Publications by authors named "Thorvardur R Halfdanarson"

109 Publications

Intensity modulated radiotherapy for anal canal squamous cell carcinoma: A 16-year single institution experience.

Clin Transl Radiat Oncol 2021 May 23;28:17-23. Epub 2021 Feb 23.

Department of Radiation Oncology, Mayo Clinic, Rochester, MN, United States.

Introduction: To report long-term efficacy and adverse events (AEs) associated with intensity modulated radiotherapy (IMRT) for patients with anal canal squamous cell carcinoma (ASCC).

Materials And Methods: This was a retrospective review of patients with ASCC who received curative-intent IMRT and concurrent chemotherapy (98%) between 2003 and 2019. Overall survival (OS), colostomy-free survival (CFS), and progression-free survival (PFS) were estimated using the Kaplan-Meier method. The cumulative incidence of local recurrence (LR), locoregional recurrence (LRR), and distant metastasis (DM) were reported. Acute and late AEs were recorded per National Cancer Institute Common Terminology Criteria for AEs.

Results: 127 patients were included. The median patient age was 63 years (interquartile range [IQR] 55-69) and 79% of patients were female. 33% of patients had T3-4 disease and 68% had clinically involved pelvic or inguinal lymph nodes (LNs).The median patient follow-up was 47 months (IQR: 28-89 months). The estimated 4-year OS, CFS, and PFS were 81% (95% confidence interval [CI]: 73%-89%), 77% (95% CI: 68%-86%), and 78% (95% CI: 70%-86%), respectively. The 4-year cumulative incidences of LR, LRR, and DM were 3% (95% CI: 1%-9%), 9% (95% CI: 5%-17%), and 10% (95% CI: 6%-18%), respectively. Overall treatment duration greater than 39 days was associated with an increased risk of LRR (Hazard Ratio [HR]: 5.2, 95% CI: 1.4-19.5, p = 0.015). The most common grade 3+ acute AEs included hematologic (31%), gastrointestinal (GI) (17%), dermatologic (16%), and pain (15%). Grade 3+ late AEs included: GI (3%), genitourinary (GU) (2%), and pain (1%). Current smokers were more likely to experience grade 3+ acute dermatologic toxicity compared to former or never smokers (34% vs. 7%, p < 0.001).

Conclusions: IMRT was associated with favorable toxicity rates and long-term efficacy. These data support the continued utilization of IMRT as the preferred treatment technique for patients with ASCC.
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http://dx.doi.org/10.1016/j.ctro.2021.02.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943964PMC
May 2021

Neuroendocrine Carcinoma of the Anus and Rectum: Patient Characteristics and Treatment Options.

Clin Colorectal Cancer 2020 Dec 17. Epub 2020 Dec 17.

Department of Oncology, Mayo Clinic, Phoenix, AZ.

Introduction: Anorectal neuroendocrine carcinomas (NECs) are uncommon malignancies with poor prognosis. Consensus guidelines exist for treating extrapulmonary NEC. However, limited data is available to guide treatment for anorectal NEC. In this study, we sought to review the clinical characteristics and outcomes of patients with NEC of the rectum and/or anus at Mayo Clinic.

Patients And Methods: This is a retrospective study of all patients with the diagnosis of NEC of the anus and/or rectum treated across Mayo Clinic sites since 2000. Baseline patient characteristics, tumor pathology, imaging profiles, treatment strategies utilized, and survival outcomes were analyzed. Kaplan-Meier analysis was used with a significance level of P < .05.

Results: The study included a total of 38 patients with primary NEC of the anus and/or rectum. The median age at diagnosis was 55.5 years. The median follow-up was 18.8 months. Fifteen patients had locoregional disease (LRD) at diagnosis. The remaining 23 had metastatic disease. Overall survival was significantly shorter in patients with LRD compared with those with metastatic disease at diagnosis (18.1 vs. 13.8 months; P = .039). The majority (n = 11) of patients with LRD were treated with concurrent chemoradiation therapy, and 10 underwent surgical resection of the primary tumor. The majority (13/15) of patients with LRD progressed, with the majority (11/15) of progressions being distant. The median progression-free survival for patients with LRD was 5.7 months (1-year progression-free survival, 26.7%).

Conclusion: Anorectal NEC is an aggressive malignancy with poor prognosis requiring multidisciplinary discussion. In addition, the systemic nature of anorectal NEC with distant recurrences in LRD and poor outcomes in metastatic disease emphasizes the need to further develop better systemic treatment options that can potentially improve outcomes in NEC.
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http://dx.doi.org/10.1016/j.clcc.2020.12.001DOI Listing
December 2020

Pilot Study Characterizing the Hematology-Oncology Fellow Job Search Process: Tools Used and Identification of Potential New Resources.

J Cancer Educ 2021 Jan 30. Epub 2021 Jan 30.

Department of Medical Oncology, Mayo Clinic, Rochester, MN, USA.

While the search for post-fellowship employment is an essential part of early career development, little is known about the tools and techniques fellows use during their job search and the specific challenges they face during the process. In this pilot survey study of hematology-oncology (HO) fellows at a large academic training program, the majority of 20 respondents (43% of all fellows) reported a plan to specialize in medical oncology, and most planned to practice in an academic setting. Fellows who had started the job search process reported using several tools/techniques including online job centers and email distribution lists, word of mouth, prior connections with other institutions, and their HO fellowship program leadership, and most reported that their current institution provided help for their job search in at least one way. Job search challenges included learning about available positions, lack of mentorship on the process, lack of sufficient time for the process, and lack of preparation for negotiation. Fellows suggested additional resources that could be helpful to future job searchers including access to information about prior HO fellowship graduates, training in negotiation and interviewing, and career development mentorship. We plan to use this information to expand our own Career Development program for fellows enacting many of these suggestions, and we encourage the use of this information as pilot data for the development of larger studies across other medical and surgical specialties.
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http://dx.doi.org/10.1007/s13187-021-01967-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7847292PMC
January 2021

Treatment Outcomes of Well-Differentiated High-Grade Neuroendocrine Tumors.

