Neuroendocrine Tumors of Unknown Primary in the Setting of Cytoreductive Hepatectomy.

BACKGROUND: Surgical cytoreduction for neuroendocrine tumor liver metastasis (NETLM) consistently shows positive long-term outcomes. Despite reservations in guidelines for surgery when the primary tumor is unidentified (UP-NET), this study compared the surgical and oncologic long-term outcomes between patients with these rare cases undergoing cytoreductive surgery and patients who had liver resection for known primaries. METHODS: The study identified 32 unknown primary liver metastases (UP-NETLM) in 522 retrospectively evaluated patients who underwent resection of well-differentiated NETLM between January 2000 and December 2020. Tumor and patient characteristics were compared with those in 490 cases of liver metastasis from small intestinal (SI-NETLM) or pancreatic (pNETLM) primaries. Survival analysis was performed to highlight long-term outcome differences. Surgical outcomes were compared between liver resections alone and simultaneous primary resections to assess surgical risk distinctions. RESULTS: The UP-NET patients had fewer NETLMs (p = 0.004), which on the average were larger than SI-NETLMs or pNETLMs (p = 0.002). Expression of Ki-67 was balanced among the groups. Major hepatectomy was performed more often in the UP-NETLM group (p = 0.017). The 10-year survival rate of 53% for UP-NETLM was comparable with that for SI-NETML (58%; p = 0.463) and pNETLMs (47%; p = 0.497). The median hepatic progression-free survival was 26 months for the UP-NETLM patients and 25 months for the SI-NETLM patients compared to 12 months for the pNETLM patients (p < 0.001). Perioperative mortality was lower than 2%, and severe postoperative morbidity occurred in 21%, similarly distributed among all the groups. CONCLUSION: The surgical risk and long-term outcomes for the UP-NETLM patients were comparable with those for other NETLM cases, affirming the validity of equally aggressive surgical cytoreduction as a therapeutic option in carefully selected cases.

Failed recovery after pancreatoduodenectomy: A significant problem even without surgical complications.

BACKGROUND: The absence of surgical complications has traditionally been used to define successful recovery after pancreas surgery. However, patient-reported outcome measures as metrics of a challenging recovery may be superior to objective morbidity. This study aims to evaluate the use of patient-reported outcomes in assessing recovery after pancreas surgery. METHODS: Patients scheduled for pancreatoduodenectomy were prospectively enrolled between 2016 to 2018. Patient-reported outcomes were collected using the linear analog self-assessment questionnaire preoperatively and on postoperative days 2, 7, 14, 30, and monthly until 6 months. Patients were also asked if they felt fully recovered at 30 days and 6 months. Thirty-day surgical morbidity was prospectively assessed, and the comprehensive complication index at 30 days was used to categorize morbidity as major or multiple minor complications (comprehensive complication index ≥26.2) vs uncomplicated (comprehensive complication index <26.2). Clinically significant International Study Group Pancreas Surgery Grade B and C pancreatic fistulas and delayed gastric emptying were reported. χ2 and Kruskal-Wallis tests were used to assess associations with recovery by 6 months and quality of life throughout the postoperative period. RESULTS: Of 116 patients who met inclusion criteria and were enrolled, 32 (28%) had major or multiple minor complications (comprehensive complication index ≥26.2). Overall, fewer than 1 in 10 patients (7%) reported feeling fully recovered at 30 days postoperatively, whereas 55% reported feeling fully recovered at 6 months. Of patients suffering major morbidity, 62% did not recover by 6 months, whereas 38% of those in the uncomplicated group reported not being recovered at 6 months (P = .03). Patients who experienced delayed gastric emptying reported low quality-of-life scores at 1 month (P = .04) compared to those with no delayed gastric emptying, but this did not persist at 6 months (P = .80). Postoperative pancreatic fistula was not associated with quality of life at 1 or 6 months (both P > .05). In the uncomplicated patients, age, sex, surgical approach, and cancer status were not associated with failed recovery at 6 months (all P > .05), and healthier patients (American Society of Anesthesiologists 1-2) were less likely to report complete recovery (42% vs 69% American Society of Anesthesiologists 3-4, P = .04). With the exception of higher preoperative pain scores (mean 2.3 [standard deviation 2.4] among patients not fully recovered at 6 months vs 1.6 [2.2] among those fully recovered, P = .04), preoperative patient-reported outcomes were not associated with failed recovery at 6 months (all P > .05). However, lower 30-day quality of life, social activity, pain, and fatigue scores were associated with incomplete recovery at 6 months. CONCLUSION: More than 1 in 3 patients with an uncomplicated course do not feel fully recovered from pancreas surgery at 6 months; the presence of surgical complications did not universally correspond with recovery failure. In patients with complications, delayed gastric emptying appears to drive quality of life more significantly than postoperative pancreatic fistula. In patients with uncomplicated recovery, healthier patients were less likely to report full recovery at 6 months. Thirty-day patient-reported outcomes may be able to identify patients who are at risk of incomplete long-term recovery.

