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1.
Clin Epigenetics ; 14(1): 3, 2022 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-34991708

RESUMO

BACKGROUND: DNA mismatch repair proficient (pMMR) metastatic colorectal cancer (mCRC) is not responsive to pembrolizumab monotherapy. DNA methyltransferase inhibitors can promote antitumor immune responses. This clinical trial investigated whether concurrent treatment with azacitidine enhances the antitumor activity of pembrolizumab in mCRC. METHODS: We conducted a phase 2 single-arm trial evaluating activity and tolerability of pembrolizumab plus azacitidine in patients with chemotherapy-refractory mCRC (NCT02260440). Patients received pembrolizumab 200 mg IV on day 1 and azacitidine 100 mg SQ on days 1-5, every 3 weeks. A low fixed dose of azacitidine was chosen in order to reduce the possibility of a direct cytotoxic effect of the drug, since the main focus of this study was to investigate its potential immunomodulatory effect. The primary endpoint of this study was overall response rate (ORR) using RECIST v1.1., and secondary endpoints were progression-free survival (PFS) and overall survival (OS). Tumor tissue was collected pre- and on-treatment for correlative studies. RESULTS: Thirty chemotherapy-refractory patients received a median of three cycles of therapy. One patient achieved partial response (PR), and one patient had stable disease (SD) as best confirmed response. The ORR was 3%, median PFS was 1.9 months, and median OS was 6.3 months. The combination regimen was well-tolerated, and 96% of treatment-related adverse events (TRAEs) were grade 1/2. This trial was terminated prior to the accrual target of 40 patients due to lack of clinical efficacy. DNA methylation on-treatment as compared to pre-treatment decreased genome wide in 10 of 15 patients with paired biopsies and was significantly lower in gene promoter regions after treatment. These promoter demethylated genes represented a higher proportion of upregulated genes, including several immune gene sets, endogenous retroviral elements, and cancer-testis antigens. CD8+ TIL density trended higher on-treatment compared to pre-treatment. Higher CD8+ TIL density at baseline was associated with greater likelihood of benefit from treatment. On-treatment tumor demethylation correlated with the increases in tumor CD8+ TIL density. CONCLUSIONS: The combination of pembrolizumab and azacitidine is safe and tolerable with modest clinical activity in the treatment for chemotherapy-refractory mCRC. Correlative studies suggest that tumor DNA demethylation and immunomodulation occurs. An association between tumor DNA demethylation and tumor-immune modulation suggests immune modulation and may result from treatment with azacitidine. Trial registration ClinicalTrials.gov, NCT02260440. Registered 9 October 2014, https://clinicaltrials.gov/ct2/show/NCT02260440 .

2.
Adv Anat Pathol ; 29(1): 37-47, 2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-34879037

RESUMO

Histology is used to confirm the diagnosis of inflammatory bowel disease, exclude superimposed infections, and to evaluate for dysplasia. Histology has rarely been used to measure disease activity and guide therapy despite evidence that histologic measurements have value in predicting important clinical outcomes. More recently, there have been numerous studies supporting a role for histologic disease activity measurements in predicting a variety of outcomes including relapse, hospitalizations, steroid use, and dysplasia. The histologic assessment was superior to endoscopic measurements in many of these studies. This review will summarize the recent literature regarding histologic disease activity measurements in ulcerative colitis and Crohn disease. A detailed description of histologic scoring systems will also be provided to provide pathologists with the necessary tools to accurately measure disease activity.


Assuntos
Colite Ulcerativa , Doenças Inflamatórias Intestinais , Colite Ulcerativa/diagnóstico , Humanos , Doenças Inflamatórias Intestinais/diagnóstico
3.
Hum Mutat ; 2021 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-34816535

RESUMO

Heterozygous POLE or POLD1 germline pathogenic variants (PVs) cause polymerase proofreading associated polyposis (PPAP), a constitutional polymerase proofreading deficiency that typically presents with colorectal adenomas and carcinomas in adulthood. Constitutional mismatch-repair deficiency (CMMRD), caused by germline bi-allelic PVs affecting one of four MMR genes, results in a high propensity for the hematological, brain, intestinal tract, and other malignancies in childhood. Nonmalignant clinical features, such as skin pigmentation alterations, are found in nearly all CMMRD patients and are important diagnostic markers. Here, we excluded CMMRD in three cancer patients with highly suspect clinical phenotypes but identified in each a constitutional heterozygous POLE PV. These, and two additional POLE PVs identified in published CMMRD-like patients, have not previously been reported as germline PVs despite all being well-known somatic mutations in hyper-mutated tumors. Together, these five cases show that specific POLE PVs may have a stronger "mutator" effect than known PPAP-associated POLE PVs and may cause a CMMRD-like phenotype distinct from PPAP. The common underlying mechanism, that is, a constitutional replication error repair defect, and a similar tumor spectrum provide a good rationale for monitoring these patients with a severe constitutional polymerase proofreading deficiency according to protocols proposed for CMMRD.

