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Digestive and Liver Disease : Official... Apr 2024The role of small-bowel (SB) cancer surveillance by capsule endoscopy (CE) in Lynch syndrome (LS) patients has been investigated in recent years, with contradicting... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND & AIMS
The role of small-bowel (SB) cancer surveillance by capsule endoscopy (CE) in Lynch syndrome (LS) patients has been investigated in recent years, with contradicting results. This meta-analysis evaluates the diagnostic yield (DY) of CE as a screening tool in asymptomatic LS patients.
METHODS
A systematic literature search was performed for all studies reporting the results of SB cancer screening in patients with LS. The primary outcome was the evaluation of the DY of CE in this setting for consecutive screening rounds.
RESULTS
Five studies comprising 428 patients and CE 677 procedures were included for data extraction and statistical analysis. The estimated pooled DY for CE-identified pathological findings was 8% in the first screening round and 6% in the second. Limiting the analysis to histologically-confirmed pathological findings, the pooled DY of second-round screening dropped to 0%. The included studies showed a significantly different prevalence of pathogenic variants in mismatch repair (path_MMR) genes, which underlie different cumulative incidences of extracolonic cancers.
CONCLUSIONS
SB surveillance by CE with a 2-year interval in asymptomatic LS individuals does not appear to be an effective screening strategy. Confirmatory prospective studies in this context are needed, considering the different cumulative incidence of SB tumors according to underlying path_MMR defects.
Topics: Humans; Capsule Endoscopy; Colorectal Neoplasms, Hereditary Nonpolyposis; Prospective Studies; Intestine, Small; Intestinal Neoplasms; Duodenal Neoplasms
PubMed: 37563008
DOI: 10.1016/j.dld.2023.07.028 -
Journal of Personalized Medicine Jun 2023Prostatic adenocarcinoma (PA) is the second most common malignancy in men globally. Signet-ring cell-like adenocarcinoma (SRCC) is a very rare PA subtype, with around... (Review)
Review
A Case of Prostatic Signet-Ring Cell-like Carcinoma with Pagetoid Spread and Intraductal Carcinoma and Long-Term Survival: PD-L1 and Mismatch Repair System Proteins (MMR) Immunohistochemical Evaluation with Systematic Literature Review.
Prostatic adenocarcinoma (PA) is the second most common malignancy in men globally. Signet-ring cell-like adenocarcinoma (SRCC) is a very rare PA subtype, with around 200 cases reported in the English literature. Histologically, the tumor cells show a vacuole compressing the nucleus to the periphery. Pagetoid spread in acini and ducts is usually related to metastases from urothelial or colorectal carcinomas, less commonly associated with intraductal carcinoma (IC); histologically, the tumor cells grow between the acinar secretory and basal cell layers. To our knowledge, we report the first prostatic SRCC (Gleason score 10, stage pT3b) associated with IC and pagetoid spread to prostatic acini and seminal vesicles. To our systematic literature review (PRISMA guidelines), it is the first tested case for both PD-L1 (<1% of positive tumor cells, clone 22C3) and mismatch repair system proteins (MMR) (MLH1+/MSH2+/PMS2+/MSH6+). We found no SRCC previously tested for MMR, while only four previous cases showed high expression of another PD-L1 clone (28-8). Finally, we discussed the differential diagnoses of prostatic SRCC.
PubMed: 37374005
DOI: 10.3390/jpm13061016 -
European Journal of Cancer (Oxford,... Aug 2023Many immuno-oncology (IO) trials are conducted without biomarker selection. We performed a meta-analysis of phase I/II clinical trials evaluating immune checkpoint... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Many immuno-oncology (IO) trials are conducted without biomarker selection. We performed a meta-analysis of phase I/II clinical trials evaluating immune checkpoint inhibitors (ICIs) to determine the association between biomarkers and clinical outcomes, if any.
METHODS
A PubMed search for phase I/II clinical trials with drugs approved by the Food and Drug Administration (labelled, off-label, combined with investigational ICIs or other treatment modalities) from 2018 to 2020 was performed. The objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) were compared between biomarker-positive and biomarker-negative groups, using studies that explored the correlation of biomarkers with outcomes.
