and the MLR model-based protocol using a single SPECT/CT study performed at t 3  = 168 h after the first cycle and at t 1  = 24 h after the subsequent cycles. Cumulative absorbed doses were obtained with mean relative differences of - 0.5% ± 5.4%, 1.6% ± 15.1%, - 6.2% ± 7.3%, - 5.5% ± 5.8% and 2.9% ± 12.7% for kidneys, bone marrow, liver, spleen and tumors, respectively (Pearson's r correlation coefficient 0.99, 0.91, 0.99, 0.99 and 0.97, respectively)., Conclusion: Dosimetry calculations using a MLR model with a single SPECT/CT study are in good agreement with the standard protocol, while avoiding the use of dosimetry software and enabling improved patient comfort and reduced scanner and staff time., (© 2021. The Author(s).)

This article presents findings from a 4-year series of surveys of new-in-practice pathologists, and a survey of physician employers of new pathologists, assessing how pathology graduate medical education prepares its graduates for practice. Using the methodology described in our previous study, we develop evidence for the importance of residency training for various practice areas, comparing findings over different practice settings, sizes, and lengths of time in practice. The principal findings are (1) while new-in-practice pathologists and their employers report residency generally prepared them well for practice, some areas-billing and coding, laboratory management, molecular pathology, and pathology informatics-consistently were identified as being important in practice but inadequately prepared for in residency; (2) other areas-autopsy pathology, and subspecialized apheresis and blood donor center blood banking services-consistently were identified as relatively unimportant in practice and excessively prepared for in residency; (3) the notion of a single comprehensive model for categorical training in residency is challenged by the disparity between broad general practice in some settings and narrower subspecialty practice in others; and (4) the need for preparation in some areas evolves during practice, raising questions about the appropriate mode and circumstance for training in these areas. The implications of these findings range from rebalancing the emphasis among practice areas in residency, to reconsidering the structure of graduate medical education in pathology to meet present and evolving future practice needs., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2021.)

Background: Image quality and quantitative accuracy of positron emission tomography (PET) depend on several factors such as uptake time, scanner characteristics and image reconstruction methods. Ordered subset expectation maximization (OSEM) is considered the gold standard for image reconstruction. Penalized-likelihood estimation (PL) algorithms have been recently developed for PET reconstruction to improve quantitation accuracy while maintaining or even improving image quality. In PL algorithms, a regularization parameter β controls the penalization of relative differences between neighboring pixels and determines image characteristics. In the present study, we aim to compare the performance of Q.Clear (PL algorithm, GE Healthcare) and OSEM (3 iterations, 8 subsets, 6-mm post-processing filter) for 68 Ga-DOTATATE ( 68 Ga-DOTA) PET studies, both visually and quantitatively. Thirty consecutive whole-body 68 Ga-DOTA studies were included. The data were acquired in list mode and were reconstructed using 3D OSEM and Q.Clear with various values of β and various acquisition times per bed position (bp), thus generating images with reduced injected dose (1.5 min/bp: β = 300-1100; 1.0 min/bp: β = 600-1400 and 0.5 min/bp: β = 800-2200). An additional analysis adding β values up to 1500, 1700 and 3000 for 1.5, 1.0 and 0.5 min/bp, respectively, was performed for a random sample of 8 studies. Evaluation was performed using a phantom and clinical data. Two experienced nuclear medicine physicians blinded to the variables assessed the image quality visually., Results: Clinical images reconstructed with Q.Clear, set at 1.5, 1.0 and 0.5 min/bp using β = 1100, 1300 and 3000, respectively, resulted in images with noise equivalence to 3D OSEM (1.5 min/bp) with a mean increase in SUV max of 14%, 13% and 4%, an increase in SNR of 30%, 24% and 10%, and an increase in SBR of 13%, 13% and 2%. Visual assessment yielded similar results for β values of 1100-1400 and 1300-1600 for 1.5 and 1.0 min/bp, respectively, although for 0.5 min/bp there was no significant improvement compared to OSEM., Conclusion: 68 Ga-DOTA reconstructions with Q.Clear, 1.5 and 1.0 min/bp, resulted in increased tumor SUV max and in improved SNR and SBR at a similar level of noise compared to 3D OSEM. Q.Clear with β = 1300-1600 enables one-third reduction of acquisition time or injected dose, with similar image quality compared to 3D OSEM.

