Metastatic organotropism: a brief overview.

Organotropism has been known since 1889, yet this vital component of metastasis has predominantly stayed elusive. This mini-review gives an overview of the current understanding of the underlying mechanisms of organotropism and metastases development by focusing on the formation of the pre-metastatic niche, immune defenses against metastases, and genomic alterations associated with organotropism. The particular case of brain metastases is also addressed, as well as the impact of organotropism in cancer therapy. The limited comprehension of the factors behind organotropism underscores the necessity for efficient strategies and treatments to manage metastases.

Identification of biomarkers predictive of metastasis development in early-stage colorectal cancer using network-based regularization.

Colorectal cancer (CRC) is the third most common cancer and the second most deathly worldwide. It is a very heterogeneous disease that can develop via distinct pathways where metastasis is the primary cause of death. Therefore, it is crucial to understand the molecular mechanisms underlying metastasis. RNA-sequencing is an essential tool used for studying the transcriptional landscape. However, the high-dimensionality of gene expression data makes selecting novel metastatic biomarkers problematic. To distinguish early-stage CRC patients at risk of developing metastasis from those that are not, three types of binary classification approaches were used: (1) classification methods (decision trees, linear and radial kernel support vector machines, logistic regression, and random forest) using differentially expressed genes (DEGs) as input features; (2) regularized logistic regression based on the Elastic Net penalty and the proposed iTwiner-a network-based regularizer accounting for gene correlation information; and (3) classification methods based on the genes pre-selected using regularized logistic regression. Classifiers using the DEGs as features showed similar results, with random forest showing the highest accuracy. Using regularized logistic regression on the full dataset yielded no improvement in the methods' accuracy. Further classification using the pre-selected genes found by different penalty factors, instead of the DEGs, significantly improved the accuracy of the binary classifiers. Moreover, the use of network-based correlation information (iTwiner) for gene selection produced the best classification results and the identification of more stable and robust gene sets. Some are known to be tumor suppressor genes (OPCML-IT2), to be related to resistance to cancer therapies (RAC1P3), or to be involved in several cancer processes such as genome stability (XRCC6P2), tumor growth and metastasis (MIR602) and regulation of gene transcription (NME2P2). We show that the classification of CRC patients based on pre-selected features by regularized logistic regression is a valuable alternative to using DEGs, significantly increasing the models' predictive performance. Moreover, the use of correlation-based penalization for biomarker selection stands as a promising strategy for predicting patients' groups based on RNA-seq data.

Genetic and microenvironmental intra-tumor heterogeneity impacts colorectal cancer evolution and metastatic development.

Colorectal cancer (CRC) is a highly diverse disease, where different genomic instability pathways shape genetic clonal diversity and tumor microenvironment. Although intra-tumor heterogeneity has been characterized in primary tumors, its origin and consequences in CRC outcome is not fully understood. Therefore, we assessed intra- and inter-tumor heterogeneity of a prospective cohort of 136 CRC samples. We demonstrate that CRC diversity is forged by asynchronous forms of molecular alterations, where mutational and chromosomal instability collectively boost CRC genetic and microenvironment intra-tumor heterogeneity. We were able to depict predictor signatures of cancer-related genes that can foresee heterogeneity levels across the different tumor consensus molecular subtypes (CMS) and primary tumor location. Finally, we show that high genetic and microenvironment heterogeneity are associated with lower metastatic potential, whereas late-emerging copy number variations favor metastasis development and polyclonal seeding. This study provides an exhaustive portrait of the interplay between genetic and microenvironment intra-tumor heterogeneity across CMS subtypes, depicting molecular events with predictive value of CRC progression and metastasis development.

Cetuximab versus bevacizumab in metastatic colorectal cancer: a comparative effectiveness study.