RESULTS
Overall, 174 clinical studies that included 19,178 patients were identified, and 132 studies investigated>30 correlative biomarkers that included PD-L1 expression (≥1%, 111 studies), tumour mutational burden (20 studies) and microsatellite instability/mismatch repair deficiency (10 studies). Overall, 123, 46 and 30 cohorts (drugs, tumour types or biomarkers) with 11,692, 3065, and 2256 patient outcomes for ORR, PFS and OS, respectively, were analysed in correlation with biomarkers. Meta-analyses demonstrated that ICIs in patients with biomarker-positive tumours were associated with higher ORR (odds ratio 2.15 [95% CI, 1.79-2.58], p < 0.0001); and longer PFS (hazard ratio [HR] 0.55 [95% CI, 0.45-0.67], p < 0.0001), and OS (HR 0.65 [95% CI, 0.53-0.80], p < 0.0001) compared with those with biomarker-negative tumours. Significance for ORR and PFS was retained in multivariate analysis (p < 0.001) (OS, not included owing to the small number of trials reporting OS).
CONCLUSION
Our data suggest that IO biomarkers should be used in patient selection for ICIs. Prospective studies are warranted.
Topics: Humans; Neoplasms; Treatment Outcome; Immunotherapy; Biomarkers; Progression-Free Survival
PubMed: 37364526
DOI: 10.1016/j.ejca.2023.05.015 -
Neoplasia (New York, N.Y.) Sep 2023With the recent success of immunotherapy, there is a growing interest in combining radiation with immunotherapy to boost abscopal response rates. Several challenges...
BACKGROUND
With the recent success of immunotherapy, there is a growing interest in combining radiation with immunotherapy to boost abscopal response rates. Several challenges exist in determining how to synergize these two modalities in the treatment of metastatic NSCLC.
METHODS
References for this review were identified through searches of MEDLINE/PubMed and Clinicaltrials.gov databases with the search terms "abscopal", "radiation OR radiotherapy," "NSCLC", and "lung" on the index date of July 2022 from 2000-2022. This systematic review focuses primarily on clinical papers.
DISCUSSION
Early work combining radiotherapy with immunotherapy show promise in unlocking the abscopal effect. Preliminary evidence suggests that radiotherapy regimens with <5 fractions and smaller fields may be superior to regimens with 15 fractions and larger fields. There does not appear to be enough evidence to draw conclusions about the optimal timing of radiotherapy in relation to immunotherapy or the optimal anatomical location of radiation to induce the abscopal effect. Several studies suggest selecting patients with a higher absolute lymphocyte count (ALC) and lower neutrophil-to-lymphocyte ratio (NLR) may help to further boost abscopal response rates. Furthermore, selecting tumors with programmed death ligand-1 (PD-L1) expression, mismatch repair deficiency, and higher tumor mutational burden may similarly achieve this goal. Lastly, additional work is needed to minimize and predict for severe toxicity associated with combination therapy.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Immunotherapy; Lung; Combined Modality Therapy; Lung Neoplasms
PubMed: 37348427
DOI: 10.1016/j.neo.2023.100914 -
Frontiers in Pharmacology 2023Urachal carcinoma (UrC) is a rare and aggressive disease. Systematic chemotherapy shows limited efficacy in patients with advanced disease, while targeted therapy and...
Urachal carcinoma (UrC) is a rare and aggressive disease. Systematic chemotherapy shows limited efficacy in patients with advanced disease, while targeted therapy and immunotherapy may provide a reasonable alternative for specific populations. The molecular pattern of colorectal cancer (CRC) have recently been identified; this understanding has significantly influenced the clinical management of CRC in terms of molecular-targeted therapy. Although some genetic alterations have been associated with UrC, there is still no systematic overview of the molecular profile of this rare malignancy. In this review, we comprehensively discuss the molecular profile of UrC and further identify potential targets for the personalized treatment of UrC as well as immune checkpoint inhibitors that represent underlying biomarkers. A systematic literature search was carried out by searching the PubMed, EMBASE, and Web of Science databases to identify all literature related to targeted therapy and immunotherapy in urachal carcinoma from inception to February 2023. A total of 28 articles were eligible, and most studies included were case report sand retrospective case series. Furthermore, 420 cases of UrC were identified to analyze the association between mutations and UrC. The most commonly mutated gene in UrC was TP53 with the prevalence of 70%, followed by KRAS mutations in 28.3%, MYC mutations in 20.3%, SMAD4 mutations in 18.2% and GNAS mutations in 18%, amongst other genes. The molecular patterns of UrC and CRC are similar yet distinct. Notably, targeted therapy, especially EGFR-targeting therapy, might provide curative efficacy for patients with UrC by applying specific molecular markers. Additional potential biomarkers for the immunotherapy of UrC are mismatch repair (MMR) status and PD-L1 expression profile. In addition, combined regimens featuring targeted agents and immune checkpoint blockers might increase antitumor activity and exert better efficacy in UrC patients with specific mutational burden.