Introduction: The lymph node ratio (LNR), which represents the proportion of metastatic lymph nodes resected, has been found to be a prognostic variable in several cancers, but data for Medullary thyroid carcinoma (MTC) are sparse. The aim of this study was to determine the value of the LNR in predicting outcome in patients with MTC., Materials and Methods: A retrospective multicenter study design of 107 patients with MTC who underwent total thyroidectomy with neck dissection between 1984 and 2016. The association of LNR with patient and tumor characteristics and prognostic factors was evaluated., Results: Study population consisted of 53.3% female, mean age at diagnosis was 50.3 ± 18.4 years; 16.8% had inherited MTC. LNR was positively correlated with tumor size (p = 0.018) and inversely correlated with age at diagnosis (p = 0.024). A higher LNR was associated with extrathyroidal extension (p < 0.001), multifocality (p = 0.001), bilateral tumor (p = 0.002), distant metastases (p < 0.001), and tumor recurrence (OR = 14.7, p < 0.001). LNR was also correlated to postoperative calcitonin levels (p < 0.001) and carcinoembryonic antigen (p = 0.011). LNR >0.1 was associated with shorter disease-specific survival in patients at risk: tumor larger than 20 mm at diagnosis (p = 0.013), sporadic MTC (p = 0.01), and age above 40 years at diagnosis (p = 0.004). Cox multivariate survival analysis revealed LNR as the only significant independent factor for disease free survival (p = 0.005)., Conclusions: This study showed that LNR correlates well with patient and tumor characteristics and prognostic variables. We suggest that LNR should be considered an important parameter for predicting outcome in MTC., Competing Interests: Declaration of competing interest None., (Copyright © 2020. Published by Elsevier Ltd.)

Objective: Von Hippel-Lindau (VHL) syndrome is a rare and complex disease. In 1996, we described a 3 generation VHL 2A kindred with 11 mutation carriers. We aim to share our experience regarding the long-term follow-up of this family and the management of all our other VHL patients focusing on frequently encountered neuroendocrine neoplasms: pheochromocytoma/paraganglioma and pancreatic neuroendocrine neoplasms (PNEN)., Methods: All VHL patients in follow-up at our tertiary center from 1980 to 2019 were identified. Clinical, laboratory, imaging, and therapeutic characteristics were retrospectively analyzed., Results: We identified 32 VHL patients in 16 different families, 7/16 were classified as VHL 2 subtype. In the previously described family, the 4 initially asymptomatic carriers developed a neuroendocrine tumor; 7 new children were born, 3 of them being mutation carriers; 2 patients died, 1 due to metastatic PNEN-related liver failure. Pheochromocytoma was frequent (22/32), bilateral (13/22;59%), often diagnosed in early childhood when active screening was timely performed, associated with paraganglioma in 5/22, rarely malignant (1/22), and recurred after surgery in some cases after more than 20 years. PNEN occurred in 8/32 patients (25%), and was metastatic in 3 patients. Surgery and palliative therapy allowed relatively satisfactory outcomes. Severe disabling morbidities due to central-nervous system and ophthalmologic hemangiomas, and other rare tumors as chondrosarcoma in 2 patients and polycythemia in 1 patient were observed., Conclusion: A multidisciplinary approach and long-term follow-up is mandatory in VHL patients to manage the multiple debilitating morbidities and delay mortality in these complex patients., (© 2020 American Association of Clinical Endocrinologists. Published by Elsevier, Inc. All rights reserved.)

