Prognostic Impact of An Integrative Landscape of Clinical, Immune, and Molecular Features in Non-Metastatic Rectal Cancer.

Rectal Cancer (RC) is a complex disease that involves highly variable treatment responses. Currently, there is a lack of reliable markers beyond TNM to deliver a personalized treatment in a cancer setting where the goal is a curative treatment. Here, we performed an integrated characterization of the predictive and prognostic role of clinical features, mismatch-repair deficiency markers, HER2, CDX2, PD-L1 expression, and CD3-CD8+ tumor-infiltrating lymphocytes (TILs) coupled with targeted DNA sequencing of 76 non-metastatic RC patients assigned to total mesorectal excision upfront (TME; n = 15) or neoadjuvant chemo-radiotherapy treatment (nCRT; n = 61) followed by TME. Eighty-two percent of RC cases displayed mutations affecting cancer driver genes such as TP53, APC, KRAS, ATM, and PIK3CA. Good response to nCRT treatment was observed in approximately 40% of the RC cases, and poor pathological tumor regression was significantly associated with worse disease-free survival (DFS, HR = 3.45; 95%CI = 1.14-10.4; p = 0.028). High neutrophils-platelets score (NPS) (OR = 10.52; 95%CI=1.34-82.6; p = 0.025) and KRAS mutated cases (OR = 5.49; 95%CI = 1.06-28.4; p = 0.042) were identified as independent predictive factors of poor response to nCRT treatment in a multivariate analysis. Furthermore, a Cox proportional-hazard model showed that the KRAS mutational status was an independent prognostic factor associated with higher risk of local recurrence (HR = 9.68; 95%CI = 1.01-93.2; p <0.05) and shorter DFS (HR = 2.55; 95%CI = 1.05-6.21; p <0.05), while high CEA serum levels were associated with poor DFS (HR = 2.63; 95%CI = 1.01-6.85; p <0.05). Integrated clinical and molecular-based unsupervised analysis allowed us to identify two RC prognostic groups (cluster 1 and cluster 2) associated with disease-specific OS (HR = 20.64; 95%CI = 2.63-162.2; p <0.0001), metastasis-free survival (HR = 3.67; 95%CI = 1.22-11; p = 0.012), local recurrence-free survival (HR = 3.34; 95%CI = 0.96-11.6; p = 0.043) and worse DFS (HR = 2.68; 95%CI = 1.18-6.06; p = 0.012). The worst prognosis cluster 2 was enriched by stage III high-risk clinical tumors, poor responders to nCRT, with low TILs density and high frequency of KRAS and TP53 mutated cases compared with the best prognosis cluster 1 (p <0.05). Overall, this study provides a comprehensive and integrated characterization of non-metastatic RC cases as a new insight to deliver a personalized therapeutic approach.

Analysis of long-term oncological results of clinical versus pathological responses after neoadjuvant treatment in locally advanced rectal cancer.

BACKGROUND: Nonoperative management after neoadjuvant treatment in low rectal cancer enables organ preservation and avoids surgical morbidity. Our aim is to compare oncological outcomes in patients with clinical complete response in watch and wait strategy with those who received neoadjuvant therapy followed by surgery with a pathological complete response. METHODS: Patients with non-metastatic rectal cancer after neoadjuvant treatment with clinical complete response in watch and wait approach (group 1, n = 26) and complete pathological responders (ypT0N0) after chemoradiotherapy and surgery (group 2, n = 22), between January 2011 and October 2018, were included retrospectively, and all of them evaluated and followed in a multidisciplinary team. A comparative analysis of local and distant recurrence rates and disease-free and overall survival between both groups was carried out. Statistical analysis was performed using log-rank test, Cox proportional hazards regression model, and Kaplan-Meier curves. RESULTS: No differences were found between patient's demographic characteristics in both groups. Group 1: distance from the anal verge mean 5 cm (r = 1-12), 10 (38%) stage III, and 7 (27%) circumferential resection margin involved. The median follow-up of 47 months (r = 6, a 108). Group 2: distance from the anal verge mean 7 cm (r = 2-12), 16 (72%) stage III, and 13 (59%) circumferential resection margin involved. The median follow-up 49.5 months (r = 3, a 112). Local recurrence: 2 patients in group 1 (8.3%) and 1 in group 2 (4.8%) (p = 0.6235). Distant recurrence: 1 patient in group 1 (3.8%) and 3 in group 2 (19.2%) (p = 0.2237). Disease-free survival: 87.9% in group 1, 80% in group 2 (p = 0.7546). Overall survival: 86% in group 1 and 85% in group 2 (p = 0.5367). CONCLUSION: Oncological results in operated patients with pathological complete response were similar to those in patients under a watch and wait strategy mediating a systematic and personalized evaluation. Surgery can safely be deferred in clinical complete responders.