Oncologist 2021 Jan 26. Epub 2021 Jan 26.

Mayo Clinic Cancer Center, Phoenix, AZ.

Introduction: Recent classification of neuroendocrine neoplasms has defined well-differentiated high-grade neuroendocrine tumors (NET G3) as a distinct entity from poorly differentiated neuroendocrine carcinoma (NEC). The optimal treatment for NET G3 has not been well-described. This study aims to evaluate metastatic NET G3 response to different treatment regimens.

Materials And Methods: This is a retrospective study of NET G3 patients within the Mayo Clinic database. Patients' demographics along with treatment characteristics, responses, and survival were assessed. Primary end points were progression-free survival (PFS) and overall survival (OS). Secondary end points were objective response rate (ORR) and disease control rate (DCR).

Results: Treatment data was available in 30 patients with median age of 59.5 years at diagnosis. The primary tumor was mostly pancreatic (73.3%). Ki-67 index was ≥55% in 26.7% of cases. Treatments included: capecitabine + temozolomide (CAPTEM) (n=20), lutetium 177 DOTATATE (PRRT) (n=10), carboplatin/cisplatin + etoposide (EP) (n=8), FOLFOX (n=7), and everolimus (n=2). CAPTEM exhibited ORR 35%, DCR 65%, and median PFS 9.4 months (95% CI 2.96-16.07). Both EP and FOLFOX showed similar radiographic response rates with ORR 25.0% and 28.6%; however median PFS durations were quite distinct at 2.94 and 13.04 months respectively. PRRT had ORR 20%, DCR 70%, and median PFS 9.13 months.

Conclusions: Among NET G3 patients, CAPTEM was the most commonly used treatment with clinically meaningful efficacy and disease control. FOLFOX or PRRT are other potentially active treatment options. EP has some activity in NET G3 but responses appear to be short-lived. Prospective studies evaluating different treatments effects in NET G3 patients are needed to determine an optimal treatment strategy.

Implications For Practice: High-grade well differentiated neuroendocrine tumors (NET G3) are considered different entity from low-grade NET and neuroendocrine carcinoma in terms of prognosis and management. The oral combination of capecitabine and temozolomide (CAPTEM) is considered a good option in the management of metastatic NET G3 and may be preferred. FOLFOX is another systemic option with reasonable efficacy. Similar to other well-differentiated NET, PRRT seems to have some efficacy in these tumors.
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http://dx.doi.org/10.1002/onco.13686DOI Listing
January 2021

Nanoliposomal irinotecan (Nal-IRI)-based chemotherapy after irinotecan -based chemotherapy in patients with pancreas cancer.

Pancreatology 2021 Mar 18;21(2):379-383. Epub 2020 Oct 18.

Division of Medical Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN, USA. Electronic address:

Background: Nanoliposomal irinotecan (Nal-IRI) is a preferred second-line treatment for metastatic pancreas cancer. It is unclear, however, whether patients who had received irinotecan derive benefit.

Methods: Medical records of metastatic pancreas cancer patients who had received irinotecan and then Nal-IRI were reviewed. The primary endpoint was overall survival after the initiation of Nal-IRI (an a priori threshold of >4 months defined success); adverse events and quotes from the medical record on decision-making were also recorded.

Results: Sixty four patients met eligibility criteria with a median age of 65 years (range: 36, 80 years). The median overall survival from initiation of Nal-IRI was 5.1 months (95% confidence interval (CI): 4.3, 5.6 months). An exploratory comparison, based on no cancer progression with irinotecan versus progression, showed improved survival with Nal-IRI in the former group: 6.1 months (95% CI: 5.1, 9.3 months) versus 4.3 months (95% CI: 2.3, 4.8 months); p = 0.0006. Nal-IRI adverse events occurred as expected. Qualitative data illustrate several themes, including "limited treatment options," which appeared to drive the decision to prescribe Nal-IRI.

Conclusion: Nal-IRI might be considered in pancreas cancer patients who had received irinotecan, particularly in the absence of disease progression with the latter.
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http://dx.doi.org/10.1016/j.pan.2020.10.042DOI Listing
March 2021

Chemoradiotherapy for patients with locally advanced or unresectable extra-hepatic biliary cancer.

J Gastrointest Oncol 2020 Dec;11(6):1408-1420

Department of Radiation Oncology, Mayo Clinic, Rochester, MN, USA.

Background: Although surgical resection is the preferred curative-intent treatment option for patients with non-metastatic, extra-hepatic biliary cancer (EBC), radiotherapy (RT) or chemoradiotherapy (CRT) may be utilized in select cases when surgical resection is not feasible. The purpose of this study is to report the efficacy and adverse events (AEs) associated with CRT for patients with locally advanced and unresectable EBC.

Methods: This was a retrospective cohort study of patients with EBC, including extra-hepatic cholangiocarcinoma or gallbladder cancer, deemed inoperable who received RT between 1998 and 2018. The median RT dose was 50.4 Gy in 28 fractions and 94% received concurrent 5-fluorouracil. The Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS) from the start of RT. The cumulative incidence of local progression (LP), locoregional progression (LRP), and distant metastasis (DM) were reported with death as a competing risk. Cox proportional hazards regression models were used to assess for correlation between patient and treatment characteristics and outcomes.