4.
J Gastrointest Surg ; 2021 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-34291365

RESUMO

BACKGROUND: Appendiceal adenocarcinoma (AA) represents a heterogenous group of neoplasms with distinct histologic features. The role and efficacy of adjuvant chemotherapy (AC) in non-metastatic disease remain controversial. The aim of this study was to ascertain the role of AC in non-metastatic AA in a national cohort of patients. METHODS: The National Cancer Database (NCDB) was queried to identify patients diagnosed with stage I-III mucinous and nonmucinous AA who underwent right hemicolectomy between 2006 and 2016. Kaplan-Meier and Cox regression analyses were used to evaluate the impact of AC on overall survival (OS) stratified by each pathologic stage. RESULTS: A total of 1433 mucinous and 1954 nonmucinous AA were identified; 578 (40%) and 722 (40%) received AC respectively. In both AC groups, there was a higher proportion of T4 disease, lymph node metastasis, pathologic stage III, and poorly/undifferentiated grade (all P<0.05). On unadjusted analysis, there was no significant association between AC and OS for stage I-III mucinous AA. For nonmucinous AA, AC significantly improved OS only for stage II and III disease. On adjusted analysis, AC was independently associated with an improved OS for stage III nonmucinous AA (HR: 0.61, 95%CI 0.45-0.84, P=0.002), while for mucinous AA, AC was associated with worse outcomes for stage I/II disease (HR: 1.4, 95%CI 1.02-1.91, P=0.038) and had no significant association with OS for stage III disease. CONCLUSION: This current analysis of a national cohort of patients suggests a beneficial role for AC in stage III nonmucinous AA and demonstrates no identifiable benefit for stage I-III mucinous AA.

5.
Histopathology ; 79(5): 826-835, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34121230

RESUMO

AIMS: Neoadjuvant therapy is the recommended treatment for locally advanced rectal adenocarcinoma; however, there remains significant variability in response to therapy. Tumour protein 53 (TP53) has been associated with therapy response and prognosis with conflicting data. Recently, we demonstrated that immune cell density and intratumoral budding (ITB) are predictive factors in rectal cancer. We investigated the predictive value of TP53 immunohistochemistry with CD8+ T cell density and ITB on pretreatment biopsies of rectal adenocarcinoma for response to neoadjuvant therapy. METHODS AND RESULTS: Pretreatment biopsies of rectal adenocarcinoma from 117 patients with neoadjuvant therapy were analysed for TP53 expression by immunohistochemistry, ITB, CD8+ T cell density and mismatch repair protein (MMR) status. Most rectal adenocarcinomas displayed aberrant TP53 expression (86 of 117, 74%). Compared to wild-type TP53, aberrant TP53 expression was associated with proficient MMR status (P = 0.003) and low CD8+ T cell density (P = 0.001). Aberrant TP53 was significantly associated with a partial to poor response to neoadjuvant therapy [odds ratio (OR) = 2.42, 95% confidence interval (CI) = 1.04-5.62, P = 0.04]. A combined histopathological risk score (HRS) was created using CD8+ T cell density, ITB and TP53 expression. Patients were separated into low (none to one factor) and high (two to three factors) HRS categories. In the multivariable model, patients with a high HRS were 3.25-fold more likely to have a partial or poor response to neoadjuvant therapy (95% CI = 1.48-7.11, P = 0.003). CONCLUSIONS: Our study demonstrates that aberrant TP53 expression, high ITB and low CD8+ T cell density in pretreatment biopsies can help predict response to neoadjuvant therapy. These biomarkers may be helpful in identifying patients at risk for therapy resistance.

