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BACKGROUND: Watch-and-wait strategy has been increasingly accepted for patients with clinical complete response (cCR) after multimodal treatment for locally advanced rectal adenocarcinoma. Close follow-up is essential to the early detection of local regrowth. It was previously demonstrated that probe-based confocal laser endomicroscopy (pCLE) scoring using the combination of epithelial and vascular features might improve the diagnostic accuracy of cCR. AIM: To validate the pCLE scoring system in the assessment of patients with cCR after neoadjuvant chemoradiotherapy (nCRxt) for advanced rectal adenocarcinoma. METHODS: Digital rectal examination, pelvic magnetic resonance imaging (MRI), and pCLE were performed in 43 patients with cCR, who presented either a scar (N = 33; 76.7%) or a small ulcer with no signs of tumor, and/or biopsy negative for malignancy (N = 10; 23.3%). RESULTS: Twenty-five (58.1%) patients were men, and the mean age was 58.4 years. During the follow-up, 12/43 (27.9%) patients presented local regrowth and underwent salvage surgery. There was an association between pCLE diagnostic scoring and final histological report (for patients who underwent surgical resection) or final diagnosis at the latest follow-up (p = 0.0001), while this association was not observed with MRI (p = 0.49). pCLE sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 66.7%, 93.5%, 80%, 88.9%, and 86%, respectively. MRI sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 66.7%, 48.4%, 66.7%, 78.9%, and 53.5%, respectively. CONCLUSIONS: pCLE scoring system based on epithelial and vascular features improved the diagnosis of sustained cCR and might be recommended during follow-up. pCLE might add some valuable contribution for identifying local regrowth. Trial Registration This protocol was registered at the Clinical Trials (ClinicalTrials.gov identifier NCT02284802).

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A 54-year-old woman with progressive and non-acute dysphagia to solid foods, post-feeding vomiting, and weight loss of 10 kg in 1 year. As personal history, she was a former smoker of 60 pack-year, heart transplant for idiopathic dilated cardiomyopathy, and type 2 diabetes. She was on daily use of metformin and immunosuppressive drugs. The laboratory tests were all normal. Upper digestive endoscopy (UDE) revealed in the middle third of the esophagus a lesion of 3 cm presenting atypical rectified vessels, covering 50% of the esophageal lumen, suggestive type 0-IIc+IIa1 (A). The chromoendoscopy with Lugol iodine at 1.25% showed a positive pink sign (B). Biopsies showed esophagitis with mixed inflammatory infiltrate and numerous macrophages (C-upper panel). The Periodic Acid-Schiff staining showed small yeasts compatible with Histoplasma capsulatum, measuring 0.5 to 2.5 µm, within the cytoplasm of macrophages (arrows), with a clear halo (inset, arrows) (C-lower panel). These findings were compatible with esophageal histoplasmosis. Treatment was started with oral Itraconazole 400mg/day. After 3 months, a new UDE with biopsies showed complete esophageal healing. Gastrointestinal histoplasmosis manifests mainly in the small bowel and colon, related to a great amount of lymphoid tissue in these areas. Patients can present with fever, weight loss, abdominal pain and diarrhea. In endoscopy, we may find ulcerations, thickened wall, plaques and pseudopolyps2. It is considered a rare condition, and in only 3% of cases, there is esophageal involvement. This manifestation is mainly in immunosuppressed patients. It can be related to direct involvement of the esophagus or secondary to infiltration of mediastinal nodes2. In endoscopy, ulcerations, inflammatory masses, strictures, and external compressions can be found. This case illustrated the difficulty in differentiating early cancer from an esophageal histoplasmosis.

