Robotic transanal minimally invasive surgery (R-TAMIS): current evidence in the treatment of early rectal neoplasia.

INTRODUCTION: Robotic transanal minimally invasive surgery (R-TAMIS) was introduced in 2012 for the excision of benign rectal polyps and low grade rectal cancer. Ergonomic improvements over traditional laparoscopic TAMIS (L-TAMIS) include increased dexterity within a small operative field, with possibility of better surgical precision. We aim to collate the existing data surrounding the use of R-TAMIS to treat rectal neoplasms from cohort studies and larger case series, providing a foundation for future, large-scale, comparative studies. METHODS: Medline, EMBASE and Web of Science were searched as part of our review. Randomised controlled trials (RCTs), cohort studies or large case series (≥ 5 patients) investigating the use of R-TAMIS to resect rectal neoplasia (benign or malignant) were eligible for inclusion in our analysis. Quality assessment of included studies was performed via the Newcastle Ottawa Scale (NOS) risk of bias tool. Outcomes extracted included basic participant characteristics, operative details and histopathological/oncological outcomes. RESULTS: Eighteen studies on 317 participants were included in our analysis. The quality of studies was generally satisfactory. Overall complication rate from R-TAMIS was 9.7%. Clear margins (R0) were reported in 96.2% of patients. Local recurrence (benign or malignant) occurred in 2.2% of patients during the specified follow-up periods. CONCLUSION: Our review highlights the current evidence for R-TAMIS in the local excision of rectal lesions. While R-TAMIS appears to have complication, margin negativity and recurrence rates superior to those of published L-TAMIS series, comparative studies are needed.

Short-Term Outcomes Analysis Comparing Open, Laparoscopic, Laparoscopic-Assisted, and Robotic Distal Gastrectomy for Locally Advanced Gastric Cancer: A Randomized Trials Network Analysis.

BACKGROUND: Minimally invasive surgery for the treatment of locally advanced gastric cancer (AGC) is debated. The aim of this study was to execute a comprehensive assessment of principal surgical treatments for resectable distal gastric cancer. METHODS: Systematic review and randomized controlled trials (RCTs) network meta-analysis. Open (Op-DG), laparoscopic-assisted (LapAs-DG), totally laparoscopic (Lap-DG), and robotic distal gastrectomy (Rob-DG) were compared. Pooled effect-size measures were the risk ratio (RR), the weighted mean difference (WMD), and the 95% credible intervals (CrIs). RESULTS: Ten RCTs (3823 patients) were included. Overall, 1012 (26.5%) underwent Lap-DG, 902 (23.6%) LapAs-DG, 1768 (46.2%) Op-DG, and 141 (3.7%) Rob-DG. Anastomotic leak, severe complications (Clavien-Dindo > 3), and in-hospital mortality were comparable. No differences were observed for reoperation rate, pulmonary complications, postoperative bleeding requiring transfusion, surgical-site infection, cardiovascular complications, number of harvested lymph nodes, and tumor-free resection margins. Compared to Op-DG, Lap-DG and LapAs-DG showed a significantly reduced intraoperative blood loss with a trend toward shorter time to first flatus and reduced length of stay. CONCLUSIONS: LapAs-DG, Lap-DG, and Rob-DG performed in referral centers by dedicated surgeons have comparable short-term outcomes to Op-DG for locally AGC.

Effect of complete mesocolic excision (cme) on long-term survival after right colectomy for cancer: multivariate meta-analysis and restricted mean survival time estimation.