PURPOSE: Uncertainty exists regarding comparative effectiveness of cetuximab versus bevacizumab in metastatic colorectal cancer (mCRC). We conducted a retrospective head-to-head multi-cohort study comparing clinical outcomes from both antibodies METHODS: Cohorts were defined by treatment line and subgroups by (K)RAS status and tumour sidedness. Among other outcomes, we estimated and compared response rates, progression-free (PFS) and overall survival (OS). RESULTS: Between January 2010 and April 2018, 311 patients were included. Except for (K)RAS mutation status, baseline characteristics were balanced across treatment groups. In the full analysis of first and second-line cohorts, PFS (first-line: HR = 0.85; 95% CI 0.64 to 1.13; P = 0.26; second-line: HR = 1.16; 95% CI 0.74 to 1.83; P = 0.51) and OS (first-line: HR = 0.83; 95% CI 0.61 to 1.15; P = 0.26; second-line: HR = 0.88; 95% CI 0.56 to 1.38; P = 0.58) were similar between bevacizumab and cetuximab arms. In subgroup analyses of first-line therapy, we found a survival difference favouring bevacizumab in right-sided tumours (PFS: HR = 0.52; 95% CI 0.29 to 0.93; P = 0.025; OS: HR = 0.60; 95% CI 0.32 to 1.12; P = 0.11), but not in left-sided (HR = 1.04; 95% CI 0.75 to 1.46; P = 0.81; OS: HR = 0.94; 95% CI 0.65 to 1.36; P = 0.74), or (K)RAS wild-type tumours (PFS: HR = 0.91; 95% CI 0.60 to 1.40; P = 0.67; OS: HR = 0.79; 95% CI 0.50 to 1.25; P = 0.31). Response rates were similar across treatment groups, except for the subgroup of patients bearing right-sided primaries, where bevacizumab performed substantially better. CONCLUSION: This study provides evidence suggesting bevacizumab and cetuximab lead to similar effectiveness outcomes in mCRC, except for right-sided tumours, where cetuximab seemed to show considerably poorer outcomes. Further research is needed to confirm these results.

Patient-reported outcomes and health-related quality of life for cetuximab versus bevacizumab in metastatic colorectal cancer: a prospective cohort study.

PURPOSE: Uncertainty exists regarding Patient-Reported Outcomes (PROs) and Health-Related Quality of Life (HRQoL) of patients with metastatic colorectal cancer (mCRC) treated with cetuximab or bevacizumab. We conducted a prospective cohort study comparing PROs and HRQoL from both therapies. METHODS: We assessed PROs and HRQoL from patients treated with cetuximab or bevacizumab using QLQ-C30 and QLQ-CR29 questionnaires at three sequential time points, including baseline. Global Health Status (GHS), functional and symptom scales, and Overall Treatment Utility (derived from clinical and patient-reported outcomes) were compared for the two treatment strategies. RESULTS: Between January 2017 and April 2018, 44 patients were allocated to cetuximab (n = 19) or bevacizumab (n = 25). Except for RAS mutation status, patient baseline characteristics were generally well balanced across treatment groups. A higher proportion of patients experienced a deterioration in GHS (≥ 10%) in cetuximab arm - 53.8% (95% CI 25.1-80.8%) at 6 weeks and 66.7% (95% CI 29.9-92.5%) at 12 weeks-comparing to bevacizumab cohort: 18.2% (95% CI 5.2-40.3%) at 6 weeks and 12.5% (95% CI:1.6-38.3%) at 12 weeks. Treatment utility rates at 6 and 12 weeks were, respectively, 88.6% and 69.8% for bevacizumab, compared to 49% and 19.1% for cetuximab (p = 0.004), a difference confirmed in subset analyses. CONCLUSIONS: In patients with mCRC, cetuximab-containing regimens led to a progressive negative impact on PROs and global HRQoL, when compared to baseline and bevacizumab. Future research is needed to confirm these results. Our findings demonstrate the value of PROs when assessing comparative effectiveness of different treatment regimens.

Triplet (FOLFOXIRI) versus doublet (FOLFOX or FOLFIRI) backbone chemotherapy as first-line treatment of metastatic colorectal cancer: A systematic review and meta-analysis.

