Circulating Polyploid Giant Cancer Cells, a Potential Prognostic Marker in Patients with Carcinoma.

Polyploid Giant Cancer Cells (PGCCs) have been recognized as tumor cells that are resistant to anticancer therapies. However, it remains unclear whether their presence in the bloodstream can be consistently detected and utilized as a clinical marker to guide therapeutic anticancer regimens. To address these questions, we conducted a retrospective study involving 228 patients diagnosed with six different types of carcinomas (colon, gastric, NSCLC, breast, anal canal, kidney), with the majority of them (70%) being non-metastatic. Employing a highly sensitive liquid biopsy approach, ISET®, and cytopathological readout, we isolated and detected circulating PGCCs in the patients' blood samples. PGCCs were identified in 46 (20.18%) out of 228 patients, including in 14.47% of 152 non-metastatic and 29.85% of 67 metastatic cases. Patients were subsequently monitored for a mean follow up period of 44.74 months (95%CI: 33.39-55.79 months). Remarkably, the presence of circulating PGCCs emerged as a statistically significant indicator of poor overall survival. Our findings suggest that circulating PGCCs hold promise as a reliable prognostic indicator. They underscore the importance of further extensive investigations into the role of circulating PGCCs as a prognostic marker and the development of anti-PGCC therapeutic strategies to improve cancer management and patient survival.

Influence of proton pump inhibitors on the pathological response of rectal cancer: a multicentre study.

Background: The standard neoadjuvant therapy for rectal cancer involves fluoropyrimidines and radiotherapy and, most recently, total neoadjuvant therapy (TNT). A drug-drug interaction between fluoropyrimidines and proton-pump inhibitors (PPI) was suggested, with a negative impact on oncological outcomes in breast, colon and gastric cancers. Little is known about such an effect on rectal tumours. We aimed to evaluate the impact of PPI utilisation on the pathological response after chemoradiation for rectal cancer. Materials and methods: Retrospective multicentre study of rectal cancer patients treated with neoadjuvant chemoradiotherapy with capecitabine (cohort 1) or 5-fluororuracil (5-FU) (cohort 2); TNT with oxaliplatin-based regimens was allowed. The pathological response was considered a complete (ypCR) or complete + partial (ypCR + ypPR) according to American Joint Committee on Cancer. PPI use was considered at any time during the neoadjuvant period if concomitant to fluoropyrimidines. Results: From January 2007 to November 2020, 251 patients received capecitabine and 196 5-FU. The rates of PPI use in cohorts 1 and 2 were 20.3% and 26.5%, respectively. TNT was offered to 18.3% in cohort 1. PPI use did not influence ypCR in cohort 1 (yes versus no: 29.4% versus 19.5%; p = 0.13) or 2 (yes versus no: 25.0% versus 26.4%; p = 1.0). Similar ypCR + ypPR were observed in both cohorts 1 (76.5% versus 72.0%; p = 0.60) and 2 (86.5% versus 76.4%; p = 0.16). PPI use was not associated with pathological response in multivariable analysis. PPI users experienced more grade 3 or higher diarrhoea and infections. Conclusion: PPI concomitant to capecitabine/5-FU chemoradiation did not influence the pathological response in rectal cancer but was associated with more treatment-related adverse events.

CD47 Expression in Circulating Tumor Cells and Circulating Tumor Microemboli from Non-Small Cell Lung Cancer Patients Is a Poor Prognosis Factor.

Circulating tumor cells (CTCs) and/or circulating tumor microemboli (CTM) from non-small cell lung cancer (NSCLC) patients may be a non-invasive tool for prognosis, acting as liquid biopsy. CTCs interact with platelets through the transforming growth factor-ß/transforming growth factor-ß receptor type 1 (TGF-ß/TGFßRI) forming clusters. CTCs also may express the Cluster of Differentiation 47 (CD47) protein, responsible for the inhibition of phagocytosis, the "don't eat me" signal to macrophages. OBJECTIVES: To isolate, quantify and analyze CTCs/CTMs from metastatic NSCLC patients, identify TGFßRI/CD47 expression in CTCs/CTMs, and correlate with progression-free survival (PFS). METHODS: Blood (10 mL) was collected at two time-points: T1 (before the beginning of any line of treatment; T2 (60 days after initial collection). CTCs were isolated using ISET®. Immunocytochemistry was conducted to evaluate TGFßRI/CD47 expression. RESULTS: 45 patients were evaluated. CTCs were observed in 82.2% of patients at T1 (median: 1 CTC/mL; range: 0.33-11.33 CTCs/mL) and 94.5% at T2 (median: 1.33 CTC/mL; 0.33-9.67). CTMs were observed in 24.5% of patients and significantly associated with poor PFS (10 months vs. 17 months for those without clusters; p = 0.05) and disease progression (p = 0.017). CTMs CD47+ resulted in poor PFS (p = 0.041). TGFßRI expression in CTCs/CTMs was not associated with PFS. CONCLUSION: In this study, we observed that CTC/CTM from NSCLC patients express the immune evasion markers TGFßRI/CD47. The presence of CTMs CD47+ is associated with poor PFS. This was the first study to investigate CD47 expression in CTCs/CTM of patients with NSCLC and its association with poor PFS.

