A Comprehensive Biomarker Analysis of Microsatellite Unstable/Mismatch Repair Deficient Colorectal Cancer Cohort Treated with Immunotherapy.

The search for immunotherapy biomarkers in Microsatellite Instability High/Deficient Mismatch Repair system (MSI-H/dMMR) metastatic colorectal cancer (mCRC) is an unmet need. Sixteen patients with mCRC and MSI-H/dMMR (determined by either immunohistochemistry or polymerase chain reaction) treated with PD-1/PD-L1 inhibitors at our institution were included. According to whether the progression-free survival with PD-1/PD-L1 inhibitors was longer than 6 months or shorter, patients were clustered into the IT-responder group (n: 9 patients) or IT-resistant group (n: 7 patients), respectively. In order to evaluate determinants of benefit with PD-1/PD-L1 inhibitors, we performed multimodal analysis including genomics (through NGS panel tumour-only with 431 genes) and the immune microenvironment (using CD3, CD8, FOXP3 and PD-L1 antibodies). The following mutations were more frequent in IT-resistant compared with IT-responder groups: B2M (4/7 versus 2/9), CTNNB1 (2/7 versus 0/9), and biallelic PTEN (3/7 versus 1/9). Biallelic ARID1A mutations were found exclusively in the IT-responder group (4/9 patients). Tumour mutational burden did not correlate with immunotherapy benefit, neither the rate of indels in homopolymeric regions. Of note, biallelic ARID1A mutated tumours had the highest immune infiltration and PD-L1 scores, contrary to tumours with CTNNB1 mutation. Immune microenvironment analysis showed higher densities of different T cell subpopulations and PD-L1 expression in IT-responders. Misdiagnosis of MSI-H/dMMR inferred by discordances between immunohistochemistry and polymerase chain reaction was only found in the IT-resistant population (3/7 patients). Biallelic ARID1A mutations and Wnt signalling activation through CTNNB1 mutation were associated with high and low T cell immune infiltrates, respectively, and deserve special attention as determinants of response to PD-1/PD-L1 inhibitors. The non-MSI-H phenotype in dMMR is associated with poor benefit to immunotherapy. Our results suggest that mechanisms of resistance to immunotherapy are multi-factorial.

The Evolving Role of Consensus Molecular Subtypes: a Step Beyond Inpatient Selection for Treatment of Colorectal Cancer.

OPINION STATEMENT: The heterogenous nature of colorectal cancer (CRC) renders it a major clinical challenge. Increasing genomic understanding of CRC has improved our knowledge of this heterogeneity and the main cancer drivers, with significant improvements in clinical outcomes. Comprehensive molecular characterization has allowed clinicians a more precise range of treatment options based on biomarker selection. Furthermore, this deep molecular understanding likely extends therapeutic options to a larger number of patients. The biological associations of consensus molecular subtypes (CMS) with clinical outcomes in localized CRC have been validated in retrospective clinical trials. The prognostic role of CMS has also been confirmed in the metastatic setting, with CMS2 having the best prognosis, whereas CMS1 tumors are associated with a higher risk of progression and death after chemotherapy. Similarly, according to mesenchymal features and immunosuppressive molecules, CMS1 responds to immunotherapy, whereas CMS4 has a poorer prognosis, suggesting that a CMS1 signature could identify patients who may benefit from immune checkpoint inhibitors regardless of microsatellite instability (MSI) status. The main goal of these comprehensive analyses is to switch from "one marker-one drug" to "multi-marker drug combinations" allowing oncologists to give "the right drug to the right patient." Despite the revealing data from transcriptomic analyses, the high rate of intra-tumoral heterogeneity across the different CMS subgroups limits its incorporation as a predictive biomarker. In clinical practice, when feasible, comprehensive genomic tests should be performed to identify potentially targetable alterations, particularly in RAS/BRAF wild-type, MSI, and right-sided tumors. Furthermore, CMS has not only been associated with clinical outcomes and specific tumor and patient phenotypes but also with specific microbiome patterns. Future steps will include the integration of clinical features, genomics, transcriptomics, and microbiota to select the most accurate biomarkers to identify optimal treatments, improving individual clinical outcomes. In summary, CMS is context specific, identifies a level of heterogeneity beyond standard genomic biomarkers, and offers a means of maximizing personalized therapy.

Up-to-date role of aflibercept in the treatment of colorectal cancer.