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BACKGROUND : Although endoscopic vacuum therapy (EVT) has been successfully used to treat postoperative upper gastrointestinal (UGI) wall defects, its use demands special materials and several endoscopic treatment sessions. Herein, we propose a technical modification of EVT using a double tube (tube-in-tube drain) without polyurethane sponges for the drainage element. The tube-in-tube drainage device enables irrigation and application of suction. A flowchart for standardizing the management of postoperative UGI wall defects with this device is presented. METHODS : An EVT modification was made to achieve frequent fistula cleansing, with 3 % hydrogen peroxide rinsing, and the application of negative pressure. A tube-in-tube drain without polyurethane sponges can be inserted like a nasogastric tube or passed through a previously positioned surgical drain. This was a retrospective two-center observational study, with data collected from 30 consecutive patients. Technical success, clinical success, adverse events, time under therapy, interval time from procedure to fistula diagnosis and treatment start, size of transmural defect, volume of cavity, number of endoscopic treatment sessions, and mortality were reviewed. RESULTS : 30 patients with UGI wall defects were treated. The technical and clinical success rates were 100 % and 86.7 %, respectively. Three patients (10 %) had adverse events and three patients (10 %) died. The median time under therapy was of 19 days (range 1-70) and the median number of endoscopic sessions was 3 (range 1-9). CONCLUSIONS : This standardized approach and EVT modification using a tube-in-tube drain, with frequent fistula cleansing, were successful and safe in a wide variety of UGI wall defects.

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Background and study aims Patients with head and neck squamous cell carcinoma (HNSCC) are at risk of a second primary tumor in the gastrointestinal tract, most commonly in the esophagus. Screening these patients for esophageal carcinoma may help detect asymptomatic dysplasia and early cancer, thus allowing curative treatment and more prolonged survival, but the impact of endoscopic screening remains uncertain. Here we aimed to describe the long-term results of an esophageal SCC screening program in patients with head and neck cancer in terms of prevalence, associated risk factors, and survival. Patients and methods We performed an observational study of a prospectively collected database including patients with HNSCC who had undergone high-definition endoscopy with chromoscopy between 2010 and 2018 at a Brazilian tertiary academic center. Results The study included 1,888 patients. The esophageal SCC prevalence was 7.9 %, with the majority (77.8 %) being superficial lesions. Significant risk factors for esophageal high-grade dysplasia (HGD) and invasive cancer included tumors of the oral cavity and oropharynx and the presence of low-grade dysplasia (LGD). Overall survival (OS) was significantly shorter among patients in whom esophageal cancer was diagnosed at an advanced stage ( P  < .001). OS did not significantly differ between patients with HGD and early esophageal cancer versus those without esophageal cancer ( P  = .210) Conclusions Endoscopic screening for superficial esophageal neoplasia in patients with HNSCC improves esophageal cancer detection. Screening could potentially benefit patients with primary cancer located at the oropharynx or oral cavity. In addition, the detection of esophageal LGD indicates a need for endoscopic surveillance.

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BACKGROUND: Neoadjuvant chemoradiotherapy (nCRxt) followed by radical surgery is the optimal treatment for advanced rectal adenocarcinoma. Patients with clinical complete response (cCR) may be followed closely without immediate surgery. Probe-based confocal laser endomicroscopy (pCLE) is a real-time in vivo method that allows acquisition of optical biopsies with 1000 times magnification, evaluating both epithelial and vascular patterns. AIM: To evaluate the role of pCLE in the diagnosis of cCR after nCRxt for advanced rectal adenocarcinoma. METHODS: pCLE was performed in 47 patients with locally advanced rectal adenocarcinoma (T3/T4, or N+) who underwent nCRxt (5-fluorouracil, 5040 cGy). RESULTS: Twenty-seven (57.5%) patients were men, and the mean age was 62.8 years. Thirty-seven had partial response confirmed by pCLE. Ten (21.3%) patients had good endoscopic response and presented small ulcer (n = 5) or residual scar (n = 5). After nCRxt, the essential features to differentiate malignancy from post-radiation alterations at pCLE were the presence of irregular crypts, budding, back-to-back glands, cribriform pattern, increased vessel/crypt ratio, and fluorescein leakage. A scoring system was created considering these epithelial and vascular features, with high accuracy for differentiating patients with complete response from those with residual neoplasia (p < 0.00001). pCLE sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 100%, 71.4%, 95.2%, 100%, and 95.7%, respectively. CONCLUSIONS: (1) pCLE evaluation of epithelial and vascular features may improve the diagnosis of cCR and may alter patient management; (2) pCLE might be valuable for identifying patients with advanced rectal cancer who will benefit from watch and wait strategy, avoiding immediate surgical treatment.