Effects of Palliative Chemotherapy in Unresectable or Metastatic Colorectal Cancer Patients With Poor Performance Status.

INTRODUCTION: Colorectal cancer is the second most common cancer in both genders and often presents as a metastatic, unresectable, or recurrent disease in early follow-up. It is uncertain the benefit of oxaliplatin-based palliative chemotherapy (CT) in the first line of treatment in patients with compromised performance status (PS), Eastern Cooperative Oncology Group (ECOG) 3 and 4. These patients are systematically excluded from clinical trials but may be treated in clinical practice. METHODS: We conducted a prospective observational cohort whose primary outcome was improving at least 2 points in the worst symptom in the Edmonton Symptom Assessment System Scale (ESAS-r), without grade 3 to 4 toxicity, comparing baseline and fourth week of treatment. Secondary endpoints included quality of life using the European Quality of Life-5 dimensions questionnaire, toxicity, response rate, clinical improvement of ECOG PS, and overall survival (OS). RESULTS: We included 28 patients, and 12 (42.8%) achieved the primary endpoint. Median overall survival was 86 days, 46% of patients did not respond to the fourth-week reevaluation due to clinical deterioration, and 17.8% presented toxicity grade ≥3, with 5 patients dying from toxicity. In addition, ECOG PS 4 or cholestasis had poorer overall survival. Finally, 25% and 53.6% of patients received these treatments in the last 14 and 30 days of life, respectively. CONCLUSION: In the present study, palliative multiagent chemotherapy in poor performance status patients with non-molecularly selected colorectal cancer tended to impact tumor symptoms control; however, there is no benefit in OS and a considerable risk of toxicity and treatment-related death.

Surgical outcomes of primary intraocular lens implantation for the treatment of aphakia in pediatric cataracts in the Brazilian public health system / Resultados cirúrgicos do implante primário de lente intraocular no Sistema Único de Saúde (SUS) para tratamento da afacia na infância, em catarata pediátrica

ABSTRACT Purpose: To evaluate primary intraocular lens implantation in the treatment of children's aphakia in the Brazilian public health system and compare the outcomes among different age groups. Methods: Children aged 0-12 years old with unilateral or bilateral congenital/developmental cataracts and underwent primary intraocular lens implantation were included. Results: A total of 108 eyes from 68 children were evaluated, and the children were divided into four age groups (<7 months [mo]; 7 mo-2 years old [y/o]; 2-5 y/o, and >5 y/o) were evaluated. Nineteen eyes (17.59%) presented visual axis opacification as a postoperative complication, which was more frequently observed in the <7 mo age group (37.93%). The difference was significant between the <7 mo and >5 y/o age groups (p=0.002). Visual axis opacification was divided into two categories: pupillary membrane and lens cell proliferation. Eight eyes presented pupillary membrane, whereas 14 showed lens cell proliferation. Out of eight eyes with pupillary membrane, seven occurred in the <7 mo age group. The difference between the <7 mo age group and the 2-5 y/o or >5 y/o age group was significant (p=0.01). Lens cell proliferation was more frequent in the <7 mo and 2-5 y/o age groups, but the difference was significant only between the < 7 mo age group and >5 y/o age group (p=0.040). Glaucoma and glaucoma suspect cases were not observed during the follow-up period. Conclusions: The main complication found in the study was visual axis opacification, which had a higher incidence in children operated on or before the age of 7 months.

RESUMO Objetivo: Avaliar o implante de lente intraocular primária para tratamento da afacia pediátrica no Sistema Único de Saúde (SUS) e comparar os resultados em diferentes faixas etárias. Métodos: Foram incluídas crianças com catarata congênita e do desenvolvimento unilateral ou bilateral de 0-12 anos de idade e submetidas a implante de lente intraocular primária. Resultados: Cento e oito olhos de 68 crianças divididas em quatro grupos de idade (<7m; 7m-2a; 2-5a e > 5a) foram avaliados. Dezenove olhos (17,59%) apresentaram opacificação do eixo visual como complicação pós-operatória. Essa complicação foi mais frequente na faixa etária <7 meses (37,93%). A diferença foi significativa entre os grupos de idade <7 meses e > 5 anos (p=0,002). A opacificação do eixo visual foi dividida em duas categorias: membrana pupilar e proliferação de células do cristalino. Oito olhos apresentaram membrana pupilar e 14 proliferação de células do cristalino. Dos oito olhos com membrana pupilar, sete ocorreram na faixa etária <7 meses. A diferença entre o grupo de idade <7 meses e os grupos de 2-5 anos e > 5 anos foi significativa (p=0,01). A proliferação de células do cristalino foi mais frequente nos grupos de idade <7 meses e 2-5 anos, mas significativa apenas quando comparados o grupo de idade <7 meses com o grupo> 5 anos de idade (p=0,040). Glaucoma e suspeitos de glaucoma não foram observados durante o acompanhamento. Conclusões: A principal complicação encontrada no estudo foi a opacificação do eixo visual. Sua incidência foi maior em crianças operadas antes dos 7 meses de idade.

