Long-Term Treatment with Telotristat Ethyl in Patients with Carcinoid Syndrome Symptoms: Results from the TELEPATH Study.

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).

VHL-Related Neuroendocrine Neoplasms And Beyond: An Israeli Specialized Center Real-Life Report.

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.

Highly favourable outcomes with peptide receptor radionuclide therapy (PRRT) for metastatic rectal neuroendocrine neoplasia (NEN).

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 177Lu-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.

Carcinoid Syndrome: Updates and Review of Current Therapy.

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.

Update in the Therapy of Advanced Neuroendocrine Tumors.

OPINION STATEMENT: Neuroendocrine tumors (NETs) are rare neoplasms, with an estimated annual incidence of ~ 6.9/100,000. NETs arise throughout the body from cells of the diffuse endocrine system. More than half originate from endocrine cells of the gastrointestinal tract and the pancreas, thus being referred to as gastroenteropancreatic NETs (GEP-NETs). The only treatment that offers a cure is surgery; however, most patients are diagnosed with metastatic disease, and curative surgery is usually not an option. These patients can be offered long-term systemic treatment, for both symptomatic relief and tumor growth suppression. Evidence-based treatment options include somatostatin analogs, everolimus (a mTOR inhibitor), sunitinib (a tyrosine kinase inhibitor), and peptide receptor radionuclide therapy, alone or combined with cytoreductive procedures (surgery or liver-directed procedures). Other treatment options being investigated are immunotherapy and epigenetic assessment that may lead to more personalized interventions. We believe that each patient should be thoroughly evaluated and their case discussed by a multidisciplinary team that is up-to-date with all treatment modalities including ongoing clinical trials, before selecting the proper treatment option.

Diagnostic Computed Tomography Coregistration With In-111-DTPA-Octreotide Single Photon Emission Tomography/Low-Dose Computed Tomography.

OBJECTIVES: In-111-DTPA-octreotide (OctreoScan) is still pivotal for neuroendocrine tumor imaging, despite the introduction of Ga-68-octreotide tracers. Low-dose computed tomography (LDCT) assists in the localization of SPECT findings but often results in uncertain interpretation. This retrospective study evaluates the impact of coregistration of In-111-DTPA-octreotide SPECT/LDCT with diagnostic CT on interpretation. METHODS: Thirty-five consecutive studies, in which coregistration was performed because of uncertain interpretation, were evaluated. Presence of somatostatin receptors was categorized retrospectively as definitely positive, probably positive, probably negative, or definitely negative with and without rigid registration with diagnostic CT, and possible added value of coregistration was evaluated. RESULTS: Coregistration was performed in 35 studies. However, on subsequent reading, 4 SPECT/CTs yielded definite results and were omitted. Coregistration was helpful in 30 of the remaining 31 cases, changing reading to definitely positive (7) or to definitely negative (23). In 13 of the 23 cases, diagnosis changed from probably positive to definitely negative. Coregistration contributed in 42 of 48 sites, with greatest benefit in the liver (13/14), pancreas (10/10), and lymph nodes (6/6). CONCLUSIONS: Coregistration is becoming increasingly easier and may be utilized when SPECT/LDCT is inconclusive.

Abrogation of Autophagy by Chloroquine Alone or in Combination with mTOR Inhibitors Induces Apoptosis in Neuroendocrine Tumor Cells.

BACKGROUND: Everolimus (RAD001), an mTORC1 inhibitor, demonstrated promising, but limited, anticancer effects in neuroendocrine tumors (NETs). Torin1 (a global mTOR inhibitor) and NVP-BEZ235 (a PI3K/mTOR inhibitor) seem to be more effective than RAD001. Autophagy, a degradation pathway that may promote tumor growth, is regulated by mTOR; mTOR inhibition results in stimulation of autophagy. Chloroquine (CQ) inhibits autophagy. AIM: To explore the effect of CQ alone or in combination with RAD001, Torin1 or NVP-BEZ235 on autophagy and on NET cell viability, proliferation and apoptosis. METHODS: The NET cell line BON1 was treated with CQ with or without different mTOR inhibitors. siRNA against ATG5/7 was used to genetically inhibit autophagy. Cellular viability was examined by XTT, proliferation by Ki-67 staining and cell cycles by flow cytometry. Apoptosis was analyzed by Western blotting for cleaved caspase 3 and staining for annexin V; autophagy was evaluated by Western blotting and immunostaining for LC3. RESULTS: RAD001, Torin1, NVP-BEZ235 and CQ all decreased BON1 cell viability. The effect of RAD001 was smaller than that of the other mTOR inhibitors or CQ. Torin1 and NVP-BEZ235 markedly inhibited cell proliferation, without inducing apoptosis. CQ similarly decreased cell proliferation, while robustly increasing apoptosis. Treatment with Torin1 or NVP-BEZ235 together with CQ was additive on viability, without increasing CQ-induced apoptosis. Inhibition of autophagy by ATG5/7 knockdown increased apoptosis in the presence or absence of mTOR inhibitors, mimicking the CQ effects. CONCLUSION: CQ inhibits NET growth by inducing apoptosis and by inhibiting cell proliferation, probably via inhibition of autophagy. CQ may potentiate the antitumor effect of mTOR inhibitors.