Objective: To evaluate the influence of light emitted from two Polywave®, LED light-curing units (LCU) on in vivo pulp temperature (PT) rise and signs of acute inflammatory response in pulps of human premolar having deep Class V preparations., Methods: Sixty intact, first premolars from 15 volunteers requiring extraction received infiltrative anesthesia. A sterile thermocouple probe was inserted within the pulp tissue through a minute occlusal pulp exposure in only 45 teeth (n = 9) to continuously monitor PT (°C). A deep buccal Class V preparation was created, and the surface was exposed to light from a commercial Polywave LCU (Bluephase 20i (20i), Ivoclar Vivadent) or from an experimental LCU (Exp) using the exposure modes (EM): 1s/Exp and 2s/Exp, 10s/20i, 20s/20i, and 60s/20i. Peak PT and PT rise values above baseline (ΔT) data were evaluated using a one-way ANOVA followed by Tukey's post-hoc test (α = 5%). Teeth used for histological and immunohistochemical analyses (n = 3) were extracted approximately 2 h after exposure to the LCU., Results: No significant difference in peak PT and ΔT values was noted between 2s/Exp and 20s/20i groups, which both exhibited higher values than 1s/Exp and 10s/20i groups (p < 0.001). Dilated and congested blood vessels were seen after exposure to 1s/Exp, 2s/Exp, or 60s/20i EMs. The expression of IL-1β and TNF-α tended to be more intense when higher irradiance was delivered., Significance: Although higher irradiance delivered over a short exposure caused lower PT rise than 5.5 °C, such EMs should be used with caution, as they have more potential to harm the pulp tissue., (Copyright © 2020 The Academy of Dental Materials. Published by Elsevier Inc. All rights reserved.)

Background: Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare lung disease associated with proliferation of neuroendocrine cells in the lung and multifocal neuroendocrine tumorlets/tumors. Although usually considered an indolent condition, DIPNECH causes chronic, progressive cough and dyspnea which can adversely impact quality of life. There is very limited information on the treatment of this condition. The objective of this study was to assess changes in symptoms and pulmonary function tests (PFTs) in response to somatostatin analog (SSA) treatment., Methods: Patients with clinical and/or pathologic diagnosis of DIPNECH and chronic respiratory symptoms were treated with SSAs at the H. Lee Moffitt Cancer Center and Research Institute, Hadassah-Hebrew University Medical Center, and Mayo Clinic Cancer Center. Their charts were reviewed to assess changes in symptoms and PFTs., Results: Forty-two patients were identified who had either chronic cough or dyspnea because of proven or suspected DIPNECH and who had received treatment with an SSA. Thirty-three patients experienced symptomatic improvement. Additionally, 14 of 15 patients in whom PFTs were checked were noted to have an improvement in FEV 1 after treatment., Conclusions: SSA treatment can improve chronic respiratory symptoms and PFTs in patients with DIPNECH., (Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: An estimated 38% of US adults are obese. Obesity is associated with socioeconomic disparities and increased rates of comorbidities, and is a known risk factor for development of pancreatic cancer. As a fourth leading cause of death in the United States, pancreatic cancer is commonly treated with a pancreatico-duodenectomy (PD), or Whipple procedure. Data regarding the effects of obesity on post-operative complication rate primarily comes from specialized centers, however the results are mixed. Our aim is to elucidate the effects that obesity has on outcomes after PD for pancreatic head cancer using a national prospectively maintained clinical database., Method: The 2010-2015 American College of Surgeons National Surgical Quality Improvement Project (ACS NSQIP) Participant Use Files (PUF) were used as the data source. We identified cases in which PD was performed (CPT code 48150) in the setting of a postoperative diagnosis of pancreatic cancer (ICD9 code 157.0). We excluded cases that had emergency admissions, BMI ≤18.5 kg/m 2 , intraoperative wound classification of III or IV, and disseminated cancer. Cases with missing BMI, preoperative albumin, operative time, LOS data were also excluded. Multiple imputation for missing sex, race, functional status, and ASA classification using chained equations was performed. 16 Patients that had BMI ≥30 kg/m 2 were considered obese, and patients with BMI <30 kg/m 2 were used as control., Results: 3484 patients underwent pancreaticoduodenectomy for pancreatic cancer. 860 patients were identified as obese. Propensity score analysis was performed matching age, sex, race, functional status, presence of dyspnea, diabetes, hypertension, acute renal failure, dialysis dependence, ascites, steroid use, bleeding disorders, history of chronic obstructive pulmonary disease (COPD), congestive heart failure (CHF), weight loss, American Society of Anesthesiologists (ASA) classification, and preoperative albumin levels. After matching, obese patients had higher risk of 30-day postoperative complications compared to control, including organ space wound infections (OR 1.38, 95% CI 1.07-1.79, p = 0.0128), returning to the operating room (OR 1.39, 95% CI 1.01-1.91, p = 0.0461), failure to extubate for greater than 48 h (OR 1.60, 95% CI 1.09-2.34, p = 0.0153), death (OR 1.68, 95% CI 1.01-2.78, p = 0.0453), septic shock (OR 2.22, 95% CI 1.46-3.38, p = 0.0002), pulmonary embolism (OR 2.42, 95% CI 1.07-5.45, p = 0.0332), renal insufficiency (OR 2.67, 95% CI 1.33-5.38, p = 0.0058). Sensitivity analysis yielded similar results with the exception of risk for return to the operating room, death, and pulmonary embolism, P > .05., Conclusion: In this large observational study using a national clinical database, obese patients undergoing PD for head of pancreas cancer had increased risk of postoperative complications and mortality in comparison to controls., Competing Interests: Declaration of competing interest The authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article. There are no organizations funding this research., (Copyright © 2019. Published by Elsevier Inc.)