INTRODUCTION: Debate exists concerning the impact of complete mesocolic excision (CME) on long-term oncological outcomes. The aim of this review was to condense the updated literature and assess the effect of CME on long-term survival after right colectomy for cancer. METHODS: PubMed, MEDLINE, Scopus, and Web of Science were searched through July 2023. The included studies evaluated the effect of CME on survival. The primary outcome was long-term overall survival. Restricted mean survival time difference (RMSTD), hazard ratio (HR), and 95% confidence intervals (CI) were used as pooled effect size measures. GRADE methodology was used to summarize the certainty of evidence. RESULTS: Ten studies (3665 patients) were included. Overall, 1443 (39.4%) underwent CME. The RMSTD analysis shows that at 60-month follow-up, stage I-III CME patients lived 2.5 months (95% CI 1.1-4.1) more on average compared with noCME patients. Similarly, stage III patients that underwent CME lived longer compared to noCME patients at 55-month follow-up (6.1 months; 95% CI 3.4-8.5). The time-dependent HRs analysis for CME vs. noCME (stage I-III disease) shows a higher mortality hazard in patients with noCME at 6 months (HR 0.46, 95% CI 0.29-0.71), 12 months (HR 0.57, 95% CI 0.43-0.73), and 24 months (HR 0.73, 95% CI 0.57-0.92) up to 27 months. CONCLUSIONS: This study suggests that CME is associated with unclear OS benefit in stage I-III disease. Caution is recommended to avoid overestimation of the effect of CME in stage III disease since the marginal benefit of a more extended resection may have been influenced by tumor biology/molecular profile and multimodal adjuvant treatments.

Detection of (pre)cancerous colorectal lesions in Lynch syndrome patients by microsatellite instability liquid biopsy.

Lynch syndrome (LS) is an inherited condition characterized by an increased risk of developing cancer, in particular colorectal cancer (CRC). Microsatellite instability (MSI) is the main feature of (pre)cancerous lesions occurring in LS patients. Close endoscopic surveillance is the only option available to reduce CRC morbidity and mortality. However, it may fail to intercept interval cancers and patients' compliance to such an invasive procedure may decrease over the years. The development of a minimally invasive test able to detect (pre)cancerous colorectal lesions, could thus help tailor surveillance programs in LS patients. Taking advantage of an endoscopic surveillance program, we retrospectively assessed the instability of five microsatellites (BAT26, BAT25, NR24, NR21, and Mono27) in liquid biopsies collected at baseline and possibly at two further endoscopic rounds. For this purpose, we tested a new multiplex drop-off digital polymerase chain reaction (dPCR) assay, reaching mutant allele frequencies (MAFs) as low as 0.01%. Overall, 78 plasma samples at the three time-points from 18 patients with baseline (pre)cancerous lesions and 18 controls were available for molecular analysis. At baseline, the MAFs of BAT26, BAT25 and NR24 were significantly higher in samples of patients with lesions but did not differ with respect to the grade of dysplasia or any other clinico-pathological characteristics. When all markers were combined to determine MSI in blood, this test was able to discriminate lesion-bearing patients with an AUC of 0.80 (95%CI: 0.66; 0.94).

Radiomics; Contemporary Applications in the Management of Anal Cancer; A Systematic Review.

INTRODUCTION: The management of anal cancer relies on clinical and histopathological features for treatment decisions. In recent years, the field of radiomics, which involves the extraction and analysis of quantitative imaging features, has shown promise in improving management of pelvic cancers. The aim of this study was to evaluate the current application of radiomics in the management of anal cancer. METHODS: A systematic search was conducted in Medline, EMBASE, and Web of Science databases. Inclusion criteria encompassed randomized and non-randomized trials investigating the use of radiomics to predict post-operative recurrence in anal cancer. Study quality was assessed using the QUADAS-2 and Radiomics Quality Score tools. RESULTS: The systematic review identified a total of nine studies, with 589 patients examined. There were three main outcomes assessed in included studies: recurrence (6 studies), progression-free survival (2 studies), and prediction of human papillomavirus (HPV) status (1 study). Radiomics-based risk stratification models were found to provide valuable insights into treatment response and patient outcomes, with all developed signatures demonstrating at least modest accuracy (range: .68-1.0) in predicting their primary outcome. CONCLUSION: Radiomics has emerged as a promising tool in the management of anal cancer. It offers the potential for improved risk stratification, treatment planning, and response assessment, thereby guiding personalized therapeutic approaches.

De novo germline pathogenic variant in Lynch Syndrome: A rare event or the tip of the iceberg?