6.
Inflamm Bowel Dis ; 2021 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-34106256

RESUMO

BACKGROUND: Eosinophils have been implicated in the pathogenesis of ulcerative colitis and have been associated with disease course and therapeutic response. However, associations between eosinophil density, histologic activity, and clinical features have not been rigorously studied. METHODS: A deep learning algorithm was trained to identify eosinophils in colonic biopsies and validated against pathologists' interpretations. The algorithm was applied to sigmoid colon biopsies from a cross-sectional cohort of 88 ulcerative colitis patients with histologically active disease as measured by the Geboes score and Robarts histopathology index (RHI). Associations between eosinophil density, histologic activity, and clinical features were determined. RESULTS: The eosinophil deep learning algorithm demonstrated almost perfect agreement with manual eosinophil counts determined by 4 pathologists (interclass correlation coefficients: 0.805-0.917). Eosinophil density varied widely across patients (median 113.5 cells per mm2, interquartile range 108.9). There was no association between eosinophil density and RHI (P = 0.5). Significant differences in eosinophil density were seen between patients with Montreal E3 vs E2 disease (146.2 cells per mm2 vs 88.2 cells per mm2, P = 0.005). Patients on corticosteroids had significantly lower eosinophil density (62.9 cells per mm2 vs 124.1 cells per mm2, P = 0.006). No association between eosinophil density and biologic use was observed (P = 0.5). CONCLUSIONS: We developed a deep learning algorithm to quantify eosinophils in colonic biopsies. Eosinophil density did not correlate with histologic activity but did correlate with disease extent and corticosteroid use. Future studies applying this algorithm in larger cohorts with longitudinal follow-up are needed to further elucidate the role of eosinophils in ulcerative colitis.

7.
Gut ; 2021 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-33952604

RESUMO

OBJECTIVE: Effective medical therapy and validated trial outcomes are lacking for small bowel Crohn's disease (CD) strictures. Histopathology of surgically resected specimens is the gold standard for correlation with imaging techniques. However, no validated histopathological scoring systems are currently available for small bowel stricturing disease. We convened an expert panel to evaluate the appropriateness of histopathology scoring systems and items generated based on panel opinion. DESIGN: Modified RAND/University of California Los Angeles methodology was used to determine the appropriateness of 313 candidate items related to assessment of CD small bowel strictures. RESULTS: In this exercise, diagnosis of naïve and anastomotic strictures required increased bowel wall thickness, decreased luminal diameter or internal circumference, and fibrosis of the submucosa. Specific definitions for stricture features and technical sampling parameters were also identified. Histopathologically, a stricture was defined as increased thickness of all layers of the bowel wall, fibrosis of the submucosa and bowel wall, and muscularisation of the submucosa. Active mucosal inflammatory disease was defined as neutrophilic inflammation in the lamina propria and any crypt or intact surface epithelium, erosion, ulcer and fistula. Chronic mucosal inflammatory disease was defined as crypt architectural distortion and loss, pyloric gland metaplasia, Paneth cell hyperplasia, basal lymphoplasmacytosis, plasmacytosis and fibrosis, or prominent lymphoid aggregates at the mucosa/submucosa interface. None of the scoring systems used to assess CD strictures were considered appropriate for clinical trials. CONCLUSION: Standardised assessment of gross pathology and histopathology of CD small bowel strictures will improve clinical trial efficiency and aid drug development.

8.
Histopathology ; 79(4): 573-583, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33847404

RESUMO

AIMS: The hallmark of Lynch syndrome (LS) is DNA mismatch repair protein (MMR) deficiency. Recently, MMR deficiency in non-neoplastic colonic crypts has been identified as a novel indicator of LS. We aimed to determine whether MMR-deficient non-neoplastic endometrial glands can distinguish patients with and without LS, and to compare the level of MMR deficiency in the normal endometrium and colon in LS patients. METHODS AND RESULTS: We evaluated the immunohistochemical expression of MMR proteins in the normal endometrial mucosa from 64 patients, including 34 patients with confirmed LS (17 with endometrial cancer and 17 without cancer), 30 patients with endometrial cancer without LS (10 with tumours with MLH1 promoter hypermethylation and 20 with MMR-proficient tumours), and in the normal colonic mucosa from 30 LS patients. MMR-deficient non-neoplastic endometrial glands were identified in 47% of LS patients and in no patients without LS (P < 0.001). MMR-deficient non-neoplastic glands were more often identified in LS patients with endometrial cancer (65%) than in those without endometrial cancer (29%) (P = 0.04). In contrast to what was seen in the normal colon, MMR-deficient glands in the normal endometrium were seen as large, contiguous groups, ranging in number from two to 101 (87% versus 45%, P = 0.02). MMR-deficient glands were identified at a higher density in the endometrium than in the colon in LS patients (median number of MMR-deficient glands, 22 versus two, P = 0.02). CONCLUSIONS: Our findings indicate that MMR-deficient non-neoplastic endometrial glands constitute an indicator of LS, and that MMR-deficient glands in the endometrium are present in a pattern of contiguous large groups.