Results: Forty-eight patients were included for analysis. The median OS was 12.0 months [95% confidence interval (CI): 2.3-73.2 months]. The 2-, 3-, and 5-year OS were 33% (95% CI: 22-50%), 20% (95% CI: 11-36%), and 7% (95% CI: 2-20%), respectively. The 2-year PFS, LP, LRP, and DM were 21% (95% CI: 12-36%), 27% (95% CI: 17-44%), 31% (95% CI: 20-48%), and 33% (95% CI: 22-50%), respectively. On univariate analysis, biologically effective dose (BED) >59.5 Gy was associated with improved OS [hazard ratio (HR): 0.40, 95% CI: 0.18-0.92, P=0.03] and PFS (HR: 0.37, 95% CI: 0.16-0.84, P=0.02) and primary tumor size (per 1 cm increase) was associated with worsened PFS (HR: 1.29, 95% CI: 1.02-1.63, P=0.04). BED >59.5 Gy remained associated with PFS on multivariate analysis (HR: 0.34, 95% CI: 0.15-0.78, P=0.01). Treatment-related grade 3+ acute and late gastrointestinal AEs occurred in 13% and 17% of patients, respectively.

Conclusions: RT is associated with 3- and 5-year survival in a subset of patients with unresectable EBC. Further exploration of the role of RT as part of a multi-modality curative treatment strategy is warranted.
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http://dx.doi.org/10.21037/jgo-20-245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7807283PMC
December 2020

Causes of Death After Neuroendocrine Tumors Diagnosis: A US Population-Based Analysis.

Pancreas 2021 Jan;50(1):47-53

Department of Oncology, Mayo Clinic Cancer Center, Rochester, MN.

Objective: In this study, we aimed to determine the cause of death (COD) after the diagnosis of neuroendocrine tumors (NET).

Methods: We used the Surveillance, Epidemiology and End Results (SEER) Program to review patients diagnosed with NET during 2000 to 2016. Patients were followed until death, and different CODs were determined.

Results: Of 94,399 patients with NETs, 40.9% died during the study period. During the first year of diagnosis, most deaths were from NETs (73%), followed by other cancers (11.2%) and cardiac diseases (4.6%). After more than 10 years, NET deaths decreased to 24.3%, whereas other cancers and cardiac disease became more common. Neuroendocrine tumors were responsible for 42.8%, 63.4%, and 81.2% of deaths in grade I, grade II, and grade III, respectively. For grade I localized NET, other cancers (22.2%) were the most common COD followed by NET (19.7%), whereas in grade 2 localized NET, NET was COD in 31.1% of cases followed by other cancers (22.4%). In metastatic disease, NET was the most common COD regardless of grade.

Conclusions: For low-grade localized NET, deaths were mostly secondary to non-NET causes. In contrast, NET is responsible for most of deaths in metastatic NET regardless of grade.
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http://dx.doi.org/10.1097/MPA.0000000000001723DOI Listing
January 2021

Constrictive bronchiolitis in diffuse idiopathic pulmonary neuroendocrine cell hyperplasia.

ERJ Open Res 2020 Oct 16;6(4). Epub 2020 Nov 16.

Dept of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN, USA.

Background: Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is characterised by multifocal proliferation of neuroendocrine cells and belongs in the spectrum of pulmonary neuroendocrine tumours. Some patients with DIPNECH develop airflow obstruction but the relationship between the two entities remains unclear.

Methods: We performed a computer-assisted search of the Mayo Clinic's electronic medical records for biopsy-proven cases of DIPNECH. We extracted clinical, pulmonary function, imaging and histopathological data along with treatments and outcomes.

Results: Among 44 patients with DIPNECH 91% were female and the median age was 65 years (interquartile range 56-69 years); 73% were never-smokers. Overall, 38 patients (86%) had respiratory symptoms including cough (68%) and dyspnoea (30%); 45% were previously diagnosed to have asthma or COPD. Pulmonary function testing showed an obstructive pattern in 52%, restrictive pattern in 11%, mixed pattern in 9%, nonspecific pattern in 23%, and was normal in 5%. On chest computed tomography scan, 95% manifested diffuse nodules and 77% manifested mosaic attenuation. For management, 25% of patients were observed without pharmacological therapy, 55% received an inhaled bronchodilator, 41% received an inhaled corticosteroid, 32% received octreotide; systemic steroids, azithromycin, or combination chemotherapy was employed in four patients (9%). Of 24 patients with available follow-up pulmonary function tests, 50% remained stable, 33% worsened and 17% improved over a median interval of 21.3 months (interquartile range 9.7-46.9 months).

Conclusion: DIPNECH occurs mostly in women and manifests diffuse pulmonary nodules and mosaic attenuation on imaging. It is commonly associated with airflow obstruction due to constrictive bronchiolitis, which manifests limited response to current pharmacological therapy.
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http://dx.doi.org/10.1183/23120541.00527-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682710PMC
October 2020

How We Do It: A Multidisciplinary Approach to Lu DOTATATE Peptide Receptor Radionuclide Therapy.

Radiology 2021 02 24;298(2):261-274. Epub 2020 Nov 24.

From the Division of Nuclear Medicine, Department of Radiology (B.J.B., A.D., J.R.Y., A.T.P., G.B.J., D.N.G., C.M.P., A.T.K.), and Department of Medical Oncology (T.R.H., R.A.E.), Mayo Clinic, 200 First St SW, Rochester, MN 55905.

Lutetium 177 (Lu) DOTA-0-Tyr3-Octreotate (DOTATATE) peptide receptor radionuclide therapy (PRRT) is an effective treatment for advanced gastroenteropancreatic neuroendocrine tumors. This review presents a clinical practice workflow that has been successful since Lu DOTATATE PRRT was approved by the U.S. Food and Drug Administration. The workflow relies heavily on the input of a multidisciplinary team and involves a nuclear medicine consultation service, tumor board, and specific preparations in advance of therapy and day-of-therapy procedures. A systematic checklist designed to ensure appropriate selection of treatment candidates and identification of any concerns to address to safely administer PRRT is provided. All patients were evaluated with gallium 68 DOTATATE PET/CT, and in cases of high-grade tumors, they were also evaluated with fluorine 18 fluorodeoxyglucose PET/CT, with imaging findings reviewed as part of the systematic checklist before PRRT. Adverse effects are discussed and imaging follow-up regimens are reviewed, including alternative diagnostic contrast materials. Approaches to multiple challenging patient scenarios are illustrated through case examples. Finally, alternative theranostic radionuclides and treatment strategies are discussed.
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http://dx.doi.org/10.1148/radiol.2020201745DOI Listing
February 2021

Borderline Resectable and Locally Advanced Pancreas Cancer: FDG PET/MRI and CT Tumor Metrics for Assessment of Neoadjuvant Therapy Pathologic Response and Prediction of Survival.