Lynch Syndrome is an autosomal dominant cancer predisposition syndrome caused by germline pathogenic variants or epimutation in one of the DNA mismatch repair genes. De novo pathogenic variants in mismatch repair genes have been described as a rare event in Lynch Syndrome (1-5%), although the prevalence of de novo pathogenic variants in Lynch Syndrome is probably underestimated. The de novo pathogenic variant was identified in a 26-year-old woman diagnosed with an adenocarcinoma of the caecum with mismatch repair protein deficiency at immunohistochemistry and a synchronous neuroendocrine tumor of the appendix with normal expression of mismatch repair proteins. DNA testing revealed deletion of exon 6 of the MLH1 gene. It appeared to be a de novo event, as the deletion was not detected in the patient's parents. The presence of a mosaicism in the patient was excluded and haplotype analysis demonstrated the paternal origin of the chromosome harboring the deletion. The de novo deletion probably originated either from a very early postzygotic or a single prezygotic mutational event, or from a gonadal mosaicism. In conclusion, the identification of de novo pathogenic variants is crucial to allow proper genetic counseling and appropriate management of the patient's family.

Quality of life after prophylactic surgery for colorectal adenomatous polyposis.

PURPOSE: Colorectal adenomatous polyposis is characterized by the onset of tens to thousands of adenomas in the colorectal epithelium and, if not treated, leads to a lifetime increased risk of developing colorectal cancer compared to the general population. Thus, prophylactic surgery is recommended. This study aims to investigate the quality of life of colorectal adenomatous polyposis patients following prophylactic surgery and indirectly compares these findings with those of healthy adults of the normative sample. METHODS: All patients who underwent prophylactic surgery for polyposis and were in follow-up at the hereditary digestive tract tumors outpatient department of our institute were eligible for the study. The Short Form-36 questionnaire and 21 ad hoc items were used at the time of clinical evaluation. RESULTS: A total of 102 patients were enrolled. For the SF-36 domains, mean values ranged from 64.18 for vitality to 88.49 for physical functioning, with the highest variability for role-physical limitations; the minimum value of functioning was reached for role-physical limitations, role-emotional limitations, and social functioning. The maximum value of functioning was reached for role-emotional limitations (73.96%) and role-physical limitations (60.42%). In total, 48.96% and 90.63% of patients reported no fecal or urinary incontinence episodes, respectively; 69.79% of patients did not have problems in work/school resumption or the personal sexual sphere. CONCLUSION: Quality of life following prophylactic surgery for these patients seems to be good when indirectly compared to HP-normative samples'. Young adult patients appear to quickly manage and adapt to changes in bowel functioning. A minority of patients may experience social and sexual issues.

Therapeutic Challenges for Gastric Neuroendocrine Neoplasms: Take It or Leave It?

Background and Objectives: Gastric neuroendocrine neoplasms (gNENs) represent rare but increasingly recognized tumors. They are distinguished into three main clinical types (type-1, type-2, and type-3) according to gastrin level and at histological evaluation in well-differentiated G1, G2, or G3 lesions, as well as poorly-differentiated lesions. Small type-1 and type-2 neoplasms with low proliferation indices demonstrated excellent survival without progression during an extended follow-up period, and for these reasons, active endoscopic observation or endoscopic resection are feasible options. On the other hand, surgery is the treatment of choice for more aggressive type-3, G3, or infiltrating neoplasms. The present study aims to comprehensively review and compare the available therapeutic strategies for gNENs. Materials and Methods: A computerized literature search was performed using relevant keywords to identify all of the pertinent articles with particular attention to gNEN endoscopic treatment. Results: In recent years, different endoscopic resective techniques (such as endoscopic mucosal dissection, modified endoscopic mucosal resection, and endoscopic full-thickness resection) have been developed, showing a high rate of complete resection for advanced and more aggressive lesions. Conclusions: Overall, gNENs represent a heterogeneous group of lesions with varying behavior which require personalized management. The non-operative approach for small type-1 gNENs seems to be feasible and should be promoted. A step-up approach with minimally invasive endoscopic therapies might be proposed, particularly for type-1 gNEN. On the other hand, it is important to recognize the negative prognostic factors in order to identify those rare cases requiring more aggressive approaches. A possible therapeutic algorithm for localized gNEN management is provided.

What is the ideal mesh location for incisional hernia prevention during elective laparotomy? A network meta-analysis of randomized trials.