Introduction: Colorectal cancer (CRC) is a major public health problem. Despite major progress understanding the biological basis of this tumor added to the incorporation of optimized diagnostic and therapeutic strategies, prognosis after progression on first-line standard treatment remains poor. Several antiangiogenic treatments have demonstrated improvement in overall survival (OS) in the second-line treatment being aflibercept, a fully humanized recombinant protein, one of them. The results of the VELOUR study showed that the addition of aflibercept to second-line FOLFIRI improved OS and progression-free survival.Areas covered: A literature review of published clinical studies was performed in order to discuss the clinical data on aflibercept in mCRC from early drug development to real-world data.Expert opinion: The combination of aflibercept with FOLFIRI provides a statistical improvement in OS and in all the efficacy endpoints analyzed in the VELOUR trial, showing efficacy independently on time to progression, molecular status, prior biological treatment, or age. Further studies are needed to find new biomarkers and molecular characterization in order to better select patients that could benefit from this treatment.

Molecular subtypes and the evolution of treatment management in metastatic colorectal cancer.

Colorectal cancer (CRC) is a heterogeneous disease representing a therapeutic challenge, which is further complicated by the common occurrence of several molecular alterations that confer resistance to standard chemotherapy and targeted agents. Mechanisms of resistance have been identified at multiple levels in the epidermal growth factor receptor (EGFR) pathway, including mutations in KRAS, NRAS, and BRAF V600E, and in the HER2 and MET receptors. These alterations represent oncogenic drivers that may co-exist in the same tumor with other primary and acquired alterations via a clonal selection process. Other molecular alterations include DNA damage repair mechanisms and rare kinase fusions, potentially offering a rationale for new therapeutic strategies. In recent years, genomic analysis has been expanded by a more complex study of epigenomic, transcriptomic, and microenvironment features. The Consensus Molecular Subtype (CMS) classification describes four CRC subtypes with distinct biological characteristics that show prognostic and potential predictive value in the clinical setting. Here, we review the panorama of actionable targets in CRC, and the developments in more recent molecular tests, such as liquid biopsy analysis, which are increasingly offering clinicians a means of ensuring optimal tailored treatments for patients with metastatic CRC according to their evolving molecular profile and treatment history.

Outcome prognostic factors in inoperable malignant bowel obstruction.

PURPOSE: Inoperable malignant bowel obstruction (MBO), a severe complication of peritoneal carcinomatosis, has a low desobstruction rate (30-40 %) and end-of-life decision-making is hampered by the lack of known prognostic factors. This study aimed to explore prognostic factors for desobstruction in MBO. METHODS: All patients with inoperable MBO admitted in our large oncology hospital between 2010 and 2013 were treated following a clinical protocol based on antiemetics, steroids and two antisecretories, octreotide, and hyoscine butylbromide. Two prognostic factor analyses using logistic regressions were performed, one based on data from day 1 of admission and the other on data from day 8. RESULTS: Forty-five patients were included. Frequency of desobstruction was 48.9 %. In the analysis of prognostic factors on day 1, MBO episodes derived from functional physiopathologic mechanisms (vs. mechanic or mixed) were more prone to resolve (p < 0.001 corrected for multiple comparisons). Considering patients alive with persistent obstruction on day 8, a better clinical condition was the variable more associated with desobstruction, but without statistical significance after correction for multiple comparisons. CONCLUSIONS: A functional physiopathologic mechanism of MBO development may be an early prognostic factor for desobstruction. A high proportion of desobstruction was observed, suggesting that the combination of antisecretories with different mechanism of action warrants further investigation.

Carcinosarcoma of the upper urinary tract with an aggressive angiosarcoma component.

Carcinosarcomas (CS) are biphasic tumors with malignant epithelial and mesenchymal elements. The sarcomatoid elements of CS can include chondrosarcoma, malignant fibrous histiocytoma, osteosarcoma, leiomyosarcoma, fibrosarcoma, or liposarcoma. CS of the upper urinary tract are extremely rare but are associated with a poor prognosis. We report a case of a 44-year-old man with a localized right renal pelvis mass treated with a right nephroureterectomy. The pathological examination showed a high-grade urothelial carcinoma of the renal pelvis, stage III (pT3aNxM0). A few days later, he developed lower back pain, hematuria, cough with hemoptoic sputum and progressive dyspnea. Radiological explorations showed multiple bilateral lung nodules and a retroperitoneal mass. A CT-guided biopsy of the retroperitoneal mass revealed a high-grade angiosarcoma. A review of the nephrectomy specimen showed a microscopic focus of angiosarcoma in the urothelial carcinoma. Therefore, the initial diagnosis was changed to CS of the renal pelvis with an angiosarcoma component. The patient developed progressive respiratory failure and died 8 weeks after surgery. An autopsy revealed a large retroperitoneal mass with metastatic nodules to the abdominal wall, diaphragm, small intestine, liver, spleen, and lung. All lesions were angiosarcoma, with no evidence of urothelial carcinoma. This is the first case reported of a patient with CS of the upper urinary tract with an angiosarcoma component with a very aggressive course that caused the immediate appearance of multiple angiosarcoma metastases. We also describe the clinical and molecular characteristics of CS, which will help to contribute to a better understanding of this type of tumor.