PubMed: 37324454
DOI: 10.3389/fphar.2023.1199395 -
Critical Reviews in Oncology/hematology Aug 2023Lynch syndrome (LS) is a genetic predisposition leading to colorectal and non-colorectal tumors such as endometrial, upper urinary tract, small intestine, ovarian,... (Review)
Review
Lynch syndrome (LS) is a genetic predisposition leading to colorectal and non-colorectal tumors such as endometrial, upper urinary tract, small intestine, ovarian, gastric, biliary duct cancers and glioblastoma. Though not classically associated with LS, growing literature suggests that sarcomas might develop in patients with LS. This systematic review of literature identified 44 studies (N = 95) of LS patients who developed sarcomas. It seems that most sarcomas developed in patients with a germline mutation of MSH2 (57 %) exhibit a dMMR (81 %) or MSI (77 %) phenotype, as in other LS-tumors. Although undifferentiated pleomorphic sarcoma (UPS), leiomyosarcoma, and liposarcoma remain the most represented histologic subtype, a higher proportion of rhabdomyosarcoma (10 %, especially pleomorphic rhabdomyosarcoma) is reported. Further studies are required to better characterize this sub-population.
Topics: Humans; Colorectal Neoplasms, Hereditary Nonpolyposis; Colorectal Neoplasms; Genetic Predisposition to Disease; Germ-Line Mutation; Sarcoma; Rhabdomyosarcoma; DNA Mismatch Repair; Microsatellite Instability
PubMed: 37301271
DOI: 10.1016/j.critrevonc.2023.104055 -
Frontiers in Medicine 2023Immune checkpoint inhibitors (ICPI) are a tumor agnostic treatment. However, trials of their use have been site specific. Here we summarize the trial data and explore...
BACKGROUND
Immune checkpoint inhibitors (ICPI) are a tumor agnostic treatment. However, trials of their use have been site specific. Here we summarize the trial data and explore the utility of programmed death-ligand 1 (PD-L1) expression as a biomarker to direct their pan-cancer use.
METHOD
A systematic review of literature, following PRISMA guidelines, was performed. Medline, Embase, Cochrane CENTRAL, NHS Health and Technology, and Web of Science were searched from their conception to June 2022 limited to the English language. The search terms and method were devised by a specialist medical librarian. Studies were limited to adults with solid cancers (excluding melanomas) treated with ICPIs. Only phase III randomized control trials (RCT) were included. The primary outcome was overall survival and secondary outcomes were progression free survival, PD-L1 expression, quality of life outcomes and adverse event data. Where present in eligible clinical trials, hazard ratios (HR), risk ratios (RR), standard error (SE) and 95% confidence intervals (CI) were extracted or calculated. Heterogeneity across studies was described with the use of an score (Low: 25, 50%: moderate, 75% low heterogeneity). HR pools inverse variance methods were adopted by Random Effects (RE). Means were standardized across any heterogenous scale limits.
RESULTS
In total 46,510 participants were included in the meta-analysis. Overall, meta-analysis favored the use of ICPIs with an overall survival (OS) HR of 0.74 (95% CI 0.71 to 0.78). Lung cancers showed the most benefit in OS [HR 0.72 (95% 0.66-0.78)] followed by head and neck cancers [HR 0.75 (95% CI 0.66-0.84)] and gastroesophageal junction cancers [HR 0.75 (95% CI 0.61-0.92)]. ICPIs seem to be efficacious at both primary presentation and recurrence [OS HR 0.73 (95% CI 0.68-0.77)] vs. [OS HR 0.79 (95% CI 0.72 to 0.87)] respectively. Interestingly, subgroup analysis comparing studies in which most cancers demonstrated PD-L1 expression vs. those studies in which a minority of cancer demonstrated PD-L1 expression reported similar effect of ICPI use on OS; oddly the data favored ICPI use in studies with a minority of PD-L1 expression. Specifically, studies with minority PD-L1 expression had an HR 0.73 (95% CI 0.68-0.78) vs. studies with majority PD-L1 expression HR 0.76 (95% CI 0.70-0.84). This was maintained even when studies exploring the same cancer site were directly compared. Subgroup analysis was performed comparing the impact on OS subdivided by the specific ICPI used. Where meta-analysis was performed, Nivolumab led to the greatest impact [HR 0.70 (95% CI 0.64-0.77)] with Avelumab failing to reach significance [HR 0.93 (95% CI 0.80-1.06)]. However, overall heterogenicity was high ( = 95%). Finally, the use of ICPIs led to an improved side effect profile when compared with standard chemotherapy [RR 0.85 (95% CI 0.73-0.98)].