BACKGROUND: Incisional hernia (IH) represents an important complication after surgery. Prophylactic mesh reinforcement (PMR) with different mesh locations [onlay (OL), retromuscular (RM), preperitoneal (PP), and intraperitoneal (IP)] has been described to possibly reduce the risk of postoperative IH. However, data reporting the 'ideal' mesh location are sparse. The aim of this study was to evaluate the optimal mesh location for IH prevention during elective laparotomy. METHODS: Systematic review and network meta-analysis of randomized controlled trials (RCTs). OL, RM, PP, IP, and no mesh (NM) were compared. The primary aim was postoperative IH. Risk ratio (RR) and weighted mean difference (WMD) were used as pooled effect size measures, whereas 95% credible intervals (CrI) were used to assess relative inference. RESULTS: Fourteen RCTs (2332 patients) were included. Overall, 1052 (45.1%) had no mesh (NM) while 1280 (54.9%) underwent PMR stratified in IP ( n =344 pts), PP ( n =52 pts), RM ( n =463 pts), and OL ( n =421 pts) placement. Follow-up ranged from 12 months to 67 months. RM (RR=0.34; 95% CrI: 0.10-0.81) and OL (RR=0.15; 95% CrI: 0.044-0.35) were associated with significantly reduced IH RR compared to NM. A tendency toward reduced IH RR was noticed for PP versus NM (RR=0.16; 95% CrI: 0.018-1.01), while no differences were found for IP versus NM (RR=0.59; 95% CrI: 0.19-1.81). Seroma, hematoma, surgical site infection, 90-day mortality, operative time and hospital length of stay were comparable among treatments. CONCLUSIONS: RM or OL mesh placement seems associated with reduced IH RR compared to NM. PP location appears promising; however, future studies are warranted to corroborate this preliminary indication.

Consequences of the COVID-19 pandemic on the diagnosis and treatment of gastric cancer in referral centers in Italy.

BACKGROUND: The coronavirus pandemic had a major impact in Italy. The Italian health system's re-organization to face the emergency may have led to significant consequences especially in the diagnosis and treatment of malignancies. This study aimed to assess the impact of the pandemic in the diagnosis and treatment of gastric cancer in nine Gruppo Italiano RIcerca Cancro Gastrico (GIRCG) centers. METHODS: All patients assessed for gastric adenocarcinoma at nine GIRCG centers between January 2019 and November 2020 were included. Patients were grouped according to the date of "patient 1's" diagnosis in Italy: preCOVID versus COVID. Clinico-pathological and outcome differences between the two groups were analyzed. RESULTS: A total of 632 patients were included in the analysis (205 in the COVID group). The cT4 weighted ratios were higher in 2020 from April to September, with the greatest differences in May, August and September. The cM+ weighted ratio was significantly higher in July 2020. The mean number of gastrectomies had the greatest reduction in March and May 2020 compared with 2019. The median times from diagnosis to chemotherapy, to complete diagnostic work-up or to operation were longer in 2019. The median time from the end of chemotherapy to surgery was 17 days longer in the preCOVID group. CONCLUSIONS: A greater number of advanced or metastatic cases were diagnosed after the spread of SARS-CoV-2 infection, especially after the "full lockdown" periods. During the pandemic, once gastric cancer patients were referred to one of the centers, a shorter time to complete the diagnostic work-up or to address them to the best treatment option was required.

Delayed-release oral mesalamine tablet mimicking a small jejunal gastrointestinal stromal tumor: A case report.