HPV virus and biomarkers of resistance to chemoradiation in circulating tumor cells from patients with squamous cell carcinoma of the anus.

Localized anal cancer is mostly represented by squamous cell carcinoma of the anus (SCCA) and is cured in ≥80 % of cases by chemoradiation (CRT). Development of techniques for detection/evaluating circulating tumor cells (CTCs) for diagnosis/ prognosis/response to therapy can change the manner we treat/follow SCCA patients. OBJECTIVE: to detect CTCs from patients with SCCA and evaluate the presence of HPV virus, p16 expression and markers related to resistance to CRT (RAD23B/ ERCC1/ TYMS) in CTCs at baseline and after CRT. METHODS: CTCs were isolated/quantified by ISET®, protein expressions were analyzed by immunocytochemistry and HPV DNA was detected by chromogenic in situ hybridization. RESULTS: We enrolled 15 patients: median age was 61 (43-73) years, the majority was women (10/15). CTCs were detected in all patients at baseline (median= 0.4 (0.4-3.33) CTCs/mL) and in 8/9 patients, after CRT (median= 2.33 (0-7.0) CTCs/mL). DNA from HPV was found in CTCs in 14/15 patients (93.33 %) at baseline and in 7/9 (77.7 %) after treatment. At a median follow-up of 22.20 (1.45-38.55) months, three patients expressed ERCC1 in CTCs after treatment, with one of them having disease recurrence. CONCLUSION: We showed that detection of HPV in CTCs from patients with non-metastatic SCCA is feasible and appears to be a sensitive diagnostic method. These results may be clinically useful for better monitoring these patients. However, future larger cohorts may demonstrate whether there is any correlation between the presence of HPV and the expression of screening markers for CRT in SCCA.

Surgical outcomes of primary intraocular lens implantation for the treatment of aphakia in pediatric cataracts in the Brazilian public health system.

PURPOSE: To evaluate primary intraocular lens implantation in the treatment of children's aphakia in the Brazilian public health system and compare the outcomes among different age groups. METHODS: Children aged 0-12 years old with unilateral or bilateral congenital/developmental cataracts and underwent primary intraocular lens implantation were included. RESULTS: A total of 108 eyes from 68 children were evaluated, and the children were divided into four age groups (<7 months [mo]; 7 mo-2 years old [y/o]; 2-5 y/o, and >5 y/o) were evaluated. Nineteen eyes (17.59%) presented visual axis opacification as a postoperative complication, which was more frequently observed in the <7 mo age group (37.93%). The difference was significant between the <7 mo and >5 y/o age groups (p=0.002). Visual axis opacification was divided into two categories: pupillary membrane and lens cell proliferation. Eight eyes presented pupillary membrane, whereas 14 showed lens cell proliferation. Out of eight eyes with pupillary membrane, seven occurred in the <7 mo age group. The difference between the <7 mo age group and the 2-5 y/o or >5 y/o age group was significant (p=0.01). Lens cell proliferation was more frequent in the <7 mo and 2-5 y/o age groups, but the difference was significant only between the < 7 mo age group and >5 y/o age group (p=0.040). Glaucoma and glaucoma suspect cases were not observed during the follow-up period. CONCLUSIONS: The main complication found in the study was visual axis opacification, which had a higher incidence in children operated on or before the age of 7 months.

The Current and Evolving Role of Immunotherapy in Metastatic Colorectal Cancer.

Immunotherapy can be considered a therapeutic revolution in oncology, with great impact on many tumor types, such as melanoma and non-small cell lung cancer. However, in metastatic colorectal cancer, the benefits in terms of prolonged tumor control and high response rate are limited to the rare subgroup of tumors with high mutation burden - mostly tumors that harbor microsatellite instability (MSI) or a deficient mismatch repair system (dMMR), or tumor microsatellite stability and damaging mutations in the exonuclease domains of POLE or POLD. The KEYNOTE-028 uncontrolled phase II trial demonstrated an impressive antitumor activity of pembrolizumab in patients with treatmentrefractory Lynch-associated tumors, including colorectal cancer. Nivolumab with or without ipilimumab confirmed the efficacy of immune checkpoint inhibitors in patients with previously treated dMMR / MSI metastatic colorectal cancer. The recent KEYNOTE-177 phase III trial demonstrated that pembrolizumab significantly reduced the relative risk of disease progression or death and improved progression-free survival in patients with treatment-naive dMMR / MSI metastatic colorectal cancer in comparison with first-line chemotherapy with or without biologics. Unfortunately, current pharmacological strategies with immunotherapy have not been successful for most patients with microsatellite stable metastatic colorectal cancer. In this review, we critically appraise the applicability of immune checkpoint inhibitors in dMMR/MSI metastatic colorectal cancer. We also discuss the recent negative trials of immunotherapy combinations in microsatellite stabl.

Molecular and Dynamic Evaluation of Proteins Related to Resistance to Neoadjuvant Treatment with Chemoradiotherapy in Circulating Tumor Cells of Patients with Locally Advanced Rectal Cancer.