Valve Replacement in Patients with Carcinoid Heart Disease: Choosing the Right Valve at the Right Time.

BACKGROUND AND AIM OF THE STUDY: The prosthetic valve of choice in patients with carcinoid valve disease (CVD) remains controversial due to the limited life expectancy of patients with advanced-stage neuroendocrine tumors (NETs) on the one hand, and concerns regarding structural valve deterioration (SVD) on the other hand. METHODS: The records of 17 patients (11 females, seven males; mean age 65 ± 11 years; undergoing 18 operations) with primarily right heart failure due to CVD were reviewed. All patients received somatostatin analogs perioperatively. Hospital and follow up data (acquired via direct patient contact and echocardiography) collected included baseline characteristics, procedural details, and clinical outcomes. RESULTS: The primary NET site was the ileum (n = 11), lungs (n = 2) and stomach, colon and appendix (n = 1 each). In one patient the primary tumor location could not be identified. Preoperative urinary levels of 5-hydroxyindole acetic acid (5-HIAA; 61 ± 36 mg/24 h) and serum levels of chromogranin A (2926 ± 4057 ng/ml) were 10- and 50-fold greater than normal, respectively. A total of 23 valves was implanted: five tricuspid valve replacements (TVR; four tissue and one mechanical), TVR and pulmonary valve replacements (PVR; three tissue and one mechanical), and TVR and mitral valve replacements (MVR; one tissue and two mechanical). The 30-day mortality was 11% (n = 2). No patient experienced a carcinoid crisis. The mean follow up was 24 ± 21 months (range: 4-85 months). Four patients (receiving seven valves) developed SVD at 12, 14, 15, and 20 months after surgery, and all of these patients died. The actuarial four-year survival and freedom from SVD were 23 ± 14% and 43 ± 15%, respectively. CONCLUSIONS: The data acquired suggested that the main advantage of tissue valve prostheses, namely to avoid lifelong, intense anticoagulation, might be offset by accelerated SVD. The use of mechanical valves should be considered in CVD patients with a large primary tumor mass and persistent high urinary levels of 5-HIAA, and who are unresponsive to therapy.

Carcinoid Heart Disease: From Pathophysiology to Treatment--'Something in the Way It Moves'.

Carcinoid heart disease (CHD) is a rare cardiac manifestation occurring in patients with advanced neuroendocrine tumours and the carcinoid syndrome, usually involving the right-sided heart valves and eventually leading to right heart failure. The pathophysiology of CHD is still obscure and believed to be multifactorial, as a variety of vasoactive substances secreted by the tumour appear to be involved. The management of patients with CHD is complex, as both the systemic malignant disease and the heart involvement have to be addressed. Timely diagnosis and early surgical treatment in appropriately selected patients are of outmost importance, as CHD is associated with increased morbidity and mortality. Valve replacement surgery alleviates right heart failure and may also contribute to improved survival. In the present study we have comprehensively reviewed the existing literature to date, mainly focusing on the pathophysiology of CHD. Other aspects of CHD (such as the clinical presentation, diagnostic tools and therapeutic approach) are addressed in brief.

Re-evaluation of the methodology for estimating the US specialty physician workforce.

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.

Laparoscopic resection of primary midgut carcinoid tumors.

BACKGROUND: Laparoscopic intestinal surgery is the preferable technique for the majority of intestinal surgical disorders. However, no series on laparoscopic resection of intestinal midgut carcinoid tumors (MCTs) has been reported to date. This is related to the rarity of these tumors as well as the technical difficulties resecting the large mesenteric root lymph node mass commonly found with these tumors and the occasional difficulty identifying the primary MCT, which may be small and undetected on preoperative imaging studies. This is the first series to report the results for laparoscopic resection of MCT. METHODS: All consecutive patients with MCT (excluding appendiceal carcinoid tumor) between 2002 and 2012 underwent laparoscopic resection. The patient's clinical data, preoperative endocrine workup, imaging studies, operative data, final histology, and outcome were recorded and analyzed. RESULTS: During the study period, 35 patients underwent surgery for primary intestinal carcinoid tumor. Of the 35 patients, 20 (12 women and 8 men ages 26-86 years) had surgery for primary MCT, and the remainder had a colorectal carcinoid tumor. In the MCT group, ten patients had liver metastases at the time of surgery. In three patients, multiple synchronous MCTs were detected intraoperatively. All the patients underwent a laparoscopic resection with en bloc resection of the corresponding mesenteric root mass. No conversion to open surgery was needed, and no major morbidity occurred. Two patients (10 %) each experienced minor morbidity with wound infection and prolonged ileus. The median hospital length of stay was 6 days (range 4-9 days). During a follow-up period of 3-96 months, no patients experienced local or regional recurrence. No distant metastases were detected during the follow-up period in any patients who had surgery with intent to cure. CONCLUSION: Although technically difficult, laparoscopic resection of primary MCTs is feasible and safe, with the additional known significant advantages of laparoscopic surgery in general. Similar to the large-scale prospective studies that proved the oncologic safety of laparoscopic surgery for colorectal cancer, this small series showed that the laparoscopic technique also may be oncologically safe for these rare tumors.