AJR Am J Roentgenol 2020 Oct 21. Epub 2020 Oct 21.

Department of Radiology, Mayo Clinic, Rochester, Minnesota.

Imaging biomarkers of response to neoadjuvant therapy (NAT) in pancreatic ductal adenocarcinoma (PDA) are needed to optimize treatment decisions and long-term outcomes. To investigate metrics from PET/MRI and CT for assessment of pathologic response of PDA to NAT and prediction of overall survival (OS). This retrospective study included 44 patients with 18F-FDG avid borderline resectable or locally advanced PDA on pre-treatment PET/MRI who also underwent post-NAT PET/MRI prior to surgery between 8/2016 and 9/2019. CA 19-9, metabolic metrics from PET/MRI, and morphologic metrics from CT (n=34) were compared between pathologic responders [College of American Pathologists scores 0 and 1] and nonresponders (scores 2 and 3). AUCs were obtained for metrics significantly associated with pathologic response. Relationships with OS were evaluated using Cox proportional hazard models. Of 44 patients (22 men, 22 women; mean age 62±11.6 years), 19 (43%) were responders, and 25 (57%) were nonresponders. Median OS was 24 months (range: 6-42 months). Pre-treatment, responders and non-responders did not differ in CA 19-9, metabolic metrics, or CT metrics (p>0.05). Post-treatment, responders and non-responders differed for complete metabolic response (CMR) [responders 90% (17/19), nonresponders 40% (10/25); p=0.04], change in SUV (ΔSUV) (mean±SD, responders -70%±13%, nonresponders -37%±42%; p<0.001), change in glucose-corrected SUV (ΔSUV gluc) (mean±SD, responders -74%±12%, nonresponders -30%±58%; p<0.001), RECIST response on CT [responders 93% (13/14), nonresponders 50% (10/20), p=0.02)], and change in tumor volume on CT (ΔTvol) (mean ±SD, responders -85%± 21%, nonresponders +57%±400%; p<0.001). AUCs of CMR, ΔSUV, ΔSUVgluc, RECIST and ΔTvol for pathologic response were 0.75, 0.83, 0.87, 0.71 and 0.86. respectively. AUCs of bivariable PET/MRI and CT models were 0.83 (CMR and ΔSUV), 0.87 (CMR and ΔSUVgluc) and 0.87 (RECIST and ΔTvol). OS was associated with CMR (p=0.03), ΔSUV (p=0.003), ΔSUVgluc (p=0.003), and RECIST (p=0.046). Unlike CA 19-9, post-NAT changes in metabolic metrics from PET/MRI and morphologic metrics from CT were associated with pathologic response and OS in patients with PDA, warranting prospective validation. Imaging metrics associated with pathologic response and overall survival in PDA could help guide clinical management and outcomes for patients with PDA receiving emergent therapeutic interventions.
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http://dx.doi.org/10.2214/AJR.20.24567DOI Listing
October 2020

Differential Diagnosis of Diarrhea in Patients With Neuroendocrine Tumors.

Pancreas 2020 10;49(9):1123-1130

Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

Patients with neuroendocrine tumors (NETs) and carcinoid syndrome experience diarrhea that can have a debilitating effect on quality of life. Diarrhea also may develop in response to other hormonal syndromes associated with NETs, surgical complications, medical comorbidities, medications, or food sensitivities. Limited guidance on the practical approach to the differential diagnosis of diarrhea in these patients can lead to delays in appropriate treatment. This clinical review and commentary underscore the complexity in identifying the etiology of diarrhea in patients with NETs. Based on our collective experience and expertise, we offer a practical algorithm to guide medical oncologists and other care providers to expedite effective management of diarrhea and related symptoms in patients with NETs.
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http://dx.doi.org/10.1097/MPA.0000000000001658DOI Listing
October 2020

Multiple Endocrine Neoplasia Type 1 (MEN1) and the Pancreas - Diagnosis and Treatment of Functioning and Non-Functioning Pancreatic and Duodenal Neuroendocrine Neoplasia within the MEN1 Syndrome - An International Consensus Statement.

Neuroendocrinology 2020 Sep 24. Epub 2020 Sep 24.

The better understanding of the biological behavior of MEN1 organ manifestations and the in-crease in clinical experience warrant a revision of previously published guidelines. DP-NENs are still the second most common manifestation in MEN1 and, besides NENs of the thymus, remain a leading cause of death. DP-NENs are thus of main interest in the effort to re-evaluate recommendations for their diagnosis and treatment. Especially over the last two years, more clinical experience has documented the follow-up of treated and untreated (natural-course) DP-NENs. It was the aim of the international consortium of experts in endocrinology, genetics, radiology, surgery, gastroenterology and oncology to systematically review the literature and to present a consensus statement based on the highest levels of evidence. Reviewing the literature published over the past decade, the focus was on the diagnosis of F- and NF-DP-NENs within the MEN1 syn-drome in an effort to further standardize and improve treatment and follow-up, as well as to es-tablish a "logbook" for the diagnosis and treatment of DP-NENs. This shall help further reduce complications and improve long-term treatment results in these rare tumors. The following international consensus statement builds upon the previously published guide-lines of 2001 and 2012 and attempts to supplement the recommendations issued by various na-tional and international societies.
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http://dx.doi.org/10.1159/000511791DOI Listing
September 2020

Comparison of benign and malignant insulinoma.