BACKGROUND: Enteric-coated medications are supposed to pass intact through the gastric environment and to release the drug content into the small intestine or the colon. Before dissolution of the enteric coating, they may appear hyperdense on computed tomography (CT). Unfortunately, few reports have been published on this topic so far. In this case report, the hyperdense appearance on contrast-enhanced CT of an enteric-coated mesalamine tablet was initially misinterpreted as a jejunal gastrointestinal stromal tumor (GIST). CASE SUMMARY: An asymptomatic 81-year-old male patient, who had undergone laparoscopic right nephrectomy four years earlier for stage 1 renal carcinoma, was diagnosed with a jejunal GIST at the 4-year follow-up thoraco-abdominal CT scan. He was referred to our hub hospital for gastroenterological evaluation, and subsequently underwent 18-fluorodeoxyglucose positron emission tomography, abdominal magnetic resonance imaging, and video capsule endoscopy. None of these examinations detected any lesion of the small intestine. After reviewing all the CT images in a multidisciplinary setting, the panel estimated that the hyperdense jejunal image was consistent with a tablet rather than a GIST. The tablet was an 800 mg delayed-release enteric-coated oral mesalamine tablet (Asacol®), which had been prescribed for non-specific colitis, while not informing the hospital physicians. CONCLUSION: Delayed-release oral mesalamine (Asacol®), like other enteric-coated medications, can appear as a hyperdense image on a CT scan, mimicking a small intestinal GIST. Therefore, a detailed knowledge of the patients' medications and a multidisciplinary review of the images are essential.

Reply to Serrano et al. Comment on "Colletti et al. Prevalence and Management of Cancer of the Rectal Stump after Total Colectomy and Rectal Sparing in Patients with Familial Polyposis: Results from a Registry-Based Study. Cancers 2022, 14, 298".

We carefully read the comment by Serrano et al. [...].

Hepatocellular carcinoma in patients with nonalcoholic fatty liver disease: A systematic review and meta-analysis: HCC and Steatosis or Steatohepatitis.

BACKGROUND AND AIMS: Hepatic steatosis of nonalcoholic etiology (nonalcoholic fatty liver disease; NAFLD) is an emergent condition that may lead to hepatic cirrhosis and finally to liver cancer. We evaluate the risk of developing hepatocellular carcinoma (HCC) and quantify the prognosis in terms of recurrence (DFS) as well as HCC-specific and overall survival (CSS and OS) of patients with and without NAFLD. METHODS: We searched published articles that evaluated the risk and outcomes of HCC in patients with steatosis/steatohepatitis from inception to July 2021 were identified by searching the PubMed, EMBASE, and Cochrane Library databases. Prospective cohort, case-control, or retrospective studies were selected that were published in English and provided incidence and survival rates of HCC patients with NAFLD. A random-effects model was created to estimate the pooled effect size. The primary outcome of interest was HCC incidence. The secondary endpoints were DFS, CSS, and OS. RESULTS: In total, 948 217 patients with NAFLD were analyzed, from n = 103 observational studies. NAFLD significantly increased the risk of HCC (HR = 1.88 [95% CI, 1.46-2.42]; P < .01] but not risk of recurrence (HR = 0.99 [95% CI, 0.85-1.15]; P = .9) or overall mortality (HR = 1.04 [95% CI, 0.88-1.24]; P = 0.64). Conversely, NAFLD increased HCC-related mortality risk (HR = 2.16 [95% CI, 0.85-5.5]; P = .1). Risk of HCC was increased in Western countries but not in Asian countries. CONCLUSIONS: Patients with NAFLD have an increased risk of HCC as compared to patients without NAFLD. NAFLD also increases liver cancer (HCC) mortality. These results justify applying general measures to patients with proven NAFLD and monitoring patients with NASH and fibrosis.

Intratumor Microbiome in Neuroendocrine Neoplasms: A New Partner of Tumor Microenvironment? A Pilot Study.

Neuroendocrine neoplasms (NENs) are rare neoplasms with heterogeneous clinical behavior. Alteration in human microbiota was reported in association with carcinogenesis in different solid tumors. However, few studies addressed the role of microbiota in NEN. We here aimed at evaluating the presence of bacterial infiltration in neuroendocrine tumoral tissue. To assess the presence of bacteria, 20 specimens from pancreatic NEN (pan-NEN) and 20 from intestinal NEN (I-NEN) were evaluated through Fluorescent In situ Hybridization and confocal microscopy. Demographic data, pre-operative investigations, operative findings, pathological diagnosis, follow-up, and survival data were evaluated. Among I-NEN, bacteria were detected in 15/20 (75%) specimens, with high variability in microbial distribution. In eight patients, a high infiltration of microorganisms was observed. Among pan-NEN, 18/20 (90%) showed microorganisms' infiltration, with a homogeneous microbial distribution. Bacterial localization in pan-NEN was observed in the proximity of blood vessels. A higher bacterial infiltration in the tumoral specimen as compared with non-tumoral tissue was reported in 10/20 pan-NEN (50%). No significant differences were observed in mean bacterial count according to age, sex, ki67%, site, tumor stage. Mean bacterial count did not result to be a predictor of disease-specific survival. This preliminary study demonstrates the presence of a significant microbiota in the NEN microenvironment. Further research is needed to investigate the potential etiological or clinical role of microbiota in NEN.