9.
J Crohns Colitis ; 15(9): 1481-1490, 2021 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-33687061

RESUMO

BACKGROUND AND AIMS: To correlate histologic activity in surveillance colonoscopies with the development of colorectal neoplasia in ulcerative colitis [UC]. METHODS: Colorectal biopsies during surveillance [N = 764] from 52 UC patients with colorectal neoplasia were compared to 122 patients without neoplasia enrolled in a prospective natural history registry. All biopsies were scored using validated histologic scoring systems (Geboes score, Nancy histopathologic index [NHI], and Robarts histopathologic index [RHI]). Clinical, endoscopic, and histologic data were correlated with the development of colorectal neoplasia. RESULTS: In multivariable analysis, mean RHI (hazard ratio [HR] 1.07 for each 1-unit increase in RHI, 95% confidence interval [CI] 1.03-1.12, p = 0.002) and mean NHI [HR 1.89 for each 1-unit increase in NHI, 95% CI 1.34-2.67, p = 0.002] for the entire surveillance period were significantly associated with colorectal neoplasia development. Shorter surveillance interval and increasing age were associated with increased risk of neoplasia development whereas mean Mayo endoscopic score was not significant. To generate a clinically useful measure of neoplasia risk, mean histologic activity in the preceding 5 years before the study endpoint was correlated with neoplasia development. In the preceding 5 years of surveillance, a mean RHI ≥ 8 had a 7.53-fold increased risk [95% CI 2.56-12.16, p < 0.001] and mean NHI ≥ 1.9 had a 5.89-fold increased risk [95% CI 2.18-15.92, p < 0.001] of developing colorectal neoplasia. CONCLUSIONS: Persistent histologic activity during multiple surveillance episodes is an independent predictor of colorectal neoplasia. Mean RHI and mean NHI during a 5-year colonoscopic surveillance period can be used to assess risk for colorectal neoplasia and optimize UC surveillance.

10.
Aliment Pharmacol Ther ; 53(10): 1108-1117, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33735522

RESUMO

BACKGROUND: Pouchitis is a condition with large unmet medical needs and no approved therapies. Lack of validated instruments to measure disease activity and treatment response is a major barrier to drug development. AIM: To conduct a modified RAND/University of California Los Angeles appropriateness process to produce a standardised assessment of pouchitis disease activity in clinical trials. METHODS: A list of 164 items generated upon a systematic review and expert opinion were rated based on a 9-point scale (appropriate, uncertain and inappropriate), by a panel including 16 gastroenterologists, surgeons and histopathologists. RESULTS: Items rated as appropriate to evaluate in pouchitis clinical trials were: (a) clinical: stool frequency and faecal urgency; (b) endoscopic: primary assessment in the pouch body according to the percentage of affected area (<50%, 50%-75% and >75%), evaluation of the presence of ulcers/erosions according to size (erosions <5 mm, ulcers ≥5 mm to 2 cm and large ulcers >2 cm) and ulcerated area (<10%, 10%-30% and >30%); (c) histologic: two biopsies from each segment, from the ulcer's edge when present, or endoscopically normal areas, assessment of lamina propria chronic inflammation, epithelial and lamina propria neutrophils, epithelial damage, erosions and ulcers; and (d) clinical trial inclusion/outcome criteria: minimum histologic disease activity for inclusion, a primary endpoint based on stool frequency and assessment of clinical, endoscopic and histologic response and remission. The overall majority of items surveyed (100/164) were rated 'uncertain'. CONCLUSION: We conducted a RAND/UCLA appropriateness process to help inform measurement of pouchitis disease activity within clinical trials and foster the development of novel therapies.


Assuntos
Pouchite , Biópsia , Consenso , Endoscopia , Humanos , Los Angeles , Pouchite/diagnóstico
12.
Gastroenterology ; 160(7): 2291-2302, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33610533

RESUMO

BACKGROUND & AIMS: Histopathology is an emerging treatment target in ulcerative colitis (UC) clinical trials. Our aim was to provide guidance on standardizing biopsy collection protocols, identifying optimal evaluative indices, and defining thresholds for histologic response and remission after treatment. METHODS: An international, interdisciplinary expert panel of 19 gastroenterologists and gastrointestinal pathologists was assembled. A modified RAND/University of California, Los Angeles appropriateness methodology was used to address relevant issues. A total of 138 statements were derived from a systematic review of the literature and expert opinion. Each statement was anonymously rated as appropriate, uncertain, or inappropriate using a 9-point scale. Survey results were reviewed and discussed before a second round of voting. RESULTS: Histologic measurements collected using a uniform biopsy strategy are important for assessing disease activity and determining therapeutic efficacy in UC clinical trials. Multiple biopsy strategies were deemed acceptable, including segmental biopsies collected according to the endoscopic appearance. Biopsies should be scored for architectural change, lamina propria chronic inflammation, basal plasmacytosis, lamina propria and epithelial neutrophils, epithelial damage, and erosions/ulcerations. The Geboes score, Robarts Histopathology Index, and Nancy Index were considered appropriate for assessing histologic activity; use of the modified Riley score and Harpaz Index were uncertain. Histologic activity at baseline should be required for enrollment, recognizing this carries operational implications. Achievement of histologic improvement or remission was considered an appropriate and realistic therapeutic target. Current histologic indices require validation for pediatric populations. CONCLUSIONS: These recommendations provide a framework for standardized implementation of histopathology in UC trials. Additional work is required to address operational considerations and areas of uncertainty.