Am J Surg 2021 02 16;221(2):437-447. Epub 2020 Aug 16.

Department of Surgery, Mayo Clinic, 200th 1st Street, Rochester MN, 55905, USA. Electronic address:

Background: How malignant insulinomas present relative to benign insulinomas is unknown.

Methods: A single-institution retrospective study identified patients with insulinoma. Malignancy was defined by distant metastases, positive lymph node(s), T stage of 4, direct invasion into surrounding peripancreatic tissue, or presence of lymphovascular invasion. Wilcoxon Rank Sum tests and Kaplan-Meier analysis were used.

Results: A total of 311 patients were identified: 51 malignant and 260 benign. Patients with malignant insulinoma presented with higher levels of insulin, proinsulin, and c-peptide. Malignant lesions were larger: 4.2 ± 3.2 vs 1.8 ± 0.8 cm in benign lesions, p < 0.01. Overall survival at 5 years was 66.8% vs 95.4% for malignant and benign insulinoma respectively, p < 0.01.

Conclusions: Larger size of insulinoma and increased serum β-cell polypeptide concentrations were associated with malignancy. Malignant insulinoma has poorer survival. Further work-up to rule out malignancy may be indicated for larger pancreatic lesions and for patients with higher pre-operative insulin and pro-insulin.
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http://dx.doi.org/10.1016/j.amjsurg.2020.08.003DOI Listing
February 2021

Pulmonary Neuroendocrine Tumors: Adjuvant and Systemic Treatments.

Curr Treat Options Oncol 2020 Aug 29;21(11):86. Epub 2020 Aug 29.

Division of Medical Oncology, Mayo Clinic, 200 First St SW, Rochester, MN, 55905, USA.

Opinion Statement: Bronchial carcinoids are uncommon tumors accounting for 20 to 30% of all neuroendocrine tumors and about 1-2% of all cancers of pulmonary origin. Bronchial carcinoids are well-differentiated neuroendocrine tumors and have a favorable survival outcome when compared with other subtypes of lung cancers. Treatment of bronchial carcinoids is not simple owing to intricacy of symptom presentation and heterogeneity of disease biology. Successful treatment of patients requires a multimodality approach. Resection is curative in the majority of patients with localized tumors and adjuvant treatment is not routinely recommended. Multiple options for systemic therapy exist for patients with advanced disease. To date, very few randomized clinical trials have been done, partly owing to the relative rarity of this malignancy. Somatostatin analogs (SSAs) are reasonable first-line choice for patients with tumors expressing somatostatin receptors. Everolimus is an appropriate first-line choice for somatostatin receptor negative tumors and for any patients with progressive disease. PRRT can also be considered for progressive tumors expressing somatostatin receptors. Based on retrospective series, cytotoxic chemotherapy can be selected in patients with progressive tumors, primarily when cytoreduction is needed. Herein, we will discuss evidence supporting the role of adjuvant and systemic treatment therapies for those with bronchial carcinoid tumors by focusing on various studies.
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http://dx.doi.org/10.1007/s11864-020-00786-0DOI Listing
August 2020

Currarino Syndrome: A Rare Condition With Potential Connection to Neuroendocrine Tumors.

Pancreas 2020 09;49(8):1104-1108

Department of Internal Medicine/Division of Medical Oncology, Mayo Clinic, Phoenix, AZ.

Objectives: Currarino syndrome (CS) is a congenital disorder that consists of a triad of anomalies: presacral mass, sacral dysgenesis, and anorectal malformations. Few cases of CS with neuroendocrine tumors (NETs) have been reported. In this study, we sought to determine the prevalence and characteristics of NET in patients with CS.

Methods: Mayo Clinic electronic medical records were searched for patients with CS. Data on demographics, CS diagnosis, family history, genetic testing, and NET diagnosis were extracted.

Results: A total of 26 patients with CS were identified with 3 (11.5%) of them having an additional diagnosis of NET. Three patients had a family history of NET (11.53%), and 7 patients had a family history of CS (26.9%). Of the 3 NET/CS patients, 2 had a confirmed primary NET from the presacral mass, with the third patient demonstrating focal uptake on the somatostatin receptor imaging within the presacral. Two patients received octreotide, followed by peptide receptor radionuclide therapy. The other patient was not treated because of complete resection of presacral mass and is currently undergoing surveillance scans.

Conclusions: In our patients with CS, the prevalence of NET is 11.53%. The coexistence of 2 rare conditions, CS and presacral NET, suggests that there may be an etiological connection.
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http://dx.doi.org/10.1097/MPA.0000000000001632DOI Listing
September 2020

Association of Sex, Age, and Eastern Cooperative Oncology Group Performance Status With Survival Benefit of Cancer Immunotherapy in Randomized Clinical Trials: A Systematic Review and Meta-analysis.

JAMA Netw Open 2020 08 3;3(8):e2012534. Epub 2020 Aug 3.

Division of Hematology, Mayo Clinic, Rochester, Minnesota.

Importance: Sex, age, and Eastern Cooperative Oncology Group (ECOG) performance status (PS) may affect immune response. However, the association of these factors with the survival benefit of cancer immunotherapy with immune checkpoint inhibitors (ICIs) remains unclear.

Objective: To assess the potential sex, age, and ECOG PS differences of immunotherapy survival benefit in patients with advanced cancer.

Data Sources: PubMed, Web of Science, Embase, and Scopus were searched from inception to August 31, 2019.

Study Selection: Published randomized clinical trials comparing overall survival (OS) in patients with advanced cancer treated with ICI immunotherapy vs non-ICI control therapy were included.