The heterogeneity of response to neoadjuvant chemoradiotherapy (NCRT) is still a challenge in locally advanced rectal cancer (LARC). The evaluation of thymidylate synthase (TYMS) and RAD23 homolog B (RAD23B) expression in circulating tumor cells (CTCs) provides complementary clinical information. CTCs were prospectively evaluated in 166 blood samples (63 patients) with LARC undergoing NCRT. The primary objective was to verify if the absence of RAD23B/TYMS in CTCs would correlate with pathological complete response (pCR). Secondary objectives were to correlate CTC kinetics before (C1)/after NCRT (C2), in addition to the expression of transforming growth factor-ß receptor I (TGF-ßRI) with survival rates. CTCs were isolated by ISET and evaluated by immunocytochemistry (protein expression). At C1, RAD23B was detected in 54.1% of patients with no pCR and its absence in 91.7% of patients with pCR (p = 0.014); TYMS- was observed in 90% of patients with pCR and TYMS+ in 51.7% without pCR (p = 0.057). Patients with CTC2 > CTC1 had worse disease-free survival (DFS) (p = 0.00025) and overall survival (OS) (p = 0.0036) compared with those with CTC2 ≤ CTC1. TGF-ßRI expression in any time correlated with worse DFS (p = 0.059). To conclude, RAD23B/TYMS and CTC kinetics may facilitate the personalized treatment of LARC.

Outcomes of Patients With Metastatic Anal Cancer According to HIV Infection: A Multicenter Study by the Latin American Gastrointestinal Oncology Group (SLAGO).

BACKGROUND: HIV-positive patients are underrepresented in clinical trials of metastatic squamous cell carcinoma of the anal canal (mSCCA). We aimed to compare the clinical outcomes of mSCCA patients according to HIV infection. METHODS: This was a retrospective multicenter cohort study of consecutive patients with mSCCA. All HIV-positive patients received antiretroviral therapy. The primary endpoint was overall survival (OS), and secondary endpoints were progression-free survival (PFS) and response rate (RR). RESULTS: From January 2005 to December 2019, 113 patients were included: 20 (17.6%) had HIV infection. HIV-positive patients were younger at diagnosis and more frequently male, and 20% (n = 8) received exclusively best supportive care in comparison with 8.6% of HIV-negative patients (P = .13). Both groups were similar in terms of Eastern Cooperative Oncology Group (ECOG) performance status, pattern of metastatic disease, and type of first-line chemotherapy. Five (25%) HIV-positive and 36 (38.7%) HIV-negative patients received second-line therapies (P = .24). RR and median PFS in first-line were similar between the groups: 35% and 30.1% (P = .78) and 4.9 and 5.3 months (P = .85) for patients with and without HIV infection, respectively. At a median follow-up of 26 months, median OS was 11.3 months (95% confidence interval [CI] 10.1 to 26.4) for HIV-infected patients versus 14.6 months (95% CI 11.1 to 18.1) for HIV-negative patients (P = .92). In the univariate analysis for OS, only ECOG performance status was significant. CONCLUSION: HIV-positive mSCCA patients under antiretroviral therapy have oncological outcomes similar to those of HIV-negative patients. These patients should be included in trials of mSCCA.

Use of Soft Contact Lens for Esthetic and Functional Rehabilitation.

OBJECTIVE: To report the outcomes and complications of colored soft contact lenses (SCLs) to improve esthetic or eye function in visually impaired (VI) or blind patients. METHODS: This retrospective study enrolled consecutive patients with unilateral or bilateral VI or blindness who had received colored SCLs to improve appearance or ocular function. Data were collected on demographics, complaints, complete ophthalmological examinations, types of SCL, follow-ups, and complications. RESULTS: The study sample was comprised of 109 patients (ages 4-80 years). Eighty-six patients (78.89%) had unilateral blindness, and 14 patients (12.84%) had functional disorder. Most of the patients presenting for improved esthetic had anterior segment pathology (74/67.88%), mainly secondary to trauma (55/50.5%) resulting in leukoma (73/66.97%). Patients with functional VI (19/17.43%) received filtered SCLs for color blindness (7/6.42%), diplopia (7/6.42%), or photophobia (5/4.58%). No serious complications were observed in any cases, and 94.49% of patients were satisfied with the SCLs. CONCLUSION: Colored SCLs can cover ocular surface imperfections in VI or blind eyes of patients who are seeking better cosmesis or improvement functional VI. Soft contact lenses with only one filter can cover imperfections of the ocular surface and improve vision in functional VI. Appropriate follow-up of these patients can reduce complication rates, resulting in good cosmesis and patient satisfaction with a positive impact on the lives of patients suffering from functional VI or blindness.

Baseline and Kinetic Circulating Tumor Cell Counts Are Prognostic Factors in a Prospective Study of Metastatic Colorectal Cancer.