CONCLUSION
ICPIs improve survival outcomes in all cancer types. These effects are seen in the primary, recurrent, chemotherapy sensitive, chemotherapy resistant disease. These data support their use as a tumor agnostic therapy. Furthermore, they are well tolerated. However, PD-L1 as a biomarker for the targeting of ICPI use seems problematic. Other biomarkers such as mismatch repair or tumor mutational burden should be explored in randomized trials. In addition, there are still limited trials looking at ICPI use outside of lung cancer.
PubMed: 37250628
DOI: 10.3389/fmed.2023.1192762 -
Lung Cancer (Amsterdam, Netherlands) May 2023Enteric-type adenocarcinoma of the lung (lung-ETAC, former pulmonary enteric adenocarcinoma, PEAC) is a rare subtype of non-small cell lung cancer (NSCLC), which shares... (Meta-Analysis)
Meta-Analysis Review
Enteric-type adenocarcinoma of the lung (lung-ETAC, former pulmonary enteric adenocarcinoma, PEAC) is a rare subtype of non-small cell lung cancer (NSCLC), which shares morphological and immunohistochemical features with lung and colorectal adenocarcinoma. Few data are available on patient prognosis, possible prognostic factors and systemic approach to metastatic disease. We performed a pooled analysis and a systematic review of published lung-ETAC, along with an additional case description. Thirty-one eligible publications were identified, providing data from 126 patients. In the 127 patients overall analyzed, median overall survival (OS) was 56.0 (range 36.7-75.3) months in early-stage patients and 14.0 (range 4.5-23.5) months in those with advanced/metastatic disease. Median disease-free survival (DFS) after radical surgery was 24 (range 22.6-35.1) months. Smoking status (HR 4.304, 95% CI: 1.261-14.693, p = 0.020) and node involvement (HR 1.853, 95% CI: 1.179-2.911, p = 0.007) were the negative independent prognostic factors at multivariate analysis. As regards systemic therapies for advanced cases, no firm conclusions were drawn about the efficacy of lung cancer-oriented chemotherapy regimens as opposed to colon cancer-oriented ones. Molecular analysis of lung-ETAC revealed a relatively high mutational rate, with alterations in several druggable molecular pathways, KRAS and NRAS (31%) were the most frequently mutated oncogenes, followed by ROS1 (15%), RET (13%), BRAF (11%), EGFR (8%) and ALK (6%). Moreover, 3 (15%) out of 20 cases showed DNA mismatch repair deficiency (dMMR). In conclusion, advanced lung-ETAC patients appeared to have a better prognosis compared to other subtypes of NSCLC. Moreover, the mutational rate and microsatellite instability found in lung-ETACs suggest that a significant proportion of these patients could benefit from target therapies and immunotherapy.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Protein-Tyrosine Kinases; Mutation; Proto-Oncogene Proteins; Adenocarcinoma; Adenocarcinoma of Lung; Prognosis; Lung
PubMed: 37015149
DOI: 10.1016/j.lungcan.2023.107176 -
International Journal of Colorectal... Mar 2023The 12-gene recurrence score (RS) is a clinically validated assay which predicts recurrence risk in patients with stage II/III colon cancer. Decisions regarding adjuvant... (Meta-Analysis)
Meta-Analysis Review
Impact of the 12-gene recurrence score in influencing adjuvant chemotherapy prescription in mismatch repair proficient stage II/III colonic carcinoma-a systematic review and meta-analysis.
INTRODUCTION
The 12-gene recurrence score (RS) is a clinically validated assay which predicts recurrence risk in patients with stage II/III colon cancer. Decisions regarding adjuvant chemotherapy may be guided using this assay or based on the judgement of tumour board.
AIMS
To assess the concordance between the RS and MDT decisions regarding adjuvant chemotherapy in colon cancer.
METHODS
A systematic review was performed in accordance with PRISMA guidelines. Meta-analyses were performed using the Mantel-Haenszel method using the Review Manager version 5.4 software.