Pre-Existing Tumoral B Cell Infiltration and Impaired Genome Maintenance Correlate with Response to Chemoradiotherapy in Locally Advanced Rectal Cancer.

Locally advanced rectal cancer (LARC) remains a medical challenge. Reliable biomarkers to predict which patients will significantly respond to neoadjuvant chemoradiotherapy (nCRT) have not been identified. We evaluated baseline genomic and transcriptomic features to detect differences that may help predict response to nCRT. Eligible LARC patients received nCRT (3D-LCRT 50.4 Gy plus capecitabine 825 mg/m2/bid), preceded by three cycles of CAPOX in high systemic-relapse risk tumors, and subsequent surgery. Frozen tumor biopsies at diagnosis were sequenced using a colorectal cancer panel. Transcriptomic data was used for pathway and cell deconvolution inferential algorithms, coupled with immunohistochemical validation. Clinical and molecular data were analyzed according to nCRT outcome. Pathways related to DNA repair and proliferation (p < 0.005), and co-occurrence of RAS and TP53 mutations (p = 0.001) were associated with poor response. Enrichment of expression signatures related to enhanced immune response, particularly B cells and interferon signaling (p < 0.005), was detected in good responders. Immunohistochemical analysis of CD20+ cells validated the association of good response with B cell infiltration (p = 0.047). Findings indicate that the presence of B cells is associated with successful tumor regression following nCRT in LARC. The prevalence of simultaneous RAS and TP53 mutations along with a proficient DNA repair system that may counteract chemoradio-induced DNA damage was associated with poor response.

Administration of the vasopressin analog desmopressin for the management of bleeding in rectal cancer patients: results of a phase I/II trial.

Purpose The vasopressin analog desmopressin (dDAVP) is known to increase plasma levels of hemostatic factors, and preclinical studies in colorectal cancer models have demonstrated that it hampers tumor vascularization and metastatic progression. We evaluated safety and preliminary efficacy of dDAVP in rectal cancer patients with bleeding, before receiving specific oncologic treatment with surgery, chemotherapy and/or radiotherapy. Methods Patients with rectal cancer having moderate or severe rectal bleeding were enrolled in an open-label, dose-finding trial. Intravenous infusions of dDAVP were administered during two consecutive days in doses from 0.25 to 2.0 µg/kg, using single or twice daily regimen. Bleeding was graded using a score based on the Chutkan scale and tumor perfusion was evaluated by dynamic contrast-enhanced magnetic resonance imaging. Results The trial accrued a total of 32 patients. Dose-limiting toxicity occurred in patients receiving 1 µg/kg or higher. The most prominent treatment-related severe adverse event was hyponatremia. Most patients receiving the maximum tolerated dose of 0.5 µg/kg showed at least a partial hemostatic response and 58% developed a complete response with absence of bleeding at day 4 and/or at the last follow-up at day 14. Tumor perfusion was decreased in two-thirds of patients after dDAVP treatment. Conclusions dDAVP appeared as a promising hemostatic agent in rectal cancer patients with bleeding. Randomized clinical trials to confirm its effectiveness are warranted.Clinical trial registration www.clinicaltrials.gov NCT01623206.