The discovery of predictive biomarkers in metastatic colorectal cancer (mCRC) is essential to improve clinical outcomes. Recent data suggest a potential role of circulating tumor cells (CTCs) as prognostic indicators. We conducted a follow-on analysis from a prospective study of consecutive patients with mCRC. CTC analysis was conducted at two timepoints: baseline (CTC1; before starting chemotherapy), and two months after starting treatment (CTC2). CTC isolation/quantification were completed by ISET® (Rarecells, France). CTC expressions of drug resistance-associated proteins were evaluated. Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. Seventy-five patients were enrolled from May 2012 to May 2014. A CTC1 cut-off of >1.5 CTCs/mL was associated with an inferior median OS compared to lower values. A difference of CTC2-CTC1 > 5.5 CTCs/mL was associated with a reduced median PFS. By multivariate analysis, CTC1 > 1.5 CTCs/mL was an independent prognostic factor for worse OS. Multi-drug resistance protein-1 (MRP-1) expression was associated with poor median OS. CTC baseline counts, kinetics, and MRP-1 expression were predictive of clinical outcomes. Larger studies are warranted to explore the potential clinical benefit of treating mCRC patients with targeted therapeutic regimens guided by CTC findings.

The Effect of Chronic and Inhospital Exposure to Renin-Angiotensin System Inhibitors on the Outcome and Inflammatory State of Coronavirus Disease 2019 Adult Inpatients.

BACKGROUND: Controversies exist about the effect of renin-angiotensin system inhibitors (RASi) on coronavirus disease 2019 (COVID-19) outcome. The inhospital use of RASi and its effect on inflammatory sate are still poorly studied during the COVID-19 pandemic. OBJECTIVES: We aimed to compare the impact of previous and inhospital RASi exposure on the outcome and inflammatory response of COVID-19 patients. METHODS: Single-centre, ambispective analysis of hospitalized adult COVID-19 patients at Hospital de Santa Maria, Lisbon, between March and August 2020 was performed. We excluded asymptomatic patients and those admitted due to another disease. The primary outcome was inhospital all-cause mortality. Illness severity was assessed based on the development of acute respiratory distress syndrome/acute lung injury (ARDS/ALI), intensive care unit (ICU) admission, and need for invasive mechanical ventilation (IMV). We used C-reactive protein (CRP), ferritin, and interleukin 6 (IL-6) as surrogate markers of the inflammatory response. RESULTS: From a total of 432 patients, 279 were selected, among whom 133 (47.7%) were receiving a RASi. Chronic treatment with RASi was not associated with the risk of death (OR 1.24, 95% CI 0.66-2.31, p=0.500), ARDS/ALI development (OR 1.12, 95% CI 0.67-1.86, p=0.676), ICU admission (OR 1.11, 95% CI 0.67-1.84, p = 0.686), and IMV need (OR 1.03, 95% CI 0.58-1.84, p=0.917) in a univariable and multivariable analysis. Inhospital RASi withdrawing was associated with the risk of death (OR 4.38, 95% CI 1.11-17.21, p=0.035) and ARDS/ALI development (OR 4.33, 95% CI 1.49-12.6, p=0.007), the latter remaining significant after adjustment. Previous exposure to RASi was associated with lower CRP levels at admission (p=0.018). IL-6 levels were significantly higher in those patients whose RASi were stopped (p=0.024). CONCLUSION: Previous and inhospital exposure to RASi was not associated with mortality nor severity of COVID-19. This study supports current guidance on RASi management during the COVID-19 pandemic.

A higher platelet-to-lymphocyte ratio is prevalent in the presence of circulating tumor microemboli and is a potential prognostic factor for non-metastatic colon cancer.

Colorectal cancer is a common and often deadly cancer. Circulating tumor cells (CTCs) have been implicated as a potentially valuable prognosis factor. The detection of circulating tumor microemboli (CTM) and of simple blood component parameters that reflect inflammatory status, such as the platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR), may provide information about tumor progression. The aim of this study was to explore the importance of CTCs, CTM, PLR, and NLR prospectively in non-metastatic colon cancer progression. CTCs were enriched using ISETⓇ (Isolation by SizE of Tumor cells) and identified by immunocytochemical exclusion of leukocytes. We evaluated CTCs and blood cell parameters in a cohort of 69 stage I-III colon cancer patients (52.2% men; median age, 61 years; age range, 19-87 years) at a baseline timepoint prior to resection surgery. The median of CTC levels at baseline was 20 cells/8 mL (0-94) and higher levels were associated with CTM presence (p = 0.02). CTM were found in 18 (26.1%) patients. Of 18 stage I patients, 33.3% had CTM and of 51 stages II or III patients, 13.7% had CTM (p = 0.08). Patients with a high PLR (>124) were mostly (75.6%) diagnosed with high-risk stages II/III cancer (stages I/low-risk II, 24.4%; p = 0.014). All 8 patients that had disease recurrence during follow-up had a high PLR (p = 0.02 vs. low PLR). NLR was not significantly associated with disease stage or recurrence. The present results indicate that CTCs and PLR analyses may be clinically useful for colon cancer management and risk stratification.