13.
Histopathology ; 79(3): 391-405, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33590485

RESUMO

AIMS: To develop and validate a deep learning algorithm to quantify a broad spectrum of histological features in colorectal carcinoma. METHODS AND RESULTS: A deep learning algorithm was trained on haematoxylin and eosin-stained slides from tissue microarrays of colorectal carcinomas (N = 230) to segment colorectal carcinoma digitised images into 13 regions and one object. The segmentation algorithm demonstrated moderate to almost perfect agreement with interpretations by gastrointestinal pathologists, and was applied to an independent test cohort of digitised whole slides of colorectal carcinoma (N = 136). The algorithm correctly classified mucinous and high-grade tumours, and identified significant differences between mismatch repair-proficient and mismatch repair-deficient (MMRD) tumours with regard to mucin, inflammatory stroma, and tumour-infiltrating lymphocytes (TILs). A cutoff of >44.4 TILs per mm2 carcinoma gave a sensitivity of 88% and a specificity of 73% in classifying MMRD carcinomas. Algorithm measures of tumour budding (TB) and poorly differentiated clusters (PDCs) outperformed TB grade derived from routine sign-out, and compared favourably with manual counts of TB/PDCs with regard to lymphatic, venous and perineural invasion. Comparable associations were seen between algorithm measures of TB/PDCs and manual counts of TB/PDCs for lymph node metastasis (all P < 0.001); however, stronger correlations were seen between the proportion of positive lymph nodes and algorithm measures of TB/PDCs. Stronger associations were also seen between distant metastasis and algorithm measures of TB/PDCs (P = 0.004) than between distant metastasis and TB (P = 0.04) and TB/PDC counts (P = 0.06). CONCLUSIONS: Our results highlight the potential of deep learning to identify and quantify a broad spectrum of histological features in colorectal carcinoma.

14.
Aliment Pharmacol Ther ; 53(7): 784-793, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33410551

RESUMO

BACKGROUND: Targeting histological remission or response in Crohn's disease (CD) is not recommended in clinical practice guidelines or as an outcome in clinical trials due to uncertainties regarding index validity and prognostic relevance. AIMS: To conduct a modified RAND/University of California Los Angeles appropriateness process with the goal of producing a framework to standardise histological assessment of CD activity in clinical trials. METHODS: A total of 115 statements generated from literature review and expert opinion were rated on a scale of 1-9 by a panel of 11 histopathologists and 6 gastroenterologists. Statements were classified as inappropriate, uncertain or appropriate based upon the median panel rating and degree of disagreement. RESULTS: The panellists considered it important to measure histological activity in clinical trials to determine efficacy and that absence of neutrophilic inflammation is an appropriate histological target. They were uncertain whether the Global Histological Activity Score was an appropriate instrument for measuring histological activity. The Geboes Score and Robarts Histopathology Index were considered appropriate. Two biopsies from five segments should be biopsied, and the colon and the ileum should be analysed separately for all indices. Endoscopic mucosal appearance should guide biopsy procurement site with biopsies taken from the ulcer edge, or the most macroscopically inflamed area in the absence of ulcers. CONCLUSION: We evaluated the appropriateness of items for assessing histological disease activity in CD clinical trials. These items will be used to develop a novel histological index.


Assuntos
Ensaios Clínicos como Assunto , Consenso , Doença de Crohn , Colo , Doença de Crohn/diagnóstico , Doença de Crohn/terapia , Humanos , Íleo , Los Angeles , Resultado do Tratamento
15.
Mod Pathol ; 34(1): 171-183, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32661298