Data Extraction And Synthesis: Pooled OS hazard ratio (HR) and 95% CI for patients of different sex, age (<65 and ≥65 years) or ECOG PS (0 and ≥1) were calculated separately using a random-effects model, and the heterogeneity between paired estimates was assessed using an interaction test by pooling study-specific interaction HRs. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline.

Main Outcomes And Measures: The difference in survival benefit of ICIs between sex, age (<65 vs ≥65 years), and ECOG PS (0 vs ≥1), as well as the difference stratified by cancer type, line of therapy, agent of immunotherapy, and immunotherapy strategy in the intervention arm.

Results: Thirty-seven phase 2 or 3 randomized clinical trials involving 23 760 patients were included. An OS benefit of immunotherapy was found for both men (HR, 0.75; 95% CI, 0.71-0.81) and women (HR, 0.79; 95% CI, 0.72-0.88); for both younger (<65 years: HR, 0.77; 95% CI, 0.71-0.83) and older (≥65 years: HR, 0.78; 95% CI, 0.72-0.84) patients; and for both patients with ECOG PS 0 (HR, 0.81; 95% CI, 0.73-0.90) and PS greater than or equal to 1 (HR, 0.79; 95% CI, 0.74-0.84). No significant difference of relative benefit from immunotherapy over control therapy was found in patients of different sex (P = .25, I2 = 19.02%), age (P = .94, I2 = 15.57%), or ECOG PS (P = .74, I2 = 0%). No significant difference was found in subgroup analyses by cancer type, line of therapy, agent of immunotherapy, and immunotherapy strategy in the intervention arm.

Conclusions And Relevance: This meta-analysis found no evidence of an association of sex, age (<65 vs ≥65 years), or ECOG PS (0 vs ≥1) with cancer immunotherapy survival benefit. This finding suggests that the use of ICIs in advanced cancer should not be restricted to certain patients in sex, age, or ECOG PS categories.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.12534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414387PMC
August 2020

Utilization of COVID-19 Treatments and Clinical Outcomes among Patients with Cancer: A COVID-19 and Cancer Consortium (CCC19) Cohort Study.

Cancer Discov 2020 10 22;10(10):1514-1527. Epub 2020 Jul 22.

Fred Hutchinson Cancer Research Center, Seattle, Washington.

Among 2,186 U.S. adults with invasive cancer and laboratory-confirmed SARS-CoV-2 infection, we examined the association of COVID-19 treatments with 30-day all-cause mortality and factors associated with treatment. Logistic regression with multiple adjustments (e.g., comorbidities, cancer status, baseline COVID-19 severity) was performed. Hydroxychloroquine with any other drug was associated with increased mortality versus treatment with any COVID-19 treatment other than hydroxychloroquine or untreated controls; this association was not present with hydroxychloroquine alone. Remdesivir had numerically reduced mortality versus untreated controls that did not reach statistical significance. Baseline COVID-19 severity was strongly associated with receipt of any treatment. Black patients were approximately half as likely to receive remdesivir as white patients. Although observational studies can be limited by potential unmeasured confounding, our findings add to the emerging understanding of patterns of care for patients with cancer and COVID-19 and support evaluation of emerging treatments through inclusive prospective controlled trials. SIGNIFICANCE: Evaluating the potential role of COVID-19 treatments in patients with cancer in a large observational study, there was no statistically significant 30-day all-cause mortality benefit with hydroxychloroquine or high-dose corticosteroids alone or in combination; remdesivir showed potential benefit. Treatment receipt reflects clinical decision-making and suggests disparities in medication access..
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http://dx.doi.org/10.1158/2159-8290.CD-20-0941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541683PMC
October 2020

The North American Neuroendocrine Tumor Society Consensus Guidelines for Surveillance and Medical Management of Pancreatic Neuroendocrine Tumors.

Pancreas 2020 08;49(7):863-881

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.

This article is the result of the North American Neuroendocrine Tumor Society consensus conference on the medical management of pancreatic neuroendocrine tumors from July 19 to 20, 2018. The guidelines panel consisted of medical oncologists, pathologists, gastroenterologists, endocrinologists, and radiologists. The panel reviewed a series of questions regarding the medical management of patients with pancreatic neuroendocrine tumors as well as questions regarding surveillance after resection. The available literature was reviewed for each of the question and panel members voted on controversial topics, and the recommendations were included in a document circulated to all panel members for a final approval.
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http://dx.doi.org/10.1097/MPA.0000000000001597DOI Listing
August 2020

Holistic review for hematology-oncology fellowship applicants: A new paradigm?

Am J Hematol 2020 Jul 6. Epub 2020 Jul 6.

Department of Medical Oncology, Mayo Clinic, Rochester, Minnesota.

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http://dx.doi.org/10.1002/ajh.25930DOI Listing
July 2020

Liver metastases from pituitary carcinomas mimicking visceral well-differentiated neuroendocrine tumors: a series of four cases.

Diagn Pathol 2020 Jul 4;15(1):81. Epub 2020 Jul 4.

Division of Anatomic Pathology, Mayo Clinic, 200 First St SW, Rochester, MN, 55905, USA.

Background: Pathologists frequently encounter neuroendocrine tumors (NETs) presenting as multiple liver masses in routine practice. Most often, these are well-differentiated tumors with characteristic histologic features. In contrast, pituitary carcinoma is very rare, and there is limited data on its natural history and pathologic characterization.

Methods: The aim of this study was to describe clinical characteristics, histomorphology, immunophenotype and follow-up of pituitary carcinoma involving the liver and mimicking well-differentiated NETs of visceral origin. We selected a group of well-differentiated NETs of the pancreas to use as immunophenotypic controls. We identified 4 patients (age range, 51 to 73) with pituitary corticotroph carcinoma with liver metastases. Three patients presented with Cushing syndrome.

Results: All cases histologically resembled well-differentiated NETs of visceral origin with Ki-67 proliferation indices of 5-42% and expression of T-PIT; metastatic tumors were not immunoreactive with CDX2, Islet 1 or TTF-1.