Value of Surgical Cytoreduction in Patients with Small Intestinal Neuroendocrine Tumors Metastatic to the Liver and Peritoneum.

BACKGROUND: Cytoreductive hepatectomy can improve survival and symptoms of hormonal excess in patients with small intestinal neuroendocrine tumor (siNET) liver metastases, but whether to proceed when peritoneal metastases are encountered at the time of planned cytoreductive hepatectomy is controversial. METHODS: This was a retrospective review of patients who underwent surgical management of metastatic siNETs at Mayo Clinic between 2000 and 2020. Patients who underwent cytoreductive operation for isolated liver metastases or both liver and peritoneal metastases were compared. RESULTS: Of 261 patients who underwent cytoreductive operation for siNETs, 211 had isolated liver metastases and 50 had liver and peritoneal metastases. Complete cytoreduction was achieved in 78% of patients with isolated liver metastases and 56% of those with liver and peritoneal metastases (p = 0.002). After complete cytoreduction, median overall survival (OS) was 11.5 years for isolated liver metastases and 11.2 years for liver and peritoneal metastases (p = 0.10), and relief of carcinoid syndrome was ≥ 97% in both groups. After incomplete cytoreduction with debulking of > 90% of hepatic disease and/or closing Lyon score of 1-2, median OS was 6.4 years for isolated liver metastases and 7.1 years for liver and peritoneal metastases (p = 0.12). CONCLUSIONS: Patients with siNETs metastatic to both the liver and peritoneum have favorable outcomes after aggressive surgical cytoreduction, with the best outcomes observed after complete cytoreduction. Therefore, the presence of peritoneal metastases should not by itself preclude surgical cytoreduction in this population.

Multimodal Approaches to Patient Selection for Pancreas Cancer Surgery.

With an overall 5-year survival rate of 12%, pancreas ductal adenocarcinoma (PDAC) is an aggressive cancer that claims more than 50,000 patient lives each year in the United States alone. Even those few patients who undergo curative-intent resection with favorable pathology reports are likely to experience recurrence within the first two years after surgery and ultimately die from their cancer. We hypothesize that risk factors for these early recurrences can be identified with thorough preoperative staging, thus enabling proper patient selection for surgical resection and avoiding unnecessary harm. Herein, we review evidence supporting multidisciplinary and multimodality staging, comprehensive neoadjuvant treatment strategies, and optimal patient selection for curative-intent surgical resections. We further review data generated from our standardized approach at the Mayo Clinic and extrapolate to inform potential future investigations.

Outcomes of Neoadjuvant Chemotherapy for Invasive Intraductal Papillary Mucinous Neoplasm Compared with de Novo Pancreatic Adenocarcinoma.