Purpose: The decreased life expectancy of MEN-1 patients is mainly related to pancreatic neuroendocrine tumors (pNETs). At best, limited data is available on the natural history of MEN-1-associated pNETs, as these tumors are rare and have a wide range of biologic behavior. Our study aims to explore the clinical course of patients with MEN-1-associated pNETs and the long-term outcomes., Methods: This longitudinal study was conducted on the MEN-1 cohort treated at our referral center over a 22-year period (1996-2018). Relevant clinical data were retrospectively analysed., Results: Among the 33 MEN-1 patients included in our study, pNETs were identified in 21 subjects with a penetrance of 48% by the age of 50. Non-functioning and functioning pNETs were diagnosed in sixteen (76%) and five (24%) patients, respectively. Two-thirds of the patients had multifocal tumors. The median number of pancreatic macroscopic lesions per individual was 4.0 ± 3.9 (range 1-8) with a mean size of 1.3 ± 2.1 cm (range 0.5-10). The metastatic rate according to the dominant pNET lesion reached 100%, 62% and 6% for tumors sized > 4 cm, 2.1-4 cm, and 1-2 cm, respectively. Over the study period, one or more therapeutic interventions for pNETs were required in 20 out of the 21 patients. pNET-related metastatic complication was the main cause of death within this MEN-1 cohort. The overall survival rate for the pNETs patients was 86% during a mean follow-up period of 8.0 ± 4.6 years., Conclusions: In our MEN-1 cohort, non-functioning pNETs were the most frequent type of pancreaticoduodenal tumor, and the tumor size correlated with the risks of metastasis and death. Increased awareness, early diagnosis, and a multidisciplinary approach may improve the associated morbidity and mortality in these patients.

Context.—: Disagreement exists within the pathology community about the status of the job market for pathologists. Although many agree that jobs in pathology were harder to come by earlier this decade, recent evidence suggests improvement is occurring., Objective.—: To assess the state of the job market for pathologists., Design.—: We analyzed data from the 2018 College of American Pathologists Practice Leader Survey. This survey contains data from 253 practice leaders on practices' hiring (and retrenchments) in 2017, the skills and level of experience being sought, success in filling those positions, and expectations for hiring in the next 3 years., Results.—: Among the surveyed practice leaders, 115 (45.5%) sought to hire at least 1 pathologist in 2017, and together tried to fill 246 full-time equivalent positions that year, of which 93.5 full-time equivalents (38%) were newly created. This hiring was not limited to larger, academic-based practices, but also occurred among smaller practices and practices based in nonacademic hospitals, independent laboratories, and other settings. Although some practices retrenched (60 full-time equivalents in 2017), the net increase was a healthy 187 full-time equivalents. Practices most frequently sought pathologists who had at least 2 years of experience, but the level of experience identified with the "optimal" candidate varied by desired areas of subspecialty expertise. Practice leaders also reported expected growth in hiring, with the number of positions they hope to fill in the next 3 years exceeding those vacated by retirement., Conclusions.—: Our findings support the proposition that the demand for pathologists is strong, at least at the current time.