Conclusions: Frequently, these cases display adrenocorticotropic hormone (ACTH) secretion and pituitary-specific transcription factor immunohistochemistry may be used as a reliable marker to distinguish metastatic pituitary carcinoma from NETs of visceral origin in addition to delineating a corticotroph carcinoma from somatotroph, lactotroph, thyrotroph, and gonadotroph lineage. Although rare, the differential diagnosis of pituitary carcinoma should be considered in metastatic well-differentiated NETs in which the site of origin is uncertain. In summary, pituitary corticotroph carcinoma can metastasize to the liver and mimic well-differentiated NET.
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http://dx.doi.org/10.1186/s13000-020-00997-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7335443PMC
July 2020

Clinical impact of COVID-19 on patients with cancer (CCC19): a cohort study.

Lancet 2020 06 28;395(10241):1907-1918. Epub 2020 May 28.

Vanderbilt-Ingram Cancer Center at Vanderbilt University Medical Center, Nashville, TN, USA. Electronic address:

Background: Data on patients with COVID-19 who have cancer are lacking. Here we characterise the outcomes of a cohort of patients with cancer and COVID-19 and identify potential prognostic factors for mortality and severe illness.

Methods: In this cohort study, we collected de-identified data on patients with active or previous malignancy, aged 18 years and older, with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection from the USA, Canada, and Spain from the COVID-19 and Cancer Consortium (CCC19) database for whom baseline data were added between March 17 and April 16, 2020. We collected data on baseline clinical conditions, medications, cancer diagnosis and treatment, and COVID-19 disease course. The primary endpoint was all-cause mortality within 30 days of diagnosis of COVID-19. We assessed the association between the outcome and potential prognostic variables using logistic regression analyses, partially adjusted for age, sex, smoking status, and obesity. This study is registered with ClinicalTrials.gov, NCT04354701, and is ongoing.

Findings: Of 1035 records entered into the CCC19 database during the study period, 928 patients met inclusion criteria for our analysis. Median age was 66 years (IQR 57-76), 279 (30%) were aged 75 years or older, and 468 (50%) patients were male. The most prevalent malignancies were breast (191 [21%]) and prostate (152 [16%]). 366 (39%) patients were on active anticancer treatment, and 396 (43%) had active (measurable) cancer. At analysis (May 7, 2020), 121 (13%) patients had died. In logistic regression analysis, independent factors associated with increased 30-day mortality, after partial adjustment, were: increased age (per 10 years; partially adjusted odds ratio 1·84, 95% CI 1·53-2·21), male sex (1·63, 1·07-2·48), smoking status (former smoker vs never smoked: 1·60, 1·03-2·47), number of comorbidities (two vs none: 4·50, 1·33-15·28), Eastern Cooperative Oncology Group performance status of 2 or higher (status of 2 vs 0 or 1: 3·89, 2·11-7·18), active cancer (progressing vs remission: 5·20, 2·77-9·77), and receipt of azithromycin plus hydroxychloroquine (vs treatment with neither: 2·93, 1·79-4·79; confounding by indication cannot be excluded). Compared with residence in the US-Northeast, residence in Canada (0·24, 0·07-0·84) or the US-Midwest (0·50, 0·28-0·90) were associated with decreased 30-day all-cause mortality. Race and ethnicity, obesity status, cancer type, type of anticancer therapy, and recent surgery were not associated with mortality.

Interpretation: Among patients with cancer and COVID-19, 30-day all-cause mortality was high and associated with general risk factors and risk factors unique to patients with cancer. Longer follow-up is needed to better understand the effect of COVID-19 on outcomes in patients with cancer, including the ability to continue specific cancer treatments.

Funding: American Cancer Society, National Institutes of Health, and Hope Foundation for Cancer Research.
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http://dx.doi.org/10.1016/S0140-6736(20)31187-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255743PMC
June 2020

Peptide Receptor Radionuclide Therapy for the Treatment of Pancreatic Neuroendocrine Tumors: Recent Insights.

Onco Targets Ther 2020 28;13:3545-3555. Epub 2020 Apr 28.

Division of Hematology/Oncology, Mayo Clinic, Rochester, MN, USA.

Peptide receptor radionuclide therapy (PRRT) is a paradigm shifting approach to the treatment of neuroendocrine tumors. Although there are no prospective randomized trials directly studying PRRT in pancreatic neuroendocrine tumors (panNETs), there are data to suggest benefit in this patient population. Collectively, the data, consisting of two prospective and six retrospective studies, show a median PFS ranging from 20 to 39 months and a median OS ranging from 37 to 79 months. There are ongoing (and upcoming) prospective, randomized trials of PRRT in panNETs, which will provide further evidence to support this approach.
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http://dx.doi.org/10.2147/OTT.S202867DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7205451PMC
April 2020

Ipilimumab and Nivolumab in Rare Tumors S1609: Neuroendocrine-Letter.

Clin Cancer Res 2020 05;26(10):2433

Mayo Clinic Cancer Center, Rochester, Minnesota.

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http://dx.doi.org/10.1158/1078-0432.CCR-20-0443DOI Listing
May 2020

Assessment of Therapy-Related Myeloid Neoplasms in Patients With Neuroendocrine Tumors After Peptide Receptor Radionuclide Therapy: A Systematic Review.

JAMA Oncol 2020 07;6(7):1086-1092

University of Mississippi Medical Center, Jackson.

Importance: Peptide receptor radionuclide therapy (PRRT) is a tumor-targeted treatment that uses radiation to induce tumor cell death in neuroendocrine tumors (NET) via β particle-emitting radionuclide linked to a somatostatin peptide analog. Therapy-related myeloid neoplasm (t-MN) has been reported as a potential long-term and frequently lethal adverse event after PRRT. However, the incidence, time of diagnosis, and nature of t-MN is unclear. Therefore, a systematic review is helpful to study the incidence and characteristics of t-MN after PRRT in patients with NET.