Uncertainty exists regarding the comparative effectiveness of triplet chemotherapy (FOLFOXIRI) as backbone first-line chemotherapy for metastatic colorectal cancer (mCRC). We conducted a systematic review and meta-analysis of randomized-controlled trials (RCTs) comparing triplet versus doublet chemotherapy (FOLFOX or FOLFIRI) as first-line therapy in mCRC. Methods and reporting followed PRISMA and SAMPL guidelines. Eight RCTs were included, comprising 1732 patients. In pooled analysis, FOLFOXIRI was associated with improvements in efficacy outcomes, notably with a 25% survival increase (95%CI: 10-37%). FOLFOXIRI was also associated with increased toxicity, with a non-significant 25% increase in the risk of patients experiencing grade ≥3 adverse events (95% CI: -3 to 61%) and with a 1.83 (95% CI: 1.62-2.07) increase in the rate ratio of grade ≥3 adverse events. Moderate quality evidence suggests that first-line FOLFOXIRI provides clinically meaningful efficacy benefits in this setting, at the expense of increased toxicity. Further research is warranted to better characterize safety and to evaluate the most beneficial combination with targeted agents.

Pazopanib-Induced Cutaneous Leukocytoclastic Vasculitis: An Exclusion Diagnosis of a Multidisciplinary Approach.

In phase II/III trials, cutaneous side effects of pazopanib were reported in less than 20% of patients, with only 1-3% being grade 3/4. We present a case of a 66-year-old man with a previous history of left nephrectomy for a stage II clear cell renal carcinoma. Approximately 18 months later, recurrent disease in the lungs, mediastinum, and left psoas and bulky abdominal/pelvic nodal metastasis were documented. He was initially treated with pazopanib 800 mg q.d. and 1 week after starting this therapy, the patient presented with palpable purpura on his ankles. These lesions regressed within 2 weeks off pazopanib, but had recurred 4 weeks after he resumed medication at 400 mg q.d. Biopsy of the lesions revealed leukocytoclastic vasculitis. Despite tumour response to therapy, pazopanib was discontinued with total resolution of this skin toxicity within 2 weeks of his cutaneous toxicity. To the best of our knowledge, we report a rare yet significant cutaneous adverse reaction to pazopanib.

Prevention of Nausea and Vomiting in Patients Undergoing Oral Anticancer Therapies for Solid Tumors.

Chemotherapy-induced nausea and vomiting (CINV) is still a common and debilitating side effect despite recent advances in its prevention and treatment. The intrinsic emetogenicity of chemotherapy agents allowed grouping into four risk groups (high, moderate, low, and minimal risk of emetogenicity). The prevention of acute and delayed CINV for intravenous agents and one day regimens is well studied, although, there are few data about management of CINV induced by oral cytotoxic agents and targeted therapies, usually administered in extended regimens of daily oral use. Until now treatment of nausea and vomiting caused by oral antineoplastic agents remains largely empirical. The level of evidence of prophylactic antiemetics recommended for these agents is low. There are differences in the classification of emetogenic potential of oral antineoplastic agents between the international guidelines and different recommendations for prophylactic antiemetic regimens. Herein we review the evidence for antiemetic regimens for the most used oral antineoplastic agents for solid tumors and propose antiemetic regimens for high to moderate risk and low to minimal risk of emetogenicity.

The Treatment of Liver Metastases in Patients with Neuroendocrine Tumors in 2012.

Neuroendocrine tumors (NETs) comprise a heterogeneous group of tumors that form a distinct entity. Approximately 75-80% of patients present with liver metastases at the time of their diagnosis, and 20%-25% will develop these lesions in the course of their disease. The presence of secondary deposits in the liver significantly increases the morbidity and mortality in these patients. The only potentially curative treatment is the surgical resection of the primary tumor and hepatic lesions. However, only 10% of patients presents under ideal conditions for that approach. Several techniques aimed at localized liver lesions have been applied also with interesting results in terms of survival and symptom control. The same has been demonstrated with new systemic therapies (target therapies). However, these are still under study, in order to define their true role in the management of these patients. This paper intends to address, in a general way, the various treatment options in patients with liver metastases from neuroendocrine tumors.

Prognostic significance of AKT/mTOR signaling in advanced neuroendocrine tumors treated with somatostatin analogs.