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The novel coronavirus disease (COVID-19) quickly spread to all continents. However, data regarding all the signs and symptoms of COVID-19 are insufficient. Patients with COVID-19 might present higher susceptibility to fungal coinfections. Mucormycosis is a rare and often life-threatening fungal disease characterized by vascular invasion by hyphae, resulting in thrombosis and necrosis. This is the first case report of mucormycosis in a COVID-19 patient. An 86-year-old male patient was admitted to the emergency room with acute diarrhea, cough, dyspnea, and fever from 5 days prior. Blood tests revealed a hemoglobin level of 14.3 mg/dL. Five days following the admission, the patient presented with melena and a hemoglobin level of 5.6 mg/dL. A transfusion of three units of red blood cells was required. Esophagogastroduodenoscopy revealed two giant gastric ulcers with necrotic debris and a deep hemorrhagic base without active bleeding. Furthermore, biopsies confirmed mucormycosis. Despite intensive care, the patient died 36 hours after the esophagogastroduodenoscopy.

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Background and study aims Gastric neoplasms are one of the leading types of cancer in the world and early detection is essential to improve prognosis. Endoscopy is the gold-standard diagnostic procedure and allows adequate treatment in selected cases. Endoscopic submucosal dissection (ESD) has been reported to safely address most early gastric cancers (EGCs), with high curability rates. However, data on prognostic factors related to ESDs of EGCs are conflicting. Therefore, we aimed to systematically review the available literature and to perform a meta-analysis to identify the relevant prognostic factors in this context. Methods We performed this study according to PRISMA guidelines. Comparative studies assessing the relationship between curative resection or long-term curability rates and relevant prognostic factors were selected. Prognostic factors were demographic data, lesion features (location, morphology of the lesion, size, and depth of invasion), histological findings, Helycobacter pylori (HP) infection, presence of gastric a atrophy and body mass index (BMI). Finally, we also evaluated risk factors related to metachronous gastric neoplasm. Results The initial search retrieved 2829 records among which 46 studies were included for systematic review and meta-analysis. The total sample comprised 28366 patients and 29282 lesions. Regarding curative resection, pooled data showed no significant influence of sex [odds ratio (OR): 1.15 (0,97, 1.36) P  = 0.10 I 2  = 47 %] , age [OR: 1.00 (0.61, 1.64) P  = 1.00 I 2  = 58 %], posterior vs non-posterior location [OR: 1.35 (0.81, 2.27) P  = 0.25 I 2  = 84 %], depressed vs von-depressed macroscopic type[OR: 1.21 (0.99, 1.49) P  = 0.07 I 2  = 0 %], non-upper vs upper location [OR: 1.41 (0.93, 2.14) P  = 0.10 I 2  = 77 %] and BMI [OR: 0.84 (0.57; 1.26) P  = 0.41 I 2  = 0 %]. Differentiated neoplasms presented greater chance of cure compare to undifferentiated [OR: 0.10 (0.07, 0.15) P  < 0.00001 I 2  = 0 %]. Ulcerated lesions had lower curative rates compared to non-ulcerated [OR: 3.92 (2.81, 5.47) P  < 0.00001 I 2  = 44 %]. Lesions smaller than 20 mm had greater chance of curative resection [OR: 3.94 (3.25, 4.78) P  < 0.00001 I 2  = 38 %]. Bleeding during procedure had lower curative rates compared to non-bleeding [OR: 2.13 (1.56, 2.93) P  < 0.0001 I 2  = 0 %]. Concerning long-term cure, female gender [OR 1.62 (1.33, 1.97) P  < 0.00001 I 2  = 0 %] and the mucosal over SM1 cancers were protective factors [OR: 0.08 (0.02, 0.39) P  = 0.002 I 2  = 86 %]. Gastric atrophy [OR: 0.60 (0.45, 0.81) P  = 0.0006 I 2  = 42 %] and the pepsinogen I/pepsinogen II ratio [OR 2.29 (1.47, 3.57) P  = 0.0002 I 2  = 0 %] were risk factors to metachronous gastric neoplasm. Conclusions Ulcerated lesions, histology, bleeding and size > 20 mm are prognostic factors concerning curative resection. Regarding long-term cure, female gender and mucosal over SM1 cancer are predictive factors. Gastric atrophy and the pepsinogen ratio are risk factors for metachronous gastric neoplasm.