Objective: To systematically evaluate the literature and report the incidence, time of diagnosis, and nature of t-MN after PRRT.

Evidence Review: MEDLINE, Embase, Scopus, Web of Science, and Cochrane Central Register of Controlled Trials for articles and abstracts reporting studies of different designs studying more than 1 patient (randomized clinical trials, prospective phase I or phase II, retrospective studies, and case series) were searched from database inception through April 2019. Studies of interest included patients with NET who were treated with PRRT and reported the incidence of t-MN, if any. The primary outcome was the incidence of t-MN.

Findings: Twenty-eight articles were identified comprising 7334 patients who were treated with PRRT for NET. The main reason of exclusion was not reporting the t-MN incidence. The incidence of t-MN was variable between studies with mean (SD) incidence of 2.61% (4.38%). Of all 134 cases, cytogenetic abnormalities were reported in 32 patients with the most common abnormality being complex cytogenetics, consistent with myeloid neoplasms following exposure to alkylating agents or irradiation.

Conclusions And Relevance: The risk of t-MN after PRRT is small but not insignificant given the poor prognosis after t-MN diagnosis. Close monitoring is warranted to identify such patients early in the disease course when hematologic abnormalities persist.
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http://dx.doi.org/10.1001/jamaoncol.2020.0078DOI Listing
July 2020

Efficacy of Second-Line Chemotherapy in Extrapulmonary Neuroendocrine Carcinoma.

Pancreas 2020 04;49(4):529-533

Division of Medical Oncology.

Objectives: A platinum/etoposide doublet is standard first-line therapy for poorly differentiated neuroendocrine carcinoma (PD NEC); however, evidence to guide treatment beyond first-line regimens is lacking. This study aimed to evaluate the efficacy of second-line regimens in PD NEC.

Methods: We performed a retrospective analysis of patients treated with second-line chemotherapy for PD NEC. Inclusion criteria were previous first-line therapy with platinum/etoposide, extrapulmonary PD NEC, and follow-up data. The primary end points were overall survival (OS) and progression-free survival (PFS) after second-line therapy. Secondary end points included OS and PFS from first-line therapy.

Results: Sixty-four patients were included. The median OS from initiation of second-line therapy was 6.2 months (95% confidence interval [CI], 4.9-8.9). The median PFS was 2.3 months (95% CI, 2.0-3.2). No second-line regimen showed a statistically significant difference in OS or PFS. There was a significant increase in OS for cisplatin first-line regimens compared with carboplatin (17.0 months [95% CI, 12.5-22.6] vs 11.7 months [95% CI, 8.0-14.0]).

Conclusions: The efficacy of current second-line therapy in PD NEC is poor. No second-line regimen showed statistically significant superiority. Cisplatin was associated with longer OS regardless of second-line regimen or age. However, unmeasured confounders such as performance status or comorbidities may explain this effect.
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http://dx.doi.org/10.1097/MPA.0000000000001529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7158760PMC
April 2020

Patient Travel Concerns After Treatment with Lu-DOTATATE.

J Nucl Med 2020 04 13;61(4):496-497. Epub 2020 Mar 13.

Mayo Clinic Cancer Center, Rochester, Minnesota.

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http://dx.doi.org/10.2967/jnumed.120.243238DOI Listing
April 2020

Somatostatin Analogs Improve Respiratory Symptoms in Patients With Diffuse Idiopathic Neuroendocrine Cell Hyperplasia.

Chest 2020 Jul 12;158(1):401-405. Epub 2020 Feb 12.

Neuroendocrine Tumor Unit, ENETS Center of Excellence, Endocrinology & Metabolism Department, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.

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 after treatment.

Conclusions: SSA treatment can improve chronic respiratory symptoms and PFTs in patients with DIPNECH.
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http://dx.doi.org/10.1016/j.chest.2020.01.031DOI Listing
July 2020

Renal Neuroendocrine Neoplasms: A Single-center Experience.

Clin Genitourin Cancer 2020 08 5;18(4):e343-e349. Epub 2019 Dec 5.

Division of Medical Oncology, Mayo Clinic, Rochester, MN. Electronic address:

Background: Primary neuroendocrine neoplasms (NENs) of the kidney are exceedingly rare malignancies and the available literature is very limited. The natural history and response to treatments is not well characterized. We aimed to describe the presenting features, demographics, tumor characteristics, and treatment outcomes of patients with renal NENs.

Patients And Methods: We performed a retrospective analysis of all Mayo Clinic patient records with a tissue diagnosis of a primary renal NEN. Baseline patient and surgical pathologic features and treatment modalities were collected. Time to recurrence after resection and overall survival (OS) were estimated using with survival analysis. Surveillance, Epidemiology, and End Results data were used to estimate the population-wide incidence and OS.

Results: A total of 17 patients were included in the present study, with a median follow-up of 62.8 months. Distant metastasis was present in 29% at diagnosis, with 76% experiencing distant metastasis at any point; 24% had a horseshoe kidney. Of the 17 patients, 14 had undergone surgical resection with no evidence of disease postoperatively. Ten of these patients had documented recurrence. The median time to recurrence was 18 months (95% confidence interval, 9-46 months). Only 1 of the 10 patients showed a radiographic response to systemic therapy. Of 9 patients, 4 had stable disease with somatostatin analogs. The median OS was 143 months (95% confidence interval, 50-143 months).

Conclusions: Renal NENs are rare malignancies affecting mostly middle-age patients, with distant metastasis being common. Approximately one half of patients experience stable disease with somatostatin analogs. The OS usually exceeds 5 years.
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http://dx.doi.org/10.1016/j.clgc.2019.11.003DOI Listing
August 2020