Introduction: Anterior cruciate ligament (ACL) injuries are common and reconstruction can be completed with either autograft or allograft tissue. However, there is concern about an increased failure rate with allograft tissue. The purpose of this study was to systematically review the available evidence to determine the effect of irradiation and level of dose on the failure rates of allograft in ACL reconstruction., Methods: A literature search was performed using PubMed, Scopus, and Web of Science from January 2000 to September 2013. Inclusion criteria consisted of the following: (1) primary, unilateral, single-bundle allograft ACL procedure, (2) studies with data documenting graft type and terminal sterilization technique, (3) subjective assessments of outcome, and (4) objective assessments of outcome. Studies without reported subjective and objective outcomes and those pertaining to revision ACL reconstruction were excluded. Failures were defined and compared between irradiated and non-irradiated grafts, as well as between grafts irradiated with 1.2 - 1.8 Mrad and those with 2.0 - 2.5 Mrad., Results: Of the 242 articles identified via initial search, 17 studies met the final inclusion criteria. A total of 1,090 patients were evaluated in this study, all having undergone unilateral primary ACL reconstruction with allograft tissue with 155 failures. The failure rate between non-irradiated (98/687, 14.7%) and irradiated (57/408, 14.0%) was not statistically significant (p = 0.86). Grafts in the high-dose irradiation group (27/135, 20.0%) had a statistically significant higher (p < 0.001) rate of failure than those in the low-dose irradiation group (30/273, 10.6%)., Conclusion: The irradiation of an allograft increases the risk of failure after an ACL reconstruction but the use of lower doses of radiation decreases that risk., (© 2020 The University of Kansas Medical Center.)

Background: After each cycle of [ 177 Lu]-DOTA-TATE peptide receptor radionuclide therapy (PRRT) dosimetry is performed to enable precise calculation of the radiation-absorbed dose to tumors and normal organs. Absorbed doses are routinely calculated from three quantitative single-photon emission computed tomography (SPECT) studies corrected by computed tomography (CT) acquired at t 1  = 24 h, t 2  = 96 h, and t 3  = 168 h after the first cycle of treatment. After following cycles, a single SPECT/CT study is performed. The aim of the present study is to assess the feasibility of a "two time point" quantitative SPECT/CT protocol after the first PRRT cycle and its impact on patient management. Quantitative SPECT/CT data of 25 consecutive patients with metastatic neuroendocrine tumors after PRRT were retrospectively analyzed. Radiation-absorbed doses calculated using the standard protocol with three SPECT/CT studies acquired at (t 1 , t 2 , t 3 ) were compared to those obtained from three different "two time point" protocols with SPECT/CT studies performed at (t 1 , t 2 ), (t 1 , t 3 ), or (t 2 , t 3 )., Results: The best agreement for the cumulative doses absorbed by the kidneys, bone marrow, liver, spleen, and tumors with the conventional protocol was obtained with the (t 1 , t 3 ) protocol with mean relative differences of - 1.0% ± 2.4%, 0.4% ± 3.1%, - 0.9% ± 4.0%, - 0.8% ± 1.1%, and - 0.5% ± 2.0%, respectively, and correlation coefficients of r = 0.99 for all. In all patients, there was no difference in the management decision of whether or not to stop PRRT because of unsafe absorbed dose to risk organs using either the standard protocol or the (t 1 , t 3 ) protocol., Conclusion: These preliminary results demonstrate that dosimetry calculations using two quantitative SPECT/CT studies acquired at 24 and 168 h after the first PRRT cycle are feasible and are in good agreement with the standard imaging protocol with no change in patient management decisions, while enabling improved patient comfort and reduced scanner and staff time.