RESUMO

Tumor budding and CD8-positive (+) T-cells are recognized as prognostic factors in colorectal adenocarcinoma. We assessed CD8+ T-cell density and intratumoral budding in pretreatment rectal cancer biopsies to determine if they are predictive biomarkers for response to neoadjuvant therapy and survival. Pretreatment biopsies of locally advanced rectal adenocarcinoma from 117 patients were evaluated for CD8+ T-cell density using automated quantitative digital image analysis and for intratumoral budding and correlated with clinicopathological variables on postneoadjuvant surgical resection specimens, response to neoadjuvant therapy, and survival. Patients with high CD8+ T-cell density (≥157 per mm2) on biopsy were significantly more likely to exhibit complete/near complete response to neoadjuvant therapy (66% vs. 33%, p = 0.001) and low tumor stage (0 or I) on resection (62% vs. 30%, p = 0.001) compared with patients with low CD8+ T-cell density. High CD8+ T-cell density was an independent predictor of response to neoadjuvant therapy with a 2.63 higher likelihood of complete response (95% CI 1.04-6.65, p = 0.04) and a 3.66 higher likelihood of complete/near complete response (95% CI 1.60-8.38, p = 0.002). The presence of intratumoral budding on biopsy was significantly associated with a reduced likelihood of achieving complete/near complete response to neoadjuvant therapy (odds ratio 0.36, 95% CI 0.13-0.97, p = 0.048). Patients with intratumoral budding on biopsy had a significantly reduced disease-free survival compared with patients without intratumoral budding (5-year survival 39% vs 87%, p < 0.001). In the multivariable model, the presence of intratumoral budding on biopsy was associated with a 3.35-fold increased risk of tumor recurrence (95% CI 1.25-8.99, p = 0.02). In conclusion, CD8+ T-cell density and intratumoral budding in pretreatment biopsies of rectal adenocarcinoma are independent predictive biomarkers of response to neoadjuvant therapy and intratumoral budding associates with patient survival. These biomarkers may be helpful in selecting patients who will respond to neoadjuvant therapy and identifying patients at risk for recurrence.


Assuntos
Adenocarcinoma/terapia , Linfócitos T CD8-Positivos/imunologia , Movimento Celular , Quimiorradioterapia Adjuvante , Linfócitos do Interstício Tumoral/imunologia , Terapia Neoadjuvante , Neoplasias Retais/terapia , Adenocarcinoma/imunologia , Adenocarcinoma/mortalidade , Adenocarcinoma/secundário , Idoso , Idoso de 80 Anos ou mais , Automação Laboratorial , Biópsia , Tomada de Decisão Clínica , Bases de Dados Factuais , Progressão da Doença , Intervalo Livre de Doença , Feminino , Humanos , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Valor Preditivo dos Testes , Neoplasias Retais/imunologia , Neoplasias Retais/mortalidade , Neoplasias Retais/patologia , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Microambiente Tumoral/imunologia
16.
Aliment Pharmacol Ther ; 53(1): 150-159, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33146440

RESUMO

BACKGROUND: Colitis is a significant complication of immune checkpoint inhibitors (ICI). Currently, clinical and endoscopic severity are used to guide therapy. AIMS: To investigate associations between clinical, endoscopic, and histological features with outcomes METHODS: We identified 149 patients from seven institutions with biopsy-proven ICI colitis. Biopsies were evaluated for histological features including the Geboes score, and the Robarts histopathological index (RHI) was calculated. Clinical, endoscopic, and histological data were tested for associations with biological use and adverse colitis outcomes (biological-refractory colitis, colectomy or death from colitis). RESULTS: Three mutually exclusive histological patterns were identified: acute colitis, chronic active colitis and microscopic colitis. Microscopic colitis was associated with older age (68.5 vs 61 years for acute colitis pattern, P = 0.02) and longer time to colitis (5.5 vs 3 months for the other patterns, P = 0.05). Biological use was associated with earlier time to colitis (2 vs 3 months, P = 0.04) and higher RHI (18 vs 12, P = 0.007). On multivariate analysis, RHI ≥14 was associated with biological use with an odds ratio of 4.5 (95% CI 1.4-13.8; P = 0.01). Adverse colitis outcomes were associated with shorter time to colitis (2 vs 3 months, P = 0.008) and higher RHI (24 vs 14, P = 0.001). On multivariate analysis, RHI ≥24 was associated with adverse colitis outcomes with an odds ratio 9.5 (95% CI 2.1-42.3 P = 0.003). CONCLUSION: Histological activity as measured by RHI is the only factor independently associated with biological use and adverse colitis outcomes. Prospective studies are needed to validate these findings to determine if histological activity should be incorporated into therapeutic algorithms.


Assuntos
Colite Ulcerativa , Colite , Idoso , Colite/induzido quimicamente , Humanos , Inibidores de Checkpoint Imunológico , Pessoa de Meia-Idade , Estudos Prospectivos , Índice de Gravidade de Doença
17.
Histopathology ; 77(5): 798-809, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32557796