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BACKGROUND: Minimally invasive treatment of early-stage rectal lesion has presented good results, with lower morbidity than surgical resection. Transanal endoscopic microsurgery (TEM) and transanal minimally invasive surgery (TAMIS) are the main methods of transanal surgery. However, endoscopic submucosal dissection (ESD) has been gaining ground because it allows en bloc resections with low recurrence rates. The aim of this study was to analyze ESD in comparison with transanal endoscopic surgery. METHODS: We searched MEDLINE, EMBASE, SciELO, Cochrane CENTRAL, and Lilacs/Bireme with no restrictions on the date or language of publication. The outcomes evaluated were recurrence rate, complete (R0) resection rate, en bloc resection rate, length of hospital stay, duration of the procedure, and complication rate. RESULTS: Six retrospective cohort studies involving a collective total of 326 patients-191 in the ESD group and 135 in the transanal endoscopic surgery group were conducted. There were no statistically significant differences between the groups for any of the outcomes evaluated. CONCLUSIONS: For the minimally invasive treatment of early rectal tumor, ESD and surgical techniques do not differ in terms of local recurrence, en bloc resection rate, R0 resection rate, duration of the procedure, length of hospital stay, or complication rate, however, evidence is very low.

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BACKGROUND: The progression of Barrett's esophagus (BE) to early esophageal carcinoma occurs sequentially; the metaplastic epithelium develops from a low-grade dysplasia to a high-grade dysplasia (HGD), resulting in early esophageal carcinoma and, eventually, invasive carcinoma. Endoscopic approaches including resection and ablation can be used in the treatment of this condition. AIM: To compare the effectiveness of radiofrequency ablation (RFA) vs endoscopic mucosal resection (EMR) + RFA in the endoscopic treatment of HGD and intramucosal carcinoma. METHODS: In accordance with PRISMA guidelines, this systematic review included studies comparing the two endoscopic techniques (EMR + RFA and RFA alone) in the treatment of HGD and intramucosal carcinoma in patients with BE. Our analysis included studies involving adult patients of any age with BE with HGD or intramucosal carcinoma. The studies compared RFA and EMR + RFA methods were included regardless of randomization status. RESULTS: The seven studies included in this review represent a total of 1950 patients, with 742 in the EMR + RFA group and 1208 in the RFA alone group. The use of EMR + RFA was significantly more effective in the treatment of HGD [RD 0.35 (0.15, 0.56)] than was the use of RFA alone. The evaluated complications (stenosis, bleeding, and thoracic pain) were not significantly different between the two groups. CONCLUSION: Endoscopic resection in combination with RFA is a safe and effective method in the treatment of HGD and intramucosal carcinoma, with higher rates of remission and no significant differences in complication rates when compared to the use of RFA alone.

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Background and study aims Colon interposition for benign strictures is associated with significant perioperative complications that carry high morbidity and mortality. Although rarely reported in the literature, adenocarcinoma can occur as a late complication in an interposed colonic segment. We report a case of a late-stage adenocarcinoma in a colonic interposition performed for benign esophageal stricture.

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[This corrects the article DOI: 10.1055/a-0591-2883.].

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BACKGROUND AND STUDY AIMS: Colorectal cancer (CRC) is the third most common malignancy and the third leading cause of cancer death worldwide. Malignant colonic obstruction (MCO) due to CRC occurs in 8 % to 29 % of patients.The aim of this study was to perform a systematic review and meta-analysis of RCTs comparing colonic SEMS versus emergency surgery (ES) for MCO in palliative patients. This was the first systematic review that included only randomized controlled trials in the palliative setting. METHODS: A literature search was performed according to the PRISMA method using online databases with no restriction regarding idiom or year of publication. Data were extracted by two authors according to a predefined data extraction form. Primary outcomes were: mean survival, 30-day adverse events, 30-day mortality and length of hospital stay. Stoma formation, length of stay on intensive care unit (ICU), technical success and clinical success were recorded for secondary outcomes. Technical success (TS) was defined as successful stent placement across the stricture and its deployment. Clinical success (CS) was defined as adequate bowel decompression within 48 h of stent insertion without need for re-intervention. RESULTS: We analyzed data from four RCT studies totaling 125 patients. The 30-day mortality was 6.3 % for SEMS-treated patients and 6.4 % for ES-treated patients, with no difference between groups (RD: - 0.00, 95 % CI [-0.10, 0.10], I 2 : 0 %). Mean survival was 279 days for SEMS and 244 days for ES, with no significant difference between groups (RD: 20.14, 95 % CI: [-42.92, 83.21], I 2 : 44 %). Clinical success was 96 % in the ES group and 86.1 % in the SEMS group (RD: - 0.13, 95 % CI [-0.23, - 0.02], I 2 : 51 %). Permanent stoma rate was 84 % in the ES group and 14.3 % in the SEMS group (RR: 0.19, 95 % CI: [0.11, 0.33], I 2 : 28 %). Length of hospital stay was shorter in SEMS group (RD: - 5.16, 95 % CI: [-6.71, - 3.61], I 2 : 56 %). There was no significant difference between groups regarding adverse events (RD 0.18, 95 % CI: [-0.19, 0.54;]) neither regarding ICU stay. (RD: - 0.01, 95 % CI: [-0.08, 0.05], I 2 : 7 %). The most common stent-related complication was perforation (42.8 % of all AE). CONCLUSION: Mortality, mean survival, length of stay in the ICU and early complications of both methods were similar. SEMS may be an alternative to surgery with the advantage of early hospital discharge and lower risk of permanent stoma.