Carcinoma de células renales y mieloma múltiple: asociación sincrónica con posible patogenia inmunológica / Renal-cell carcinoma and multiple mieloma: synchronic association with posible immunologic pathogenesis

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[Liver abscess: clinical, imaging and management features in a 5 year study in the Arzobispo Loayza National Hospital]. / Absceso Hepático: Caracteristicas Clínicas, Imagenologicas y manejo en el Hospital Loayza en 5 años.

UNLABELLED: The liver abscess (LA) continues to cause a high morbidity and mortality worldwide. OBJECTIVES: To determine demographic characteristics, clinical presentation, imaging and management at the Arzobispo Loayza Hospital in 5 years. METHODS: A descriptive retrospective study, based on medical records of patients diagnosed with LA between January 2003 to December 2007. RESULTS: Of 106 medical records reviewed, 46 entered the study. The mean age was 47.8 years (95% CI 41.9-53.8 years), 21 patients were over 50 years (45.6%) and 52.2% were male. The main symptoms were fever (95.6%) and right upper quadrant pain (73.5%). The average time of disease was 2.5 weeks. We found high frequency of hypoalbuminemia, elevated alkaline phosphatase, leukocytosis and anemia. The diagnosis was mostly based on ecography (97.8%), AH were mainly a single abscess (73%) located in the right lobe (77%), with an average diameter of 70 mm (p25-75: 44-90 mm), and 69.6% had more than 5 cm in diameter. Antibiotics were administered for 18.6 days (range: 3-30), being the combination administered more frequently metronidazole and ciprofloxacin. Seventeen patients (36.9%) underwent surgery, 7 patients (15.2%) received external drainage by percutaneous catheter and 10.9% (5 patients) was aspirated directly. CONCLUSION: LA is an acute or subacute disease of middle age without gender bias, whose main symptoms are fever and right upper quadrant pain. It is necessary to protocolize the management of this condition.

Absceso hepático: características clínicas, imagenológicas y manejo en el Hospital Nacional Arzobispo Loayza en 5 años / Liver abscess: clinical, imaging and management features in a 5 year study in the Arzobispo Loayza National Hospital

El absceso hepático (AH) sigue siendo causa de alta morbilidad y mortalidad en el mundo. Objetivo : Conocer las características demográficas, presentación clínico - imagenológica y manejo en el Hospital Nacional Arzobispo Loayza en 5 años.Métodos: Estudio descriptivo û retrospectivo, basado en la revisión de historias clínicas de pacientes con diagnóstico de AH entre Enero 2003 a Diciembre 2007. Resultados : De 106 historias clínicas revisadas, 46 ingresaron al estudio. La edadmedia fue de 47,8 años (95 por ciento IC 41,9-53,8 años), 21 pacientes eran mayores de 50 años (45,6 por ciento) y 52,2 por ciento fueron varones. Los síntomas principales fueron fiebre (95,6 por ciento) y dolor en hipocondrio derecho (73,5 por ciento); el tiempo promedio de enfermedad fue 2,5 semanas. Encontramos elevada frecuencia de hipoalbuminemia, incremento de fosfatasa alcalina, leucocitosis y anemia. El diagnóstico principalmente fue ecográfico (97,8 por ciento), como absceso único (73 por ciento), ubicado en lóbulo derecho (77), con un diámetro promedio de 70mm (p25-75: 44-90mm) y 69,6 por ciento tuvieron más de 5 cm de diámetro. Todos recibieron antibioticoterapia por 18,6 días en promedio (rango: 3-30); siendo la combinación más frecuente metronidazol y ciprofloxacino. Diecisiete pacientes (36,9 por ciento) fueron operados, 7 pacientes (15,2 por ciento) recibieron drenaje externo con catéter percutáneo y en 10,9 por ciento (5 pacientes) se manejó con aspiración directa. Conclusión : El AH es una patología aguda o subaguda, de mediana edad, sin preferencia de género, cuya sintomatología principal es fiebre y dolor en hipocondrio derecho. Es necesario protocolizar el manejo de esta patología.