RESUMO

AIMS: Peritoneal spread is the most common route of metastasis in appendiceal goblet cell adenocarcinoma. The aim of this study was to assess the prognostic significance of the World Health Organization (WHO) 5th edition grading criteria in peritoneal metastases of goblet cell adenocarcinoma. METHODS AND RESULTS: We evaluated the clinicopathological features and survival of 63 patients with peritoneal metastasis of goblet cell adenocarcinoma who underwent cytoreductive surgery with hyperthermic intraperitoneal chemoperfusion (CRS-HIPEC), stratified according to the WHO 5th edition and the Tang et al. grading schemes. The patients were also compared with 120 patients with peritoneal metastasis of appendiceal mucinous neoplasia. Most (73%) peritoneal metastases of goblet cell adenocarcinoma were WHO Grade 3 (G3), there being fewer cases of Grade 2 (G2) (16%) and Grade 1 (G1) (11%) disease. No significant differences in overall survival were observed between WHO G1 and G2 tumours or between the three Tang grades. In the multivariable model of survival, WHO G3 [hazard ratio (HR) 2.81, 95% confidence interval (CI) 1.02-7.70] and the presence of >50% extracellular mucin (HR 2.30, 95% CI 1.09-4.88) were associated with reduced overall survival for patients with goblet cell adenocarcinoma. As compared with patients with peritoneal metastasis of mucinous neoplasia, patients with goblet cell adenocarcinoma had significantly reduced survival (median overall survival of 37 months versus 102 months, P < 0.001), which was attributed to the reduced survival of patients with G1/G2 goblet cell adenocarcinoma as compared with patients with G1 mucinous neoplasia (median survival of 98 months versus 204 months, P < 0.001). CONCLUSIONS: Grade of peritoneal goblet cell adenocarcinoma determined according to the WHO 5th edition criteria is a clinically relevant measure that independently predicts survival in patients treated with CRS-HIPEC.


Assuntos
Neoplasias do Apêndice/patologia , Tumor Carcinoide/secundário , Neoplasias Peritoneais/secundário , Adulto , Idoso , Neoplasias do Apêndice/mortalidade , Neoplasias do Apêndice/terapia , Tumor Carcinoide/mortalidade , Tumor Carcinoide/terapia , Procedimentos Cirúrgicos de Citorredução/mortalidade , Feminino , Humanos , Quimioterapia Intraperitoneal Hipertérmica/mortalidade , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Neoplasias Peritoneais/mortalidade , Neoplasias Peritoneais/terapia , Estudos Retrospectivos , Resultado do Tratamento , Organização Mundial da Saúde
18.
Histopathology ; 77(3): 481-491, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32431062

RESUMO

AIMS: Abnormal p53 protein expression detected by immunohistochemistry (IHC) in Barrett's oesophagus (BO) is reported to be a prognostic biomarker for progression to high-grade dysplasia (HGD) or oesophageal adenocarcinoma (OAC). We evaluated our use of p53 IHC for patients with BO under surveillance from 2010 to 2016 in a single academic institution. METHODS AND RESULTS: We identified 78 patients under surveillance for BO who had biopsies evaluated for abnormal p53 expression in conjunction with routine histology and 892 patients who had histological evaluation alone. All available p53 IHC slides were rescored as wild-type or abnormal. We evaluated the risk of subsequent diagnosis with HGD and OAC. p53-tested patients were significantly more likely to be diagnosed with indefinite dysplasia (IND) or low-grade dysplasia (LGD), compared to patients who were not tested (79.5 versus 10.8%, P = 7.4 × 10-40 ). Almost half (46.9%) of patients with abnormal p53 expression were diagnosed with HGD or OAC within 5 years, compared to 5.9% with wild-type p53, and 7.6% of patients not tested (P = 2.6 × 10-18 ). However, this difference was heavily influenced by other risk factors, including dysplasia grade, in multivariate analyses. In the subgroup of patients diagnosed with IND (n = 109), abnormal p53 expression was associated with a fourfold increase (1.2-13.3, P = 0.023) in risk of HGD/OAC relative to untested patients diagnosed with IND, independent of other risk factors. CONCLUSION: In patients under surveillance for BO in a single academic institution, we found evidence that selective use of p53 IHC in conjunction with routine histology modestly improved risk stratification by identifying patients with IND at higher risk of a subsequent diagnosis of HGD or OAC.


Assuntos
Esôfago de Barrett/patologia , Biomarcadores Tumorais/análise , Lesões Pré-Cancerosas/patologia , Proteína Supressora de Tumor p53/biossíntese , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Progressão da Doença , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Adulto Jovem
19.
Am J Surg Pathol ; 44(7): 991-1001, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32205483