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AIM: To determine the best option for bowel preparation [sodium picosulphate or polyethylene glycol (PEG)] for elective colonoscopy in adult outpatients. METHODS: A systematic review of the literature following the PRISMA guidelines was performed using Medline, Scopus, EMBASE, Central, Cinahl and Lilacs. No restrictions were placed for country, year of publication or language. The last search in the literature was performed on November 20th, 2017. Only randomized clinical trials with full texts published were included. The subjects included were adult outpatients who underwent bowel cleansing for elective colonoscopy. The included studies compared sodium picosulphate with magnesium citrate (SPMC) and PEG for bowel preparation. Exclusion criteria were the inclusion of inpatients or groups with specific conditions, failure to mention patient status (outpatient or inpatient) or dietary restrictions, and permission to have unrestricted diet on the day prior to the exam. Primary outcomes were bowel cleaning success and/or tolerability of colon preparation. Secondary outcomes were adverse events, polyp and adenoma detection rates. Data on intention-to-treat were extracted by two independent authors and risk of bias assessed through the Jadad scale. Funnel plots, Egger's test, Higgins' test (I 2) and sensitivity analyses were used to assess reporting bias and heterogeneity. The meta-analysis was performed by computing risk difference (RD) using Mantel-Haenszel (MH) method with fixed-effects (FE) and random-effects (RE) models. Review Manager 5 (RevMan 5) version 6.1 (The Cochrane Collaboration) was the software chosen to perform the meta-analysis. RESULTS: 662 records were identified but only 16 trials with 6200 subjects were included for the meta-analysis. High heterogeneity among studies was found and sensitivity analysis was needed and performed to interpret data. In the pooled analysis, SPMC was better for bowel cleaning [MH FE, RD 0.03, IC (0.01, 0.05), P = 0.003, I 2 = 33%, NNT 34], for tolerability [MH RE, RD 0.08, IC (0.03, 0.13), P = 0.002, I 2 = 88%, NNT 13] and for adverse events [MH RE, RD 0.13, IC (0.05, 0.22), P = 0.002, I 2 = 88%, NNT 7]. There was no difference in regard to polyp and adenoma detection rates. Additional analyses were made by subgroups (type of regimen, volume of PEG solution and dietary recommendations). SPMC demonstrated better tolerability levels when compared to PEG in the following subgroups: "day-before preparation" [MH FE, RD 0.17, IC (0.13, 0.21), P < 0.0001, I 2 = 0%, NNT 6], "preparation in accordance with time interval for colonoscopy" [MH RE, RD 0.08, IC (0.01, 0.15), P = 0.02, I 2 = 54%, NNT 13], when compared to "high-volume PEG solutions" [MH RE, RD 0.08, IC (0.01, 0.14), I 2 = 89%, P = 0.02, NNT 13] and in the subgroup "liquid diet on day before" [MH RE, RD 0.14, IC (0.06,0.22), P = 0.0006, I 2 = 81%, NNT 8]. SPMC was also found to cause fewer adverse events than PEG in the "high-volume PEG solutions" [MH RE, RD -0.18, IC (-0.30, -0.07), P = 0.002, I 2 = 79%, NNT 6] and PEG in the "low-residue diet" subgroup [MH RE, RD -0.17, IC (-0.27, 0.07), P = 0.0008, I 2 = 86%, NNT 6]. CONCLUSION: SPMC seems to be better than PEG for bowel preparation, with a similar bowel cleaning success rate, better tolerability and lower prevalence of adverse events.