Identificação e correlação molecular e dinâmica de proteínas relacionadas à resistência ao tratamento neoadjuvante em células tumorais circulantes de pacientes com câncer de reto localmente avançado / Molecular and dynamic evaluation of proteins related to resistance to neoadjuvant treatment with chemoradiotherapy in circulating tumor cells of patients with locally advanced rectal cancer

INTRODUÇÃO: A quimiorradioterapia neoadjuvante (QRTN) consolidou-se como a principal estratégia para o tratamento do câncer de reto localmente avançado (CRLA). No entanto, respostas heterogêneas são observadas com o tratamento neoadjuvante, com apenas 15-20% dos pacientes com resposta patológica completa (RPC). Diante da necessidade de estratificar os pacientes em respondedores e não respondedores à QRTN antes do seu início, com o objetivo de aprimorar a seleção daqueles com maior probabilidade de obter uma RPC, vários estudos avaliam a identificação de possíveis biomarcadores. O objetivo primário deste estudo prospectivo foi analisar se a ausência da expressão do homólogo B de RAD23 (RAD23B) e da timidilato sintase (TYMS) nas células tumorais circulantes (CTCs) se correlacionaria com a RPC para os pacientes submetidos à QRTN e, assim, identificar possíveis respondedores ao tratamento. Os desfechos secundários foram avaliar a cinética das CTCs antes (C1) e após QRTN (C2), além da correlação da expressão de marcadores de resposta imune, como o Tumor Growth Factor ß Receptor I (TGF-ßRI) e Programmed Death ligand-1 (PD-L1) com a sobrevida livre de doença (SLD) e sobrevida global (SG). MÉTODOS: Entre 2016 e 2020, 63 pacientes com CRLA (cT3/T4 e/ou N+) submetidos a QRTN foram incluídos no estudo. As CTCs foram isoladas por ISET e avaliadas por imunocitoquímica. A expressão de RAD23B, TYMS, PD-L1 e TGF-ßRI foi avaliada nesta ordem de prioridade de acordo com o objetivo primário do estudo em cada momento de coleta e a disponibilidade de células (contagem de CTCs > 0) na amostra. RESULTADOS: Em C1, RAD23B foi detectado em 54,1% dos pacientes sem RPC e sua ausência em 91,7% dos pacientes com RPC (p = 0,014); Na segunda coleta, dos 13 pacientes com RPC, 10 não apresentaram expressão de RAD23B nas CTCs. Para os pacientes que não obtiveram RPC com QRTN, 51,7% apresentavam a expressão de RAD23B em CTC em C2 (p = 0,06). Na análise univariada (OR =0,077;IC 95%, 0,009-0,661; p = 0,019) e multivariada (OR= 0,064;CI 95%, 0,006-0,75; p = 0,029) para RPC, observamos que a expressão de RAD23B foi associado com menor chance de resposta em comparação com os pacientes com a ausência da expressão do RAD23B na C1. A ausência da expressão da TYMS foi observado em 90% dos pacientes com RPC e sua expressão em 51,7% sem RPC (p = 0,057). Na avaliação da cinética da CTCs pacientes com CTC2> CTC1 (cinética desfavorável) tiveram pior SLD (p = 0,00025) e SG (p = 0,0036) em comparação com aqueles com CTC2 ≤CTC1 (cinética favorável). A expressão de TGF-ßRI em qualquer momento das coletas correlacionou-se com pior SLD (p = 0,059). CONCLUSÃO: Demonstramos uma possível correlação entre a ausência de expressão de RAD23B e TYMS nas CTCs com a RPC, sendo um resultado importante para identificar os respondedores ao tratamento neoadjuvante, ajudando individualizar a abordagem terapêutica. Além disso, a cinética desfavorável e a expressão de TGF-ßRI nas CTCs se correlacionaram com pior sobrevida

INTRODUCTION: Neoadjuvant chemoradiotherapy (NCRT) has established itself as the main strategy for the treatment of locally advanced rectal cancer (LARC). However, heterogeneous responses are observed with neoadjuvant treatment, with only 15-20% of patients with complete pathological response (pCR). Given the need to stratify patients into responders and non-responders to NCRT prior to its initiation, in order to improve the selection of those most likely to obtain a pCR, several studies have assessed the identification of potential biomarkers capable of stratifying and monitoring the patient's response. The primary objective of this prospective study was to analyze whether the absence of RAD23 homolog B expression (RAD23B) and thymidylate synthase (TYMS) in circulating tumor cells (CTCs) would correlate with pCR for patients undergoing NCRT and thus identify possible responders to treatment. The secondary outcomes were to evaluate the kinetics of CTCs before (C1) and after NCRT (C2), in addition to the correlation of the expression of immune response markers, such as Tumor Growth Factor ß Receptor I (TGF-ßRI) and Programmed Death ligand- 1 (PD-L1) with clinical outcomes such as disease-free survival (DFS) and overall survival (OS). METHODS: Between 2016 and 2020, 63 patients (pts) with LARC (cT3 / T4 or N +) submitted to NCRT were included in the study. CTCs were isolated by ISET and evaluated by immunocytochemistry (protein expression). The expression of RAD23B, TYMS, PD-L1 and TGF-ßRI was evaluated in this order of priority according to the primary objective of the study at each time of collection (C1, C2 and C3) and the availability of cells (CTC count> 0) in the sample. RESULTS: In C1, RAD23B was detected in 54.1% of patients without pCR and its absence in 91.7% of patients with pCR (p = 0.014). In the second collection, of the 13 patients with pCR, 10 did not show RAD23B expression in the CTCs. For patients who did not obtain pCR with NCRT, 51.7% had RAD23B expression in CTC in C2 (p = 0.06). In the univariate (OR = 0.077; 95% CI, 0.009-0.661; p = 0.019) and multivariate (OR = 0.064; 95% CI, 0.006-0.75; p = 0.029) logistic regression models for pCR, we observed that the expression of RAD23B was associated with a lower chance of response compared to patients with the absence of RAD23B expression in C1. The absence of TYMS expression was observed in 90% of patients with pCR and its expression in 51.7% without pCR (p = 0.057). In the evaluation of CTCs kinetics patients with CTC2> CTC1 (unfavorable kinetics) had worse DFS (p = 0.00025) and overall survival (OS) (p = 0.0036) compared with those with CTC2 ≤CTC1 (favorable kinetics). TGF-ßRI expression at any time of the collections was correlated with worse DFS (p = 0.059). CONCLUSION: We demonstrated a possible correlation between the absence of RAD23B and TYMS expression in CTCs with pCR, being an important result to identify respondents to neoadjuvant treatment, helping to individualize the therapeutic approach. In addition, the unfavorable kinetics and expression of TGF-ßRI in CTCs correlated with worse survival.