Introduction: With the popularization of damage control surgery and the use of the open abdomen, a new permutation of fistula arose; the enteroatmospheric fistula (EAF), an opening of exposed intestine spilling uncontrollably into the peritoneal cavity. EAF is the most devastating complication of the open abdomen. We describe and analyze a single institution's experience in controlling high-output EAFs in patients with peritonitis., Methods: We analyzed 189 consecutive procedures to achieve and maintain definitive control of 24 EAFs in 13 patients between 2006 and 2017. EAFs followed surgery for either trauma (seven patients) or non-traumatic abdominal conditions (six patients). All procedures were mapped onto an operative timeline and analyzed for: success in achieving definitive control, number of reoperations, and feasibility of bedside procedures in the surgical intensive care unit. The end point was controlled enteric drainage through a healed abdominal wound., Results: There was a mean delay of 8.5 days (range 2-46 days) from the index operation until the EAF was identified. Most EAFs required several attempts (mean: 2.7 per patient, range 1-7) until definitive control was achieved. Multiple reoperations were then required to maintain control (mean: 13). While the most effective techniques were endoscopic (1) and proximal diversion (1), these were applicable only in select circumstances. A 'floating stoma' where the fistula edges are sutured to an opening in a temporary closure device, while technically effective, required multiple reoperations. Tube drainage through a negative pressure dressing (tube vac) required the most maintenance usually through bedside procedures. Primary closure almost always failed. Twelve of the 13 patients survived., Conclusion: An EAF is a highly complex surgical challenge. Successful source control of the potentially lethal ongoing peritonitis requires tenacity and tactical flexibility. The appropriate control technique is often found by trial and error and must be creatively tailored to the individual circumstances of the patient., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

We describe a unique case of a 53-year-old woman who underwent a nonrelated living donor kidney transplant 9 years after a previous small bowel transplant from her sister. The patient had suffered from short bowel syndrome secondary to volvulus after undergoing bariatric surgery for morbid obesity. Her entire small bowel had to be resected emergently, but she also developed acute kidney failure at the time. This initial kidney injury associated with long-term exposure to calcineurin-inhibitor medication eventually led to end-stage renal disease. A successful kidney transplant from a different, nonrelated adult donor was performed. Of note, the unrelated kidney donor matched exactly the 2 HLA-A and HLA-B antigens that the recipient had not matched with her sister. We discuss the unique HLA configuration between the patient and her 2 living donors, the absence of posttransplant rejection and posttransplant immunosuppressive therapy. To our knowledge this is the first published report of a successful kidney after a previous bowel transplant using (2 different) living donors., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Opinion Statement: Carcinoid syndrome (CS) is a complex disorder caused by functional neuroendocrine tumors (NETs). This debilitating disease is characterized by hyper-secretion of biologically active substances eliciting major hormonal symptoms burden and fibrotic changes that are often challenging for management. There have been a number of insights that have substantially advanced treatments since the introduction of somatostatin analogs (SSAs). Second-line treatments are needed in a substantial proportion of patients with advanced disease that have uncontrolled hormone secretion on the highest labeled doses of SSAs. International guidelines suggest several available options including dose escalation of SSAs, interferon alpha, everolimus, radionuclide therapy, liver-directed therapies, and the novel tryptophan hydroxylase 1 inhibitor, telotristat ethyl. The clear preference of one second-line therapy over the other is not stated since their relative and long-term efficacy are largely unknown, and standardized approach of hormonal response assessment is lacking in the literature. In the clinical setting, the treatment of CS is guided in conjunction with patients' performance status, tumor origin, grade, stage, and growth rate, with regard to both anti-hormonal, as well as anti-proliferative effect. There is an unmet need for further well-designed randomized placebo-controlled and head-to-head studies that systematically assess CS symptom control and biochemical response following a specific intervention.

Context: Endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) is rapidly emerging as feasible therapy for patients with pancreatic neuroendocrine tumors (pNETs) in selected cases, as a result of its favorable safety profile., Objective: To assess the feasibility, safety, and efficacy of EUS-RFA in a cohort of patients with functional and nonfunctional pNETs (NF-pNETs)., Design: Data on pNET patients treated with EUS-RFA between March 2017 and October 2018 at two tertiary centers was retrospectively analyzed., Results: The cohort included 18 adults (eight women, 10 men), aged 60.4 ± 14.4 years (mean ± SD), seven insulinoma patients, and 11 patients with NF-pNETs. Twenty-seven lesions with a mean diameter of 14.3 ± 7.3 mm (range 4.5 to 30) were treated. Technical success defined as typical postablative changes on a surveillance imaging was achieved in 26 out of 27 lesions. Clinical response with normalization of glucose levels was observed in all (seven of seven) insulinoma cases within 24 hours of treatment. Overall, there were no major complications 48 hours postprocedure. No clinically significant recurrences were observed during mean follow-up of 8.7 ± 4.6 months (range 2 to 21 months)., Conclusions: EUS-guided RFA of pNETs is a minimally invasive, safe, and technically feasible procedure for selected patients., (Copyright © 2019 Endocrine Society.)