The liver abscess (LA) continues to cause a high morbidity and mortality worldwide. Objetives: To determine demographic characteristics, clinical presentation, imaging and management at the Arzobispo Loayza Hospital in 5 years. Methods: A descriptive retrospective study, based on medical records of patients diagnosed with LA between January 2003 to December 2007. Results : Of 106 medical records reviewed, 46 entered the study. The mean age was 47.8 years (95 percent CI 41.9-53.8 years), 21 patients were over 50 years (45.6 percent) and 52.2 percent were male. The main symptoms were fever (95.6 percent) and right upper quadrant pain (73.5 percent). The average time of disease was 2.5 weeks. We found high frequency of hypoalbuminemia, elevated alkaline phosphatase, leukocytosis and anemia. The diagnosis was mostly based on ecography (97.8 percent), AH were mainly a single abscess (73 percent) located in the right lobe (77 percent), with an average diameter of 70 mm (p25-75: 44-90mm), and 69.6 percent had more than 5 cm in diameter. Antibiotics were administered for 18.6 days (range: 3-30), being the combination administered more frequently metronidazole and ciprofloxacin. Seventeen patients (36.9 percent) underwent surgery, 7 patients (15.2 percent) received external drainage by percutaneous catheter and 10.9 percent (5 patients) was aspirated directly. Conclusion : LA is an acute or subacute disease of middle age without gender bias, whose main symptoms are fever and right upper quadrant pain. It is necessary to protocolize the management of this condition.

[Tumoral microembolism and cor-pulmonar as manifestation of hepatocelular carcinoma]. / Microembolismo tumoral y cor-pulmonar como manifestación de carcinoma hepatocelular.

The tumour pulmonary micro-embolism is a rare condition characterized by the occlusion of pulmonary small arteries, arteriolas, and alveolar capillaries septales, accompanied of trombosis. Occasionally the development of pulmonary hypertension is the first manifestation of an occult neoplasia, in series of autopsies, an incidence from 3 to 26% has been reported in solid tumors, being clinical evident in 8%. Few cases have documented the development of this condition in patients with carcinoma hepatocelular, we report the case of a 16-year-old male who comes to the emergency with signs of cardiac insufficiency and cor pulmonare whose anatomopatological study confirmed a tumour massive microembolic compromise at pulmonary level and hepatocarcinoma.

Microembolismo tumoral y cor-pulmonar como manifestación de carcinoma hepatocelular / Tumoral microembolism and cor-pulmonar as manifestation of hepatocelular carcinoma

El micro-embolismo tumoral pulmonar es una rara condición caracterizada por la oclusión de arteria pulmonares pequeñas, arteriolas y capilares alveolares septales, acompañado de trombosis. Desarrolla ocasionalmente hipertensión pulmonar como primera manifestación de una neoplasia oculta, en series de autopsias se ha reportado una incidencia de 3 a 26 por ciento en tumores sólidos, siendo clínicamente evidentes en un 8 por ciento. Pocos casos se han documentado de esta condición en pacientes con carcinoma hepatocelular; nosotros reportamos el caso de un varón de 16 años que acude a la emergencia con signos de insuficiencia cardiaca y cor pulmonar cuyo estudio anatomopatológico confirmó la presencia de un hepatocarcinoma asociado a un compromiso tumoral micro-embólico masivo a nivel pulmonar.

The tumour pulmonary micro-embolism is a rare condition characterized by occlusion of pulmonary small arteries, arteriolas and alveolar capillaries septales, accompanied of trombosis. Occasionally the development of pulmonary hypertension is the first manifestation of an occult neoplasia, in series of autopsies, an incidence from 3 to 26 percentage has been reported in solid tumors, being clinical evident in 8 percentage. Few cases have documented the development of this condition in patients with carcinoma hepatocelular, we report the case of a 16 year-old male who comes to the emergency with signs of cardiac insufficiency and cor pulmonare wose anatomophatological study confirmed a tumour massive microembolic compromise at pulmonary level and hepatocarcinoma.