BACKGROUND: The management of invasive intraductal papillary mucinous cystic neoplasm (I-IPMN) does not differ from de novo pancreatic ductal adenocarcinoma (PDAC); however, I-IPMNs are debated to have better prognosis. Despite being managed similarly to PDAC, no data are available on the response of I-IPMN to neoadjuvant chemotherapy. METHODS: All patients undergoing pancreatic resection for a pancreatic adenocarcinoma from 2011 to 2022 were included. The PDAC and I-IPMN cohorts were compared to evaluate response to neoadjuvant therapy (NAT) and overall survival (OS). RESULTS: This study included 1052 PDAC patients and 105 I-IPMN patients. NAT was performed in 25% of I-IPMN patients and 65% of PDAC patients. I-IPMN showed a similar pattern of pathological response to NAT compared with PDAC (p = 0.231). Furthermore, positron emission tomography (PET) response (71% vs. 61%; p = 0.447), CA19.9 normalization (85% vs. 76%, p = 0.290), and radiological response (32% vs. 37%, p = 0.628) were comparable between I-IPMN and PDAC. A significantly higher OS and disease-free survival (DFS) of I-IPMN was denoted by Kaplan-Meier analysis, with a p-value of < 0.001 in both plots. In a multivariate analysis, I-IPMN histology was independently associated with lower risk of recurrence and death. CONCLUSIONS: I-IPMN patients have a longer OS and DFS after surgical treatment when compared with PDAC patients. The more favorable oncologic outcome of I-IPMNs does not seem to be related to early detection, as I-IPMN histological subclass is independently associated with a lower risk of disease recurrence. Moreover, neoadjuvant effect on I-IPMN was non-inferior to PDAC in terms of pathological, CA19.9, PET, and radiological response and thus can be considered in selected patients.

Importance of Diversity, Equity, and Inclusion in the Hepatopancreatobiliary Workforce.

Diversity is a catalyst for progress that prevents institutional stagnation and, by extension, averts descent to mediocrity. This review focuses on the available data concerning hepatopancreatobiliary (HPB) surgical workforce demographics and identifies evidence-based strategies that may enhance justice, equity, diversity, and inclusion for HPB surgeons and their patients. We report that the current United States HPB surgical workforce does not reflect the population it serves. We review data describing disparity-perpetuating hurdles confronting physicians from minority groups underrepresented in medicine at each stage of training. We further examine evidence showing widespread racial and socioeconomic disparities in HPB surgical care and review the effects of workforce diversity and physician-patient demographic concordance on healthcare outcomes. Evidence-based mitigators of structural racism and segregation are reviewed, including tailored interventions that can address social determinants of health toward the achievement of true excellence in HPB surgical care. Lastly, select evidence-based data driving surgical workforce solutions are reviewed, including intentional compensation plans, mentorship, and sponsorship.

Quality of Life and Gastrointestinal Symptoms in Long-term Survivors of Pancreatic Cancer Following Pancreatoduodenectomy.

OBJECTIVE: To describe long-term quality of life (QOL) and gastrointestinal (GI) symptoms in patients who underwent pancreatoduodenectomy for pancreatic cancer in the modern era. BACKGROUND: As advances in pancreatic cancer management improve outcomes, it is essential to assess long-term patient-reported outcomes after surgery. METHODS: Patients who underwent curative intent pancreatoduodenectomy for pancreatic cancer between January 2011 and June 2019 from a single center were identified. Patients alive ≥3 years after surgery were considered long-term survivors (LTS). LTS who were alive in June 2022 received a 55-question survey to assess their QOL (EORTC-QLQ-C30) and GI symptoms (EORTC-PAN26 and Problem Areas in Diabetes Questionnaire). Responses were compared against population norms. Clinicodemographic characteristics in LTS versus non-LTS and survey completion were compared. RESULTS: Six hundred seventy-two patients underwent pancreatoduodenectomy for pancreatic cancer; 340 were LTS. One hundred thirty-seven patients of the 238 eligible to complete the survey responded (response rate: 58%). Compared to the US general population, LTS reported significantly higher QOL (75 vs 64; P <0.001), less nausea/vomiting, pain, dyspnea, insomnia, appetite loss, and constipation, but more diarrhea (all P <0.001). Most patients (n=136/137, 99%) reported experiencing postoperative GI symptoms related to pancreatic insufficiency (n=71/135, 53%), reflux (n=61/135, 45%), and delayed gastric emptying (n=31/136, 23%). Most patients (n=113/136, 83%) reported that digestive symptoms overall had little to no impact on QOL, and 91% (n=124/136) would undergo surgery again. CONCLUSIONS: Despite known long-term complications following pancreatoduodenectomy, cancer survivors appear to have excellent QOL. Specific long-term gastrointestinal symptoms data should be utilized for preoperative education and follow-up planning.

International Hepato-Pancreato-Billiary Association (IHPBA) registry study on COVID-19 infections in HPB surgery patients.