Assessment of early response to imatinib 800 mg after 400 mg progression by ¹8F-fluorodeoxyglucose PET in patients with metastatic gastrointestinal stromal tumors.

INTRODUCTION: Imatinib is the standard first-line therapy for advanced gastrointestinal stromal tumor. (18)F-fluorodeoxyglucose PET computed tomography (FDG PET/CT) shows a faster response than computed tomography in nonpretreated patients. PATIENTS & METHODS: After disease progression on imatinib 400 mg, 16 patients were exposed to 800 mg. Tumor response was evaluated by FDG PET/CT on days 7 and 37. Primary objective was to correlate early metabolic response (EMR) with progression-free survival (PFS). RESULTS: EMR by FDG PET/CT scan was not predictive of PFS. Median PFS in these patients was 3 months. Overall survival was influenced by gastric primary site (p = 0.05). CONCLUSION: The assessment of EMR by FDG PET/CT in patients with advanced gastrointestinal stromal tumor exposed to imatinib 800 mg was not predictive of PFS or overall survival.

Is one eye better than two in strabismus? Or does the misaligned amblyopic eye interfere with binocular vision? A preliminary functional MRI study.

PURPOSE: The aim of this study was to determine if patients with strabismic amblyopia could have increased occipital visual cortex activation with monocular stimulation of the sound fixing eye, rather than with simultaneous stimulation of both eyes. METHODS: A prospective study was performed including 12 patients with strabismus and amblyopia, who were evaluated using functional MRI with visual stimulation paradigms. The measurements were made in the occipital visual cortex, assessing the response to the binocular and monocular stimulation. RESULTS: 12 out of 12 patients showed an increased cortical response of the healthy eye in comparison to the amblyopic one. Nine of the 12 patients showed larger cortical activation with visual stimulation of the healthy eye compared to the binocular condition analysis. Three out of the 12 cases had a greater activation area when the stimulation was binocular rather than monocular, 2 of whom had a relatively small angle of strabismus. CONCLUSIONS: Patients with amblyopia and strabismus could see better with only one eye instead of both eyes. This could be related to inhibition of the binocular function of the brain by the misaligned amblyopic eye.

Factors related to surgical complications and their impact on the functional status in 236 open surgeries for malignant tumors in a Latino-American hospital.

BACKGROUND: There are not many studies that address the selection of patients harboring malignant brain tumors for open surgery. It is necessary, especially in developing countries, to establish the standards because of their impact not only on the efficacy but also on the cost-effectiveness of surgery. With the concern to add information that may help in future studies about the decision making, we proposed to analyze factors associated with surgical complications and evaluate their influence on the functional status at 30 days after surgery. METHODS: A consecutive series of 236 surgeries performed between June 1999 and June 2005 were retrospectively analyzed (168 gliomas, 65 metastases, 3 others). Variables evaluated were age, sex, pre- and postoperative KPS, ASA status, anatomic localization, extent of tumor resection, tumor histology, and number of surgeries. RESULTS: The incidence of complicated craniotomies was 15.68% and mortality was 2.97%. Postoperatively, 92% of the patients improved or maintained the functional status, whereas 8% worsened. In multivariate analysis, only preoperative KPS (P = .009), ASA status (P = .02), and histology type (P = .03) showed significant association with postoperative complications. CONCLUSIONS: We found that the neurologic and clinical preoperative condition and grade III gliomas were factors related to postoperative complications, whereas age, extent of resection, and number of surgeries were not risk factors. We believe that these conclusions provide an additional benchmark for future multicentric studies that focus on the selection criteria for resection of malignant brain tumors.

Superior oblique muscle MRI asymmetry and vertical deviation in patients with unilateral superior oblique palsy.