Impact of Single-Time-Point Estimates of 177Lu-PRRT Absorbed Doses on Patient Management: Validation of a Trained Multiple-Linear-Regression Model in 159 Patients and 477 Therapy Cycles.

Dosimetry after 177Lu-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 177Lu-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 χ2 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.

Strong Job Market for Pathologists: Results From the 2021 College of American Pathologists Practice Leader Survey.

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.

COVID-19 in patients with neuroendocrine neoplasms: 2-year results of the INTENSIVE study.

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.

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia and the associated lung neuroendocrine tumors: clinical experience with a rare entity.

BACKGROUND: Normal adult lungs contain pulmonary neuroendocrine cells (PNECs). PNEC hyperplasia may be either reactive or idiopathic, and the idiopathic type is defined as diffuse idiopathic PNEC hyperplasia (DIPNECH). It is believed that DIPNECH is a neuroendocrine proliferative process associated with carcinoid tumors. The available data regarding this rare condition are very limited. The objective of the current study was to describe the clinical, radiologic, and pathologic characteristics of patients with DIPNECH and the effect of various therapeutic modalities on patient well being. METHODS: The authors retrospectively studied 11 consecutive patients with DIPNECH who were followed at 2 referral centers in Israel between 2000 and 2010. RESULTS: All patients were women, and their median age was 62.8 years. Six patients presented with respiratory symptoms, such as prolonged dyspnea, wheezing, and cough. All patients had carcinoid tumor together with multiple, small pulmonary nodules observed on thoracic high-resolution computerized tomography images. The mean size of the dominant lesion was 19.4 ± 9.6 mm. Nine patients underwent thoracotomy and resection of the dominant lesion. The disease was stable in 5 of 11 patients; in 6 of 10 patients, it progressed, and the patients received treatment with somatostatin analogs, which induced disease stabilization in all patients. Metastatic disease was diagnosed in 3 of 11 patients (36%). All patients were alive at the end of follow-up (mean, 4.63 ± 2.04 years; ongoing). CONCLUSIONS: The association of lung neuroendocrine tumor with multiple nodules in women, together with complains of chronic cough and wheezing, should raise suspicion of DIPNECH. Whenever possible, these patients should undergo surgical excision of the dominant lesion, and somatostatin analogs may be considered for symptomatic or tumor control in patients with progressive disease.

Metastatic hepatocellular carcinoma to the skin staining positive with HMB-45.

Hepatocellular carcinoma (HCC) is uncommonly observed as a cutaneous metastasis. We report a 76-year-old man with metastatic HCC to the skin of the nasal ala, diagnosed antecedent to the primary tumor. HCC was confirmed by positive immunostaining with Hep Par 1 in tissue from the metastasis and from a needle biopsy of the primary lesion. In addition, tumor cells from both the metastasis and liver stained positive with HMB-45. To our knowledge, HMB-45 positive staining has not been reported in either primary or metastatic HCC.

Prognostic Factors in Advanced Adrenocortical Carcinoma: Summary of a National Referral Center's 20 years of Experience.

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.

Efficacy and Safety of 177Lu-DOTATATE in Lung Neuroendocrine Tumors: A Bicenter study.

The purpose of this study was to assess the efficacy and safety of 177Lu-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 177Lu-DOTATATE at 2 ENETS Centers of Excellence. Morphologic imaging (RECIST 1.1) and 68Ga-DOTATATE PET/CT responses were assessed at 3 mo after completion of 177Lu-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 68Ga-DOTATATE PET/CT. Patients received a median 4 (range, 1-4) cycles of 177Lu-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 68Ga-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 68Ga-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 68Ga-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, 177Lu-DOTATATE is effective and safe with a high disease control rate and encouraging PFS and OS.

Features of burnout amongst pathologists: A reassessment.

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.