Objective: Multiple clinical, pathological and biochemical variables, including the response to initial treatment, are associated with medullary thyroid carcinoma (MTC) prognosis. Studies that include separate analyses of familial and sporadic MTC patients followed for long period are scarce. This study evaluated the association between baseline clinico-pathologic variables and response to initial treatment and short- and long-term disease outcomes in sporadic and familial MTC., Methods: Patients treated for MTC at four tertiary medical centers were retrospectively analyzed. Clinical and pathological data were collected. The outcomes measured included disease persistence 1 year after diagnosis, disease persistence at last follow-up, disease-related mortality (DRM) and all-cause mortality., Results: The study enrolled 193 patients (mean age: 48.9 ± 18.7, 44.7% males), of whom 18.1% were familial cases. The mean follow-up period was 10.1 ± 9.4 years (8.5 ± 8.1 in sporadic and 16.9 ± 11.6 in familial MTC). Disease persistence 1-year after diagnosis and at last follow-up was detected in 56.1 and 60.4% patients, respectively. All-cause and DRM were 28.5 and 12.6%, respectively. Extra-thyroidal extension (ETE) and distant metastases (DM) were associated with disease persistence at last follow-up. ETE and DM were also significantly associated with DRM. Complete remission 1 year after diagnosis had high correlation with no evidence of disease at last follow-up (Cramer's V measure of association 0.884, P < 0.001) and with 100% disease-specific survival (Cramer's V measure of association 0.38, P < 0.001)., Conclusions: Apart from clinico-pathologic parameters, close correlation was found between 1-year status and long-term prognosis. These results underscore the importance of combining classical and dynamic factors for both sporadic and familial MTC prognostication and treatment decision making.

Purpose: To study the evolution and optimal management of metastatic bone disease (mBD) in patients with neuroendocrine neoplasms (NENs)., Methods: Seventy-four patients were recruited from four NEN centers in this observational multicenter study., Results: Pancreas and small bowel were the most common primaries (30 and 27%, respectively). Almost all gastrointestinal (GI)-NENs were grades 1 and 2, whereas bronchopulmonary-thymic were atypical carcinoids. Thirty-two (43%) patients had synchronous metastatic bone disease (mBD) and three patients reported bone-specific symptoms; metachronous mBD developed at a median of 35 (range: 4-395) months. Thirty-six (86%) of patients with metachronous mBD had stage IV disease at diagnosis. Somatostatin receptor functional imaging and computed tomography were the modalities mostly used for mBD identification. Fifty-two patients received assessable bone-related therapy (bisphosphonates, denosumab, local radiotherapy, and radionuclide treatment). Improvement in mBD was seen in 5, stable disease in 22, and deterioration in 25 patients. The presence of synchronous mBD and the negative outcome of bone-related therapy negatively affected overall survival (OS). In the multivariate analysis, the stronger predictor of OS was the outcome of bone-related therapy (HR: 4.753; 95% CI: 1.589-14.213). Bisphosphonates therapy was the mostly used bone-specific treatment but its monthly administration did not affect OS. At last follow-up, 39 patients were alive with OS 50 (14-463) months., Conclusions: Early investigation for mBD offers a prognostic marker of patients with NENs, since synchronous mBD has a negative impact on survival. The outcome of bone-related therapy affects OS but the monthly administration of bisphosphonates did not show a benefit over less intense schemes.