BACKGROUND: In response to the pandemic, the International Hepato-Pancreato-Biliary Association (IHPBA) developed the IHPBA-COVID Registry to capture data on HPB surgery outcomes in COVID-positive patients prior to mass vaccination programs. The aim was to provide a tool to help members gain a better understanding of the impact of COVID-19 on patient outcomes following HPB surgery worldwide. METHODS: An online registry updated in real time was disseminated to all IHPBA, E-AHPBA, A-HPBA and A-PHPBA members to assess the effects of the pandemic on the outcomes of HPB procedures, perioperative COVID-19 management and other aspects of surgical care. RESULTS: One hundred twenty-five patients from 35 centres in 18 countries were included. Seventy-three (58%) patients were diagnosed with COVID-19 preoperatively. Operative mortality after pancreaticoduodenectomy and major hepatectomy was 28% and 15%, respectively, and 2.5% after cholecystectomy. Postoperative complication rates of pancreatic procedures, hepatic interventions and biliary interventions were respectively 80%, 50% and 37%. Respiratory complication rates were 37%, 31% and 10%, respectively. CONCLUSION: This study reveals a high risk of mortality and complication after HPB surgeries in patient infected with COVID-19. The more extensive the procedure, the higher the risk. Nonetheless, an increased risk was observed across all types of interventions, suggesting that elective HPB surgery should be avoided in COVID positive patients, delaying it at distance from the viral infection.

Supply and demand of hepatopancreatobiliary surgeons in the United States.

BACKGROUND: Hepatopancreatobiliary (HPB) surgery requires specialized training and adequate case volumes to maintain procedural proficiency and optimal outcomes. Studies of individual HPB surgeon supply related to annual HPB case demand are sparse. This study assesses the supply and demand of the HPB surgical workforce in the United States (US). METHODS: The National Inpatient Sample (NIS) was queried from 1998-2019 to estimate the number of HPB procedures performed. To approximate the number of HPB surgeons, models based on previous HPB workforce publications were employed. We then calculated the number of HPB surgeons needed to maintain volume-outcome thresholds at current reported levels of centralization. RESULTS: In 2019, approximately 37,335 patients underwent inpatient HPB procedures in the US, while an estimated 905-1191 HPB surgeons were practicing. Assuming 50% centralization and an optimal volume-outcome threshold of 24 HPB cases-per-year, only 778 HPB surgeons were needed. Without adjustment in centralization, by 2030 there will be a demand of fewer than 12 annual cases per HPB surgeon. CONCLUSION: The current supply of HPB surgeons may exceed demand in the United States. Without alteration in training pathways or improved care centralization, by 2030, there will be insufficient HPB case volume per surgeon to maintain published volume-outcome standards.

Early vs conventional onset pancreatic ductal adenocarcinoma: analysis of surgical and oncologic outcomes in patients undergoing curative intent resection.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) impacts patients in their 60s, but its incidence in younger patients is increasing. We hypothesize that younger patients may have worse oncologic outcomes. METHODS: Patients who underwent curative pancreatic resection for PDAC between January 2011 and December 2021 at a single institution were analyzed. Early-onset pancreatic cancer (EOPC) was defined as pancreatic cancer diagnosed in patients ≤50 years. Clinical and survival outcomes were compared between EOPC and Conventional Onset Pancreas Cancer (COPC). RESULTS: A total of 1133 patients were identified, 65 (5.7%) were EOPC. Preoperative patient characteristics including sex, smoking status, alcohol habitus, diabetes mellitus, CA 19-9, and neoadjuvant therapy were similar between EOPC and COPC (p > 0.05). EOPC patients were more likely non-white (p = 0.03), had lower ASA scores (p = 0.02) and larger median tumor size (33 vs 28 mm, p = 0.04), but had similar pathological stages and rate of R0 resections (p > 0.05). Postoperative outcomes were similar (p > 0.05). There was no statistically significant difference in overall (HR 0.93, CI 0.64, 1.33; p = 0.68) or recurrence free (HR 1.05, CI 0.75, 1.48; p = 0.77) survival between the EOPC and COPC after adjusting for significant factors. CONCLUSION: Patients with EOPC who underwent surgical resection had similar oncological outcomes compared to patients with COPC.

An APRI+ALBI Based Multivariable Model as Preoperative Predictor for Posthepatectomy Liver Failure.