PURPOSE: To evaluate the MRI cross sectional greater area of the unilateral superior oblique (SO) muscle in patients with congenital or acquired superior oblique palsy to detect asymmetries and to determine if there is any relationship between the degree of vertical deviation and the muscle size determined by imaging. METHODS: Magnetic Resonance Imaging coronal images were obtained in primary position, supraversion and infraversion. Interocular differences and intergroup differences were compared in 17 patients with unilateral acquired or congenital SO palsy and 15 orthotropic control subjects. RESULTS: Mean maximal difference was 3.56 +/-0.83 mm(2) (p 0.01) between healthy and paretic eye in the paretic group, and 1.08 +/-0.40 mm(2) (p 0.02) in the control group. Statistical Intergroup comparison was p 0.02 (conventionally statistically significant). In 9 patients the maximal interocular difference was detected in 44.4% in infraversion, 33.3% indistinctly in supra- and infraversion and 22.2% in primary position. The correlation coefficient between vertical deviation and interocular asymmetry was not conventionally statistically significant at p>0.05. CONCLUSIONS: Patients with unilateral superior oblique palsy showed significant MRI asymmetry, which was represented by a relatively greater healthy SO muscle size, in the paretic congenital group. We found no association between the SO muscle size and the degree of any vertical deviation present.

Imágenes moleculares: morfología y función / Molecular imaging: morphology and function

Las imágenes son importantes para el diagnóstico, pronóstico y plan terapéutico de muchas enfermedades debido a su capacidad para demostrar la morfología de los tejidos y órganos normales y patológicos. Sin embargo, las imágenes convencionales tienen limitaciones para explorar la función normal y patológica. En los últimos 30 años las imágenes, el laboratorio y la histología y citología sumados a los avances en marcaciones celulares mediante técnicas de inmunohistoquímica han permitido distinguir células con morfología similar pero de diferente estirpe neoplásica, lo que significa un progreso extraordinario. Una nueva generación de métodos por imágenes puede ir más allá del nivel morfológico y explorar las funciones orgánicas normales y patológicas. A partir de los años 90, se utilizó el nombre imagen molecular o funcional, para denominar a estos métodos que exploran procesos bioquímicos y funciones biológicas in vivo a nivel celular o molecular. El futuro de esta nueva dimensión de las imágenes dependerá del progreso de diversas disciplinas científicas y al desarrollo de los métodos en uso (AU)

Imágenes moleculares: morfología y función / Molecular imaging: morphology and function

Las imágenes son importantes para el diagnóstico, pronóstico y plan terapéutico de muchas enfermedades debido a su capacidad para demostrar la morfología de los tejidos y órganos normales y patológicos. Sin embargo, las imágenes convencionales tienen limitaciones para explorar la función normal y patológica. En los últimos 30 años las imágenes, el laboratorio y la histología y citología sumados a los avances en marcaciones celulares mediante técnicas de inmunohistoquímica han permitido distinguir células con morfología similar pero de diferente estirpe neoplásica, lo que significa un progreso extraordinario. Una nueva generación de métodos por imágenes puede ir más allá del nivel morfológico y explorar las funciones orgánicas normales y patológicas. A partir de los años '90, se utilizó el nombre imagen molecular o funcional, para denominar a estos métodos que exploran procesos bioquímicos y funciones biológicas in vivo a nivel celular o molecular. El futuro de esta nueva dimensión de las imágenes dependerá del progreso de diversas disciplinas científicas y al desarrollo de los métodos en uso

Evaluación de pacientes con enfermedad de Crohn mediante RM con enteroclisis y ecografía Doppler / Doppler ultrasound and MR enteroclysis imaging of Crohns disease