RESUMO

Despite their association with DNA mismatch repair (MMR) protein deficiency, colonic adenocarcinomas with mucinous, signet ring cell, or medullary differentiation have not been associated with improved survival compared with conventional adenocarcinomas in most studies. Recent studies indicate that increased T-cell infiltration in the tumor microenvironment has a favorable prognostic effect in colonic adenocarcinoma. However, the prognostic effect of tumor-associated T cells has not been evaluated in histologic subtypes of colonic adenocarcinoma. We evaluated CD8-positive T-cell density in 259 patients with colonic adenocarcinoma, including 113 patients with tumors demonstrating mucinous, signet ring cell, or medullary differentiation, using a validated automated quantitative digital image analysis platform and correlated CD8-positive T-cell density with histopathologic variables, MMR status, molecular alterations, and survival. CD8-positive T-cell densities were significantly higher for MMR protein-deficient tumors (P<0.001), BRAF V600E mutant tumors (P=0.004), and tumors with medullary differentiation (P<0.001) but did not correlate with mucinous or signet ring cell histology (P>0.05 for both). In the multivariable model of factors predicting disease-free survival, increased CD8-positive T-cell density was associated with improved survival both in the entire cohort (hazard ratio=0.34, 95% confidence interval, 0.15-0.75, P=0.008) and in an analysis of patients with tumors with mucinous, signet ring cell, or medullary differentiation (hazard ratio=0.06, 95% confidence interval, 0.01-0.54, P=0.01). The prognostic effect of CD8-positive T-cell density was independent of tumor stage, MMR status, KRAS mutation, and BRAF mutation. Venous invasion was the only other variable independently associated with survival in both the entire cohort and in patients with tumors with mucinous, signet ring cell, or medullary differentiation. In summary, our results indicate that the prognostic value of MMR protein deficiency is most likely attributed to increased tumor-associated CD8-positive T cells and that automated quantitative CD8 T-cell analysis is a better biomarker of patient survival, particularly in patients with tumors demonstrating mucinous, signet ring cell, or medullary differentiation.


Assuntos
Adenocarcinoma/diagnóstico , Biomarcadores Tumorais/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Neoplasias do Colo/diagnóstico , Reparo de Erro de Pareamento de DNA , Proteínas de Ligação a DNA/deficiência , Adenocarcinoma/metabolismo , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Adulto , Idoso , Biomarcadores Tumorais/deficiência , Neoplasias do Colo/metabolismo , Neoplasias do Colo/mortalidade , Neoplasias do Colo/patologia , Feminino , Seguimentos , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida
20.
Hum Pathol ; 99: 53-61, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32222462

RESUMO

The switch/sucrose nonfermenting (SWI/SNF) nucleosome complex consists of several proteins that are involved in cellular proliferation and tumor suppression. The aim of this study was to correlate immunohistochemical expression of four SWI/SNF complex subunits, SMARCA2, SMARCB1, SMARCA4, and ARID1A, with clinicopathologic and molecular features and patient survival in 338 patients with colorectal adenocarcinoma using a tissue microarray approach. Twenty-three (7%) colorectal adenocarcinomas demonstrated deficient SWI/SNF expression: 7 had SMARCA2 deficiency, 12 had ARID1A deficiency, and 4 had both SMARCA2 and ARID1A deficiency. No cases were SMARCB1 or SMARCA4 deficient. Twelve (52%) SWI/SNF complex-deficient tumors demonstrated mismatch repair (MMR) deficiency (p = 0.02), 6 (26%) showed medullary differentiation (p = 0.001), and 9 were negative for CDX2 expression (p < 0.001). Among the MMR-deficient SWI/SNF complex-deficient tumors, 8 were sporadic MLH1 deficient, and 4 were seen in patients with Lynch syndrome. Compared with tumors with ARID1A deficiency alone, SMARCA2-deficient tumors were less likely to exhibit MMR deficiency (27% vs. 75%, p = 0.04), medullary differentiation (0% vs. 50%, p = 0.01), and mucinous differentiation (0% vs. 42%, p = 0.04). Conventional gland-forming histology was more often identified in SMARCA2-deficient tumors (11/11, 100%) than in tumors with ARID1A deficiency alone (4/12, 33%) (p = 0.001). There was no difference in KRAS mutation, BRAF mutation, stage, disease-specific survival, or disease-free survival for patients stratified by SWI/SNF expression (all with p > 0.05). In conclusion, SMARCA2-deficient and ARID1A-deficient colorectal carcinomas had distinctly different clinicopathologic features, with ARID1A-deficient tumors exhibiting medullary and mucinous differentiation and MMR deficiency and SMARCA2-deficient tumors demonstrating conventional gland-forming histologic growth with less frequent MMR deficiency.


Assuntos
Adenocarcinoma/química , Biomarcadores Tumorais/análise , Neoplasias Colorretais/química , DNA Helicases/análise , Proteínas de Ligação a DNA/análise , Proteínas Nucleares/análise , Proteína SMARCB1/análise , Fatores de Transcrição/análise , Adenocarcinoma/genética , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Diferenciação Celular , Proliferação de Células , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Neoplasias Colorretais/cirurgia , Reparo de Erro de Pareamento de DNA , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Proteína 1 Homóloga a MutL/análise , Prognóstico , Estudos Retrospectivos , Análise Serial de Tecidos , Adulto Jovem
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