OBJECTIVE AND BACKGROUND: Clinically significant posthepatectomy liver failure (PHLF B+C) remains the main cause of mortality after major hepatic resection. This study aimed to establish an APRI+ALBI, aspartate aminotransferase to platelet ratio (APRI) combined with albumin-bilirubin grade (ALBI), based multivariable model (MVM) to predict PHLF and compare its performance to indocyanine green clearance (ICG-R15 or ICG-PDR) and albumin-ICG evaluation (ALICE). METHODS: 12,056 patients from the National Surgical Quality Improvement Program (NSQIP) database were used to generate a MVM to predict PHLF B+C. The model was determined using stepwise backwards elimination. Performance of the model was tested using receiver operating characteristic curve analysis and validated in an international cohort of 2,525 patients. In 620 patients, the APRI+ALBI MVM, trained in the NSQIP cohort, was compared with MVM's based on other liver function tests (ICG clearance, ALICE) by comparing the areas under the curve (AUC). RESULTS: A MVM including APRI+ALBI, age, sex, tumor type and extent of resection was found to predict PHLF B+C with an AUC of 0.77, with comparable performance in the validation cohort (AUC 0.74). In direct comparison with other MVM's based on more expensive and time-consuming liver function tests (ICG clearance, ALICE), the APRI+ALBI MVM demonstrated equal predictive potential for PHLF B+C. A smartphone application for calculation of the APRI+ALBI MVM was designed. CONCLUSION: Risk assessment via the APRI+ALBI MVM for PHLF B+C increases preoperative predictive accuracy and represents an universally available and cost-effective risk assessment prior to hepatectomy, facilitated by a freely available smartphone app.

Circumstances and implications of conversion from minimally invasive to open liver resection: a multi-center analysis from the AMILES registry.

BACKGROUND: Minimally invasive approaches to liver resection (MILR) are associated with favorable outcomes. The aim of this study was to determine the implications of conversion to an open procedure on perioperative outcomes. METHODS: Patients who underwent MILR at 10 North American institutions were identified from the Americas Minimally Invasive Liver Resection (AMILES) database. Outcomes of patients who required conversion were compared to those who did not. Additionally, outcomes after conversion due to unfavorable findings (poor visualization/access, lack of progress, disease extent) versus intraoperative events (bleeding, injury, cardiopulmonary instability) were compared. RESULTS: Of 1675 patients who underwent MILR, 102 (6.1%) required conversion. Conversion rate ranged from 4.4% for left lateral sectionectomy to 10% for right hepatectomy. The primary reason for conversion was unfavorable findings in 67 patients (66%) and intraoperative adverse events in 35 patients (34%). By multivariable analysis, major resection, cirrhosis, prior liver surgery, and tumor proximity to major vessels were identified as risk factors for conversion (p < 0.05). Patients who required conversion had higher blood loss, transfusion requirements, operative time, and length of stay, (p < 0.05). They also had higher major complication rates (23% vs. 5.2%, p < 0.001) and 30-day mortality (8.8% vs. 1.3%, p < 0.001). When compared to those who required conversion due to unfavorable findings, patients who required conversion due to intraoperative adverse events had significantly higher major complication rates (43% vs. 14%, p = 0.012) and 30-day mortality (20% vs. 3.0%, p = 0.007). CONCLUSIONS: Conversion from MILR to open surgery is associated with increased perioperative morbidity and mortality. Conversion due to intraoperative adverse events is rare but associated with significantly higher complication and mortality rates, while conversion due to unfavorable findings is associated with similar outcomes as planned open resection. High-risk patients may benefit from early conversion in a controlled fashion if difficulties are encountered or anticipated.

Minimally invasive vs. open approach to the simultaneous treatment of colorectal tumors with synchronous liver metastasis: a single center, propensity-score matched analysis from Mayo clinic.