Objetivo: presentar nuestra experiencia en pacientes con enfermedad de Crohn del intestino delgado evaluados con ecografía Doppler (ED) y resonancia magnética con enteroclisis (RM). Material y métodos: se evaluaron 12 pacientes mediante ED y RM con contraste negativo (bario y metilcelulosa) y gadolinio. Se analizó la presencia de flujo en ED y tinción en la pared de las asas en RM, espesor parietal y complicaciones. Resultados: Todos los pacientes mostraron tinción de la pared por RM y en once flujo por ED. La correlación entre ambos métodos fue total en 10 pacientes. La RM mostró en 10 pacientes áreas de estenosis, mientras que la ecografía en 5 pacientes. Ambos métodos mostraron engrosamiento parietal, y en igual porcentaje fístulas y abscesos. Conclusión: Ambos métodos permiten identificar y cuantificar alteraciones en el intestino delgado en pacientes con enfermedad de Crohn, pudiendo ser útiles en la evaluación y seguimiento de estos pacientes (AU)

Evaluación de pacientes con enfermedad de Crohn mediante RM con enteroclisis y ecografía Doppler / Doppler ultrasound and MR enteroclysis imaging of Crohn's disease

Objetivo: presentar nuestra experiencia en pacientes con enfermedad de Crohn del intestino delgado evaluados con ecografía Doppler (ED) y resonancia magnética con enteroclisis (RM). Material y métodos: se evaluaron 12 pacientes mediante ED y RM con contraste negativo (bario y metilcelulosa) y gadolinio. Se analizó la presencia de flujo en ED y tinción en la pared de las asas en RM, espesor parietal y complicaciones. Resultados: Todos los pacientes mostraron tinción de la pared por RM y en once flujo por ED. La correlación entre ambos métodos fue total en 10 pacientes. La RM mostró en 10 pacientes áreas de estenosis, mientras que la ecografía en 5 pacientes. Ambos métodos mostraron engrosamiento parietal, y en igual porcentaje fístulas y abscesos. Conclusión: Ambos métodos permiten identificar y cuantificar alteraciones en el intestino delgado en pacientes con enfermedad de Crohn, pudiendo ser útiles en la evaluación y seguimiento de estos pacientes

Ateneo radiológico / Radiology conference

Se trata de un paciente de sexo masculino de 35 años de edad que consulta a nuestro Hospital por un cuadro de cólico renal y hematuria. Se le descubre un cálculo en el uréter izquierdo, internándose posteriormente a fin de realizar tratamiento del mismo. El examen prequirúrgico muestra en la radiografía (Rx) de tórax múltiples lesiones nodulares en ambos campos pulmonares. Posteriormente se le realiza una tomografía computada (TC) y una fibrobroncoscopía revelando el estudio citológico procedente del lavado bronquial células carcinomatosas

Ateneo radiológico / Radiology conference

Se trata de un paciente de sexo masculino de 35 años de edad que consulta a nuestro Hospital por un cuadro de cólico renal y hematuria. Se le descubre un cálculo en el uréter izquierdo, internándose posteriormente a fin de realizar tratamiento del mismo. El examen prequirúrgico muestra en la radiografía (Rx) de tórax múltiples lesiones nodulares en ambos campos pulmonares. Posteriormente se le realiza una tomografía computada (TC) y una fibrobroncoscopía revelando el estudio citológico procedente del lavado bronquial células carcinomatosas

Angiotomografía del endocráneo: examen multiplanar, tridimensional y 4D / Intracranial computed angiotomography: multiplanar, 3D and 4D

A fin de evaluar la sensibilidad de la angiotomografía en el diagnóstico de la anatomía y patología vascular del endocráneo se evaluaron, entre septiembre de 1996 y septiembre de 1997, 39 pacientes mediante TC helicoidal (TEH) con técnica angiográfica, con inyección de contraste iodado por vía endovenosa mediante bomba inyectora. Las imágenes fueron procesadas para obtener reconstrucciones multiplanares y tridimensionales. A 23 pacientes se les realizó, como método comparativo, angiografía con sustracción digital de las imágenes. La TC demostró ser un estudio no invasivo de alta sensibilidad para el estudio de la patología vascular del endocráneo. Permitió además determinar las relaciones vasculares de tumores encefálicos. Resulta sumamente útil para el planeamiento prequirúrgico por su capacidad de resolución espacial, la vinculación de la patología vascular y tumoral con el resto del endocráneo y las estructuras óseas (AU)