Is there a role for rechallenge and reintroduction of anti-EGFR plus chemotherapy in later lines of therapy for metastatic colorectal carcinoma? A retrospective analysis.

BACKGROUND: Mechanisms of resistance have been described during disease progression (PD) for patients under treatment with anti-EGFR plus chemotherapy (CT). The aim of our study was to evaluate efficacy of anti-EGFR rechallenge (ReCH) and reintroduction (ReIn) in metastatic colorectal cancer (mCRC). MATERIALS AND METHODS: This is a retrospective analysis of patients with mCRC that previously received anti-EGFR + CT and interrupted therapy due to PD in the ReCH group and other reasons in the ReIn group. We aimed to describe progression-free survival (PFS), overall survival (OS) and response rate (RR) after re-exposure and to evaluate prognostic factors associated with PFS. RESULTS: Sixty-eight patients met the inclusion criteria. The median follow-up after re-exposure was 39.3 months. ReCH was adopted in 25% and ReIn in 75%. The median anti-EGFR free interval was at 10.5 months. At re-exposure, the main CT regimen was FOLFIRI in 58.8%. Cetuximab and Panitumumab were used in 59 and 9 patients, respectively. mPFS for ReCH and ReIn was 3.3 × 8.4 months, respectively (p 0.001). The objective response rate for ReCH and ReIn was 18% and 52%, respectively. In univariate analysis, adverse prognostic factors related to PFS were: stable disease or PD at first anti-EGFR exposure (HR: 2.12, CI:1.20-3.74; p = 0.009); ReCH (HR: 3.44, CI:1.88-6.29, p < 0.0001); rechallenge at fourth or later lines (HR: 2.51, CI:1.49-4.23, p = 0.001); panitumumab use (HR: 2.26 CI:1.18-5.54, p = 0.017). In the multivariate model, only ReCH remained statistically significant (HR = 2.63, CI: 1.14-6.03, p = 0.022). CONCLUSION: In our analysis, ReCH resulted in short PFS and low RR. However, reintroduction of anti-EGFR plus CT before complete resistance arose resulted in prolonged PFS. These data could be clinically useful to guide a treatment break due to side effects or patient decisions. Our data should be confirmed by larger and prospective trials.

Acalculous Acute Pancreatitis in a COVID-19 Patient.

Coronavirus disease 2019 (COVID-19) is a multisystemic condition caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with manifestations ranging from mild upper respiratory symptoms to cytokine storm causing acute respiratory distress syndrome. Pancreatic exocrine tissue and endocrine islets both express angiotensin-converting enzyme 2 (ACE2), the proven receptor for SARS-CoV-2 cell internalization. An increase in pancreatic enzymes has been increasingly recognized in patients with COVID-19, but little is known about the real prevalence of acute pancreatitis in this population. We report a case of acute acalculous pancreatitis in a COVID-19 patient. LEARNING POINTS: Acute pancreatitis may be a manifestation of SARS-CoV-2 infection.Future studies must address the real impact of pancreatic involvement in COVID-19 patients.

Disease-Free Survival and Time to Complete Response After Definitive Chemoradiotherapy for Squamous-Cell Carcinoma of the Anus According to HIV Infection.