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BACKGROUND AND AIMS: Surveillance programs of patients with head and neck cancer (HNC) detect synchronous or metachronous esophageal squamous cell carcinoma (ESCC) in up to 15% of patients. Noninvasive, probe-based confocal laser endomicroscopy (pCLE) technique may improve the diagnosis allowing acquisition of high-resolution in vivo images at the cellular and microvascular levels. The aim of this study was to evaluate the accuracy of pCLE for the differential diagnosis of nonneoplastic and neoplastic Lugol-unstained esophageal lesions in patients with HNC. METHODS: Twenty-seven patients with HNC who exhibited Lugol-unstained esophageal lesions at surveillance endoscopy were prospectively included for pCLE. Diagnostic pCLE was followed by subsequent biopsies or endoscopic resection of suspected lesions. A senior pathologist was blinded to the pCLE results. RESULTS: Patients mean age was 59 years (SD = 8.8) and 70.4% were men. All patients were smokers, and 22 patients (81.5%) had a history of alcohol consumption. The locations of HNC were oral cavity (n = 13), larynx (n = 10), and pharynx (n = 4). Thirty-seven lesions in 27 patients were studied. The final diagnoses were ESCC in 17 patients and benign lesions in 20 patients. Sensitivity, specificity, and accuracy of pCLE for the histologic diagnosis of ESCC in patients with HNC were 94.1%, 90.0%, and 91.9%, respectively. CONCLUSIONS: First, pCLE is highly accurate for real-time histology of Lugol-unstained esophageal lesions in patients with HNC. Second, pCLE may alter the management of patients under surveillance for ESCC, guiding biopsies and endoscopic resection, avoiding further diagnostic workup or therapy of benign lesions.

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BACKGROUND: To investigate the available data on the treatment of early colorectal cancer (CRC), either endoscopically or surgically. METHODS: Two independent reviewers searched MEDLINE, EMBASE, CENTRAL COCHRANE, LILACS and EBSCO for articles published up to August 2015. No language or dates filters were applied. Inclusion criteria were studies with published data about patients with early colonic or rectal cancer undergoing either endoscopic resection (i.e., mucosectomy or submucosal dissection) or surgical resection (i.e., open or laparoscopic). Extracted data items undergoing meta-analysis were en bloc resection rate, curative resection rate, and complications. A complementary analysis was performed on procedure time. The risk of bias among studies was evaluated with funnel-plot expressions, and sensitivity analyses were carried out whenever a high heterogeneity was found. The risk of bias within studies was assessed with the Newcastle score. RESULTS: A total of 12,819 articles were identified in the preliminary search. After applying inclusion and exclusion criteria, three cohort studies with a total of 768 patients undergoing endoscopic resection and 552 patients undergoing surgical resection were included. The en bloc resection rate risk difference was -11% [-13%, -8% confidence interval (CI)], demonstrating worse outcome results for the endoscopic resection group as compared to the surgical resection group [number need to harm (NNH) =10]. The curative resection rate risk difference was -9% [(-12%, 6% CI)] after a sensitivity analysis was performed, which also demonstrated worse outcomes in the intervention group (NNH =12). The complications rate exhibited a -7% risk difference [(-11%, -4% CI)], denoting a lesser number of complications in the endoscopic group [Number Need to Treat (NNT =15). A complementary analysis of procedure time with two of the selected studies demonstrated a mean difference of -118.32 min [(-127.77, -108.87 CI)], in favor of endoscopic resection, even though such data lacks homogeneity across studies, and could be heavily influenced by local expertise. Long-term results were found in only one study and therefore were not included in the final analysis. CONCLUSIONS: According to the current available data, the treatment of early CRC by surgical resection is associated with higher curative resection rates and higher en bloc resection rates, despite of higher complications rates, as compared to endoscopic resection. Shorter procedure times are associated with the endoscopic methods of treatment, however high heterogeneity levels limit this conclusion.