BACKGROUND: Open combined resections of colorectal primary tumors and synchronous liver metastases have become common in selected cases. However, evidences favoring a minimally invasive (MIS) approach are still limited. The aim of this study is to evaluate the outcomes of MIS vs. open synchronous liver and colorectal resections. METHODS: 384 cases of synchronous colorectal and liver resections performed at one institution were identified during the study period. MIS vs open approach were compared after a propensity score matching; surgical outcomes were analyzed. RESULTS: MIS cases featured longer operative time (399 vs 300 min, p < 0.001), fewer blood loss (200 vs 500 ml, p = 0.003), and shorter hospitalization (median LOS 4 vs 6 days, p = 0.001). No difference was observed between the two groups for use of Pringle maneuver (p = 0.083), intraoperative blood transfusion (p = 0.061), achievement of negative colorectal (p = 0.176) and liver margins (p = 1.000), postoperative complications (p = 1.000) and significant (Clavien-Dindo ≥ 3a) complications (p = 0.817), delay of adjuvant therapy due to complications (p = 0.555), 30- and 90-day mortality. CONCLUSION: Synchronous colorectal and liver metastases resections via a minimally-invasive approach in high-volume centers with appropriate expertise result in significantly lower blood loss and length of stay despite longer operative time in comparison to open, with no oncological inferiority.

Accuracy of DOTATATE PET imaging in the preoperative planning of small bowel neuroendocrine tumor resection.

BACKGROUND AND OBJECTIVES: We assessed the accuracy of preoperative gallium-68 DOTA-Tyr3-octreotate (DOTATATE) positron emission tomography (PET) imaging in estimating multifocality and nodal metastases of small bowel neuroendocrine tumors (sbNETs). METHODS: A multicenter analysis was performed on patients with sbNETs who underwent preoperative DOTATATE PET imaging and surgical resection, with manual palpation of the entire length of the small bowel, between January 2016 and August 2022. Preoperative imaging reports and blinded secondary imaging reviews were compared to the final postoperative pathology reports. Descriptive statistics were applied. RESULTS: One-hundred and four patients met inclusion criteria. Pathology showed 53 (51%) patients had multifocal sbNETs and 96 (92%) had nodal metastases. The original preoperative DOTATATE PET imaging identified multifocal sbNET in 28 (27%) patients and lymph node (LN) metastases in 80 (77%) patients. Based on original radiology reports, sensitivity for multifocal sbNET identification was 45%, specificity was 92%, positive predictive value (PPV) was 86%, and negative predictive value (NPV) was 62%. For the identification of LN metastases, sensitivity was 82%, specificity was 88%, PPV was 99%, and NPV was 29%. CONCLUSIONS: Although DOTATATE PET imaging is specific and relatively accurate, sensitivity and NPV are insufficient to guide surgical planning. Preoperative use should not replace open palpation to identify additional synchronous lesions or to omit regional lymphadenectomy.

Oncologic Outcomes of Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Highly Selected Patients with Metastatic Pancreatic Ductal Adenocarcinoma.

BACKGROUND: Peritoneal metastases (PM) from pancreatic ductal adenocarcinoma (PDAC) are currently treated with palliative systemic chemotherapy alone, with unsatisfactory results. Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) may provide an oncologic benefit for highly selected patients. PATIENTS AND METHODS: Patients with PDAC and isolated PM who completed ≥ 6 months of systemic chemotherapy with objective response between 2017 and 2022 were retrospectively reviewed. All patients met the inclusion/exclusion criteria as per our previously published PDAC CRS/HIPEC protocol. Patients who underwent CRS/HIPEC were compared with matched patients who underwent systemic therapy alone. Overall survival (OS) from diagnosis of PM and progression-free survival (PFS) from CRS/HIPEC was evaluated. RESULTS: In total, 61 patients met the inclusion criteria: 38 underwent systemic therapy alone and 23 CRS/HIPEC. There were no differences in baseline prognostic factors, including age, sex, tumor size, tumor location, anatomic resectability, or serum cancer antigen (CA) 19-9 (p > 0.05). Median OS from PM diagnosis in patients who underwent systemic therapy alone was 19 months with 1, 2, and 3 year OS of 81%, 31%, and 8%, respectively. In contrast, median OS from PM diagnosis in patients who underwent CRS/HIPEC was 41 months with improved 1, 2, and 3 year OS of 91%, 66%, and 59%, respectively (p = 0.002). In the 21 patients who achieved complete cytoreduction (CC-0), no adjuvant therapy was administered and the median PFS was 17 months. CONCLUSIONS: CRS/HIPEC in highly selected patients with PDAC and PM results in promising oncologic outcomes that are unlikely to be achieved with systemic chemotherapy alone. Further investigation is warranted and ongoing (NCT04858009).