BACKGROUND: The standard treatment for localized squamous-cell carcinoma of the anal canal is definitive chemoradiotherapy. A meta-analysis of published studies conducted by our group showed significantly lower rates of disease-free survival (DFS) and overall survival at 3 years among HIV-positive patients. We aimed to compare detailed treatment outcomes between the groups of HIV-positive and -negative patients. PATIENTS AND METHODS: We performed a retrospective multicenter study of a comparative cohort of consecutive patients with histologic diagnosis of localized squamous-cell carcinoma of the anal canal who received definitive chemoradiotherapy. Patients' characteristics and outcomes were compared according to HIV status. The primary end points were time to complete response (CR) and DFS time. RESULTS: From June 2001 to September 2018, a total of 185 patients were included; 43 (30.2%) were HIV positive and 142 (69.8%) were HIV negative. The overall CR rates were 67.4% and 91.5% for HIV-positive and -negative patients, respectively (P < .001). The median follow-up was 47.8 months and the median time to experience CR was 7.8 months (95% confidence interval [CI], 5.7-10.5) for HIV-positive versus 4.89 months (95% CI, 4.54-5.25) for HIV-negative (P < .001) patients. The median DFS times were 79.7 months (95% CI, 56.8-102.6) and 127.9 months (95% CI, 112.6-143.2) for HIV-positive and -negative patients, respectively (P = .02). There was a trend toward greater grade 3/4 toxicity in the HIV-positive group. CONCLUSION: HIV-positive patients take longer to experience CR and present worse DFS. These findings have clinical implications because waiting longer to define CR among these patients may prevent unnecessary anorectal amputations.

Molecular and Kinetic Analyses of Circulating Tumor Cells as Predictive Markers of Treatment Response in Locally Advanced Rectal Cancer Patients.

Neoadjuvant chemoradiation (NCRT) followed by total mesorectal excision is the standard treatment for locally advanced rectal cancer (LARC). To justify a non-surgical approach, identification of pathologic complete response (pCR) is required. Analysis of circulating tumor cells (CTCs) can be used to evaluate pCR. We hypothesize that monitoring of thymidylate synthase (TYMS) and excision repair protein, RAD23 homolog B (RAD23B), can be used to predict resistance to chemotherapy/radiotherapy. Therefore, the aims of this study were to analyze CTCs from patients with LARC who underwent NCRT plus surgery for expression of TYMS/RAD23B and to evaluate their predictive value. Blood samples from 30 patients were collected prior to NCRT (S1) and prior to surgery (S2). CTCs were isolated and quantified by ISET®, proteins were analyzed by immunocytochemistry, and TYMS mRNA was detected by chromogenic in situ hybridization. CTC counts decreased between S1 and S2 in patients exhibiting pCR (p = 0.02) or partial response (p = 0.01). Regarding protein expression, TYMS was absent in 100% of CTCs from patients with pCR (p = 0.001) yet was expressed in 83% of non-responders at S2 (p < 0.001). Meanwhile, RAD23B was expressed in CTCs from 75% of non-responders at S1 (p = 0.01) and in 100% of non-responders at S2 (p = 0.001). Surprisingly, 100% of non-responders expressed TYMS mRNA at both timepoints (p = 0.001). In addition, TYMS/RAD23B was not detected in the CTCs of patients exhibiting pCR (p = 0.001). We found 83.3% of sensitivity for TYMS mRNA at S1 (p = 0.001) and 100% for TYMS (p = 0.064) and RAD23B (p = 0.01) protein expression at S2. Thus, TYMS mRNA and/or TYMS/RAD23B expression in CTCs, as well as CTC kinetics, have the potential to predict non-response to NCRT and avoid unnecessary radical surgery for LARC patients with pCR.

Treatment outcomes of patients with localized anal squamous cell carcinoma according to HIV infection: systematic review and meta-analysis.

BACKGROUND: Definitive chemoradiation (CRT) is the standard treatment for localized squamous cell carcinoma of the anus (SCCA). Because most phase III trials in SCCA have excluded patients with HIV, the evidence on treatment outcomes of these patients is lacking. We performed a systematic review and meta-analysis on the efficacy and toxicity profiles of HIV-positive SCCA patients treated with definitive CRT. METHODS: The systematic search was conducted Embase, Medline, Cochrane Libary, Scopus, Lilacs and Opengrey, from inception until September 2017. Eligible studies were clinical trials, prospective or retrospective cohort studies. The main outcome variables were 3-year disease-free survival (DFS) and overall survival (OS) rates and frequency of grade 3 or 4 (G3/4) treatment-related toxicities, according to HIV status. Meta-analyses using pooled risk ratios were performed for binary outcomes from comparative studies from the antiretroviral therapy (HAART) era with the fixed effects model. RESULTS: Out of 3,951 studies, 40 were deemed eligible, with a total of 3,720 patients. One third (N=1,298; 34%) were HIV-positive and their median pre CRT CD4 count was 347 µm/L. HIV-positive patients presented higher risk of G3/4 cutaneous toxicities [risk ratio (RR) =1.34; 95% CI, 1.10-1.64; P=0.004; I2=77.7%], worse 3-year DFS rate (RR =1.32; 95% CI, 1.01-1.74; P=0.043; I2=52.19%), and 3-year OS rate (RR =1.77; 95% CI, 1.35-2.32; P<0.001; I2=6%). CONCLUSIONS: Patients with localized SCCA and HIV infection treated with CRT tend to experience higher risk of toxicities and worse DFS and OS rates. Our findings suggest that future trials should be tailored to HIV-positive patients.