RESULTS
Four studies including 855 patients with a mean age of 68 years (range: 25-90 years) met inclusion criteria. Overall, 79.2% had stage II disease (677/855) and 20.8% had stage III disease (178/855). For the entire cohort, concordant results between the 12-gene assay and MDT were more likely than discordant (odds ratio (OR): 0.38, 95% confidence interval (CI): 0.25-0.56, P < 0.001). Patients were more likely to have chemotherapy omitted than escalated when using the RS (OR: 9.76, 95% CI: 6.72-14.18, P < 0.001). For those with stage II disease, concordant results between the 12-gene assay and MDT were more likely than discordant (OR: 0.30, 95% CI: 0.17-0.53, P < 0.001). In stage II disease, patients were more likely to have chemotherapy omitted than escalated when using the RS (OR: 7.39, 95% CI: 4.85-11.26, P < 0.001).
CONCLUSIONS
The use of the 12-gene signature refutes the decision of tumour board in 25% of cases, with 75% of discordant decisions resulting in omission of adjuvant chemotherapy. Therefore, it is possible that a proportion of such patients are being overtreated when relying on tumour board decisions alone.
Topics: Humans; Aged; DNA Mismatch Repair; Antineoplastic Combined Chemotherapy Protocols; Neoplasm Staging; Colonic Neoplasms; Chemotherapy, Adjuvant; Carcinoma
PubMed: 36912973
DOI: 10.1007/s00384-023-04364-2 -
JAMA Network Open Feb 2023Although small intestinal adenocarcinomas (SIAs) are rare, they have a poor prognosis, and the optimal treatment strategies are largely unknown. Because of the lack of... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
Although small intestinal adenocarcinomas (SIAs) are rare, they have a poor prognosis, and the optimal treatment strategies are largely unknown. Because of the lack of high-quality evidence, guidelines for colorectal cancer are often followed in the treatment of SIAs.
OBJECTIVE
To review the current evidence regarding survival benefit of systemic therapies, including chemotherapy, targeted agents, and immunotherapy, for patients with SIAs.
DATA SOURCES
Following the Preferred Reporting Items for Systematic Reviews and Meta-analyses, MEDLINE and Embase were searched for articles published from January 1, 2005, until June 1, 2022.
STUDY SELECTION
Retrospective cohort studies and prospective phase 2 or 3 trials describing survival after systemic therapies for patients with SIAs were eligible for inclusion. Assessment of study eligibility was blinded and performed by 3 reviewers.
DATA EXTRACTION AND SYNTHESIS
The reviewers independently extracted data. Random effects, inverse variance, pairwise meta-analyses were performed.
MAIN OUTCOMES AND MEASURES
Primary outcomes were overall survival (OS) and progression-free survival (PFS) of patients with SIAs after systemic therapies. Measures of interest included hazard ratios for survival and median survival times.
RESULTS
Overall, 57 retrospective cohort and phase 2 studies of 35 176 patients were included. Adjuvant chemotherapy, generally fluoropyrimidine-based, was associated with increased OS in stage I to III SIAs (hazard ratio [HR], 0.60; 95% CI, 0.53-0.68), especially in stage III tumors (HR, 0.55; 95% CI, 0.48-0.64), irrespective of tumor localization. Palliative chemotherapy was also associated with an OS benefit (HR, 0.48; 95% CI, 0.40-0.58). Fluoropyrimidine-oxaliplatin combinations were superior to other regimens (OS: HR, 0.54; 95% CI, 0.30-0.99; PFS: HR, 0.46; 95% CI, 0.30-0.71). Furthermore, bevacizumab added to chemotherapy compared with chemotherapy alone was associated with significantly prolonged PFS (HR, 0.62; 95% CI, 0.43-0.89). Immunotherapy showed a 50% overall response rate in previously treated defective mismatch repair tumors.
CONCLUSIONS AND RELEVANCE
In this systematic review and meta-analysis, adjuvant and palliative chemotherapy were both associated with improved survival of patients with SIAs, especially fluoropyrimidine-based regimens and fluoropyrimidine-oxaliplatin combinations. Adding bevacizumab to chemotherapy appears to prolong PFS and deserves further investigation. Immunotherapy seems beneficial and should be considered for patients with defective mismatch repair tumors. International collaborations should be undertaken to confirm and improve efficacy of systemic therapies for patients with SIAs.
Topics: Humans; Bevacizumab; Retrospective Studies; Oxaliplatin; Prospective Studies; Adenocarcinoma
PubMed: 36826817
DOI: 10.1001/jamanetworkopen.2023.0631