Does ProCore Fine-Needle Biopsy Really Improve the Clinical Outcome of Endoscopic Ultrasound-Guided Sampling of Pancreatic Masses?

INTRODUCTION: Fine-needle biopsy (FNB) has been suggested to provide better histological samples as compared to endoscopic ultrasound fine-needle aspiration (EUS-FNA). However, studies comparing EUS-FNA and EUS-FNB for pancreatic lesions reported contrasting results. The aim of this study was to compare the clinical performance of EUS-FNA versus EUS-FNB with the ProCore needle for the investigation of pancreatic lesions. METHODS: We reviewed all patients undergoing EUS for the investigation of pancreatic lesions from August 2012 to September 2018. From August 2012 to January 2015, all procedures were performed with standard needles, whereas from February 2015 to September 2018, the use of ProCore needles had been introduced. Data on diagnostic accuracy, number of needle passes, and/or adverse events were collected. RESULTS: Three hundred twenty-four patients were retrospectively evaluated: 190 (58.6%) underwent EUS-FNA and 134 (41.4%) EUS-FNB. Both EUS-FNA and EUS-FNB showed high diagnostic accuracy for malignancy (94% [95% CI: 89-97%] vs. 94% [95% CI: 89-98%]). Notably, there were no differences between EUS-FNA and EUS-FNB in terms of sensitivity, specificity, positive and negative likelihood ratio, histological core tissue retrieval, adverse events, or number of needle passes. However, subgroup analysis noted a higher diagnostic accuracy for 25G EUS-FNB as compared to 25G EUS-FNA (85.7 vs. 55.5%; *p = 0.023). CONCLUSION: EUS-FNB with the ProCore needle is safe and feasible in pancreatic lesions. The ProCore needle did not provide any advantage in terms of diagnostic accuracy, sensitivity, specificity, positive and/or negative likelihood ratio, or acquisition of the core specimen; therefore, its routine application is not supported.

Gastrointestinal Stromal Tumours (GIST) of the Rectum: A Systematic Review and Meta-Analysis.

Background: Rectal gastrointestinal stromal tumours (GISTs) have many treatment options, but uncertainty remains regarding the best treatment regimen for this rare pathology. The aim of this review is to assess the optimal management approach including timing of chemotherapy. Methods: PubMed, EMBASE, and Cochrane databases were searched for relevant articles comparing the impact of radical vs. local excision, and neoadjuvant vs. adjuvant therapy had on outcomes in the management of rectal GISTs. We specifically evaluated the influence that the aforementioned factors had on margins, recurrence, overall survival, 5-year disease-free survival, and hospital length of stay. Results: Twenty-eight studies met our predefined criteria and were included in our study, twelve of which were included in the quantitative synthesis. When comparing neoadjuvant versus adjuvant chemotherapy, our meta-analysis noted no significance in terms of margin negativity (R0) (odds ratio [OR] 2.01, 95% confidence interval [CI], 0.7−5.79, p = 0.20) or recurrence rates (OR 0.22, 95% CI, 0.02−1.91, p = 0.17). However, there was a difference in overall 5-year survival in favour of neoadjuvant therapy (OR 3.19, 95% CI, 1.37−7.40, * p = 0.007). Comparing local excision versus radical excision, our meta-analysis observed no significance in terms of overall 5-year survival (OR1.31, 95% CI, 0.81−2.12, p = 0.26), recurrence (OR 0.67, 95% CI, 0.40−1.13, p = 0.12), or 5-year disease-free survival (OR 1.10, 95% CI, 0.55−2.19, p = 0.80). There was a difference in length of hospital stay with a reduced mean length of stay in local excision group (mean difference [MD] 6.74 days less in the LE group; 95% CI, −6.92−−6.56, * p =< 0.00001) as well as a difference in R0 rates in favour of radical resection (OR 0.68, 95% CI, 0.47−0.99, * p = 0.05). Conclusion: Neoadjuvant chemotherapy is associated with improved overall 5-year survival, while local excision is associated with reduced mean length of hospital stay. Further large-volume, prospective studies are required to further define the optimal treatment regimen in this complex pathology.