Context.—: As part of its value-based care initiative, the College of American Pathologists has pursued research to better understand the role pathologists can have in population health., Objectives.—: To answer the following questions: (1) what is the impact of population health and population health management on pathologists; (2) what roles are pathologists playing in population health management; (3) is population health something that pathologists in both larger and smaller settings can engage in; (4) are pathologists in a position to analyze laboratory data for population health, and, if so, what are the key information sources those pathologists must access; and (5) what steps can a pathologist take to become involved in population health?, Design.—: We conducted 10 semistructured interviews with pathologists and other medical laboratory leaders who have been active in population health. These interviews were supplemented with a review of the medical literature., Results.—: Pathologists have demonstrated that laboratory data can provide unique value-added contributions to improving the health of populations. These contributions are not limited to pathologists in large, integrated settings. However, pathologists need to be proactive to contribute to health systems' population health efforts and may need to both enhance their own skills and the quality of their data to maximize the value of their contributions., Conclusions.—: Although not necessarily a definitive summary of the roles that pathologists are playing in population health, this article identifies some of the promising and innovative activities occurring among pathologists and laboratorians.

Background: With the advent of minimally invasive techniques, the standard approaches to many surgeries have changed. We compared the financial costs and health care outcomes between standard thymectomy via sternotomy and video assisted thoracoscopic surgery (VATS)., Methods: A 3-year review [2010-2012] of the National Inpatient Sample (NIS) was performed. All patients undergoing thymectomy were included. Patients undergoing VATS thymectomy were identified. Outcomes measured were hospital length of stay (LOS), hospital charges, and mortality. Univariate and multivariate analyses were performed to control for demographics and comorbidities., Results: The results of 2,065 patients who underwent thymectomy were analyzed, of which 373 (18.1%) had VATS thymectomy and 1,692 (81.9%) had standard thymectomy. Mean age was 52.8±16, 42.5% were male, and 65.5% were Caucasian. There was a significant interval increase in number of patients undergoing VATS thymectomy (10% in 2010 vs . 19.2% in 2012, P<0.001). Patients undergoing standard thymectomy had longer hospital LOS (6.8±6.6 vs . 3.3d±3.4 d, P<0.001), hospital charges $88,838±$120,892 vs . $57,251±$54,929) and hospital mortality (0.9% vs . 0%, P=0.01). In multivariate analysis, thymectomy via sternotomy was independently associated with increased hospital LOS B =1.6 d, P<0.001) and charges (B = $13,041, P=0.041)., Conclusions: Our study demonstrates decreased hospital length of stay and reduced hospital charges in patients undergoing VATS thymectomy compared to standard thymectomy. Our data demonstrates that the prevalence of VATS thymectomies is increasing, likely related to improved healthcare and financial outcomes., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Purpose: Rectal neuroendocrine neoplasia (NEN) is more common than other NEN origins, but is less commonly metastatic. However, when present, distant disease carries a particularly poor prognosis. Evidence guiding optimal treatment of such patients is lacking. We assessed PRRT outcomes in patients with somatostatin receptor (SSTR) positive metastatic rectal NEN from two referral centres., Methods: Patients treated with PRRT were retrospectively reviewed. Morphologic (RECIST 1.1), SSTR imaging responses and toxicity were assessed 3 months post-PRRT. Kaplan-Meier estimate was used to determine progression-free survival (PFS) and overall survival (OS) from start of PRRT., Results: Twenty-seven consecutive patients (M = 20, age 31-81 years) were reviewed. The majority (70%) had ENETs grade 2 disease (19 patients), three had Grade 3, one Grade 1, and four not documented. Overall, 63% (10/16 patients with available FDG PET/CT) had FDG avid disease. Twenty-six patients were treated for disease progression. Most had 177 Lu-DOTA-octreotate with median cumulative activity of 30 GBq, median four cycles. 14 patients had radiosensitising chemotherapy (5FU or capecitabine). At 3 months post-PRRT, CT disease control rate (DCR) was 96%: partial response was observed in 70% (19/27) and stable disease in 26%. All but one had partial SSTR imaging response. The median PFS was 29 months. Ten patients died, with median overall survival 81 months with a median follow-up of 67 months. Seventeen patients had further treatments after initial PRRT (10 had further cycles of PRRT). Three patients had grade 3 lymphopenia, without significant renal toxicity, MDS or leukaemia., Conclusion: Our results indicate high efficacy and morphologic responses with minimal toxicity and very encouraging survival from PRRT in patients with metastatic rectal NEN despite the adverse prognostic features of this cohort. Further prospective PRRT trials are warranted in this subgroup.