Human papillomavirus (HPV) types 16 and 18 infection and esophageal squamous cell carcinoma: a systematic review and meta-analysis.

OBJECTIVE: The human papillomavirus (HPV) is implicated in the pathogenesis of several cancers among humans. The role of HPV as one of the etiological agents in esophageal carcinogenesis is partially unknown. We assessed whether the available evidence supports the association of HPV with risk and prognosis in patients with esophageal squamous cell carcinomas (ESCCs). DESIGN: For this systematic review and meta-analysis, PubMed, Embase, Cochrane Library, and SCOPUS were searched up to February 2021. The included studies were prospective or retrospective studies that evaluated the incidence, risk, and prognosis of HPV-16/18-related ESCCs in adult subjects. The primary outcome was the incidence rate of ESCC in HPV-16/18 carriers. Secondary outcomes included the risk of ESCCs compared with healthy HPV-16/18 carriers (expressed as odds ratios [ORs] with 95% confidence intervals [CIs]) and the survival of HPV + versus HPV- ESCCs. RESULTS: The search identified 1649 unique citations, of which 145 met the inclusion criteria and were included in the pooled analysis (16,484 patients). The pooled HPV prevalence in ESCCs was 18.2% (95% CI 15.2-21.6%; P < 0.001). A significantly increased ESCC risk was associated with HPV infection (OR = 3.81; 95% CI 2.84-5.11; P < 0.001). Main limitation were methods of HPV detection (DNA only), race of populations included (mainly Asiatic countries) and lack of adjustment for other prognostic factors. CONCLUSIONS: The findings suggest that HPV-16/18 is detectable in about 1 on 5 cases of ESCC with different prevalences across the world. It is moderately but significantly associated with a diagnosis of ESCC. Further epidemiological studies are needed to confirm and increase the current knowledge of the subject.

Personalized therapeutic strategies in HER2-driven gastric cancer.

BACKGROUND: Trastuzumab is the only approved targeted therapy in patients with HER2-amplified metastatic gastric cancer (GC). Regrettably, in clinical practice, only a fraction of them achieves long-term benefit from trastuzumab-based upfront strategy. To advance precision oncology, we investigated the therapeutic efficacy of different HER2-targeted strategies, in HER2 "hyper"-amplified (≥ 8 copies) tumors. METHODS: We undertook a prospective evaluation of HER2 targeting with monoclonal antibodies, tyrosine kinase inhibitors and antibody-drug conjugates, in a selected subgroup of HER2 "hyper"-amplified gastric patient-derived xenografts (PDXs), through the design of ad hoc preclinical trials. RESULTS: Despite the high level of HER2 amplification, trastuzumab elicited a partial response only in 2 out of 8 PDX models. The dual-HER2 blockade with trastuzumab plus either pertuzumab or lapatinib led to complete and durable responses in 5 (62.5%) out of 8 models, including one tumor bearing a concomitant HER2 mutation. In a resistant PDX harboring KRAS amplification, the novel antibody-drug conjugate trastuzumab deruxtecan (but not trastuzumab emtansine) overcame KRAS-mediated resistance. We also identified a HGF-mediated non-cell-autonomous mechanism of secondary resistance to anti-HER2 drugs, responsive to MET co-targeting. CONCLUSION: These preclinical randomized trials clearly indicate that in HER2-driven gastric tumors, a boosted HER2 therapeutic blockade is required for optimal efficacy, leading to complete and durable responses in most of the cases. Our results suggest that a selected subpopulation of HER2-"hyper"-amplified GC patients could strongly benefit from this strategy. Despite the negative results of clinical trials, the dual blockade should be reconsidered for patients with clearly HER2-addicted cancers.