INTRODUCTION: Somatostatin analogs (SSAs) are used as part of standard treatment for advanced neuroendocrine tumors (NETs). The mechanisms behind the antiproliferative action of SSAs remain largely unknown, but a connection with the mammalian target of rapamycin (mTOR) signaling pathway has been suggested. Our purpose was to evaluate the activation status of the AKT/mTOR pathway in advanced metastatic NETs and identify biomarkers of response to SSA therapy. PATIENTS AND METHODS: Expression of phosphatase and tensin homolog (PTEN), phosphorylated (p)-AKT(Ser473), and p-S6(Ser240/244) was evaluated using immunohistochemistry in archival paraffin samples from 23 patients. Expression levels were correlated with clinicopathological parameters and progression-free survival under treatment with SSAs. RESULTS: A positive association between p-AKT and p-S6 expression was identified (P = 0.01) and higher expression of both markers was observed in pancreatic NETs. AKT/mTOR activation was observed without the loss of PTEN expression. Tumors showing AKT/mTOR signaling activation progressed faster when treated with SSAs: higher expression of p-AKT or p-S6 predicted a median progression-free survival of 1 month vs 26.5 months for lower expression (P = 0.02). CONCLUSION: Constitutive activation of the AKT/mTOR pathway was associated with shorter time-to-progression in patients undergoing treatment with SSAs. Larger case series are needed to validate whether p-AKT(Ser473) and p-S6(Ser240/244) can be used as prognostic markers of response to therapy with SSAs.

High temperature long period grating thermo-mechanically written.

An optical fiber transducer able to work in high temperature environments is experimentally demonstrated in the laboratory. It is based on a permanent long period grating (LPG) written using a new technique based on a thermo-mechanical approach. Device precision was experimentally checked by means of repetitive thermal cycles between 25 and 950 °C. In addition device stability was assured by maintaining the temperature in steady state at 800 °C during 23 hours.

[Thyroid carcinoma with thymus-like differentiation (CASTLE): case report and review of the literature]. / Carcinoma da tireóide com diferenciação semelhante a timo (CASTLE): relato de caso e revisão da literatura.

Carcinoma with thymus-like differentiation (CASTLE) is a rare malignant epithelial tumor which arises on soft tissue of the neck or thyroid gland. It is important to differentiate CASTLE from primary or metastatic squamous cell carcinoma of head and neck, and from squamous cell thyroid carcinoma, because it has a different prognosis. CD5 immunoreactivity might be helpful in CASTLE diagnosis. CASTLE behaves generally in an indolent fashion, even though it has a high relapse rate, while the other have a dismal prognosis due its high dissemination rate. Treatment includes surgical excision and radiotherapy. Chemotherapy can be offered, although its efficacy is not clear. Authors present a case of a 52 year-old male that complaints with cough, disphony, asthenia, and thyroid mass. Thyroidectomy was performed and the pathology revealed a CASTLE. After radiotherapy and chemotherapy, minimal response was obtained. The authors intend to discuss the differential pathologic diagnosis and the best therapy of this indolent but recurrent neoplasm, that demands strict long term follow-up.

Carcinoma da tireóide com diferenciação semelhante a timo (CASTLE): relato de caso e revisão da literatura / Thyroid carcinoma with thymus-like differentiation (CASTLE): case report and review of the literature

O carcinoma com diferenciação semelhante a timo (CASTLE) é uma neoplasia epitelial maligna rara, que surge nos tecidos moles do pescoço ou na glândula tireóide. O diagnóstico diferencial deve ser estabelecido com carcinoma pavimento-celular primário ou secundário da cabeça e do pescoço ou da tireóide, visto que têm prognósticos distintos. A imunorreatividade para CD5 pode ser útil no diagnóstico de CASTLE. O CASTLE possui elevada taxa de recidiva local, apesar de o seu curso clínico indolente, ao contrário das neoplasias previamente referidas, que têm um prognóstico muito reservado, dada a elevada taxa de disseminação sistêmica. O tratamento inclui excisão cirúrgica e radioterapia. A quimioterapia também tem sido realizada, apesar de até a presente data não existir evidência clara da sua eficácia. Relata-se caso de doente de sexo masculino, com 52 anos, que surge com tosse seca, disfonia e massa da tireóide, que foi submetido à tireoidectomia. O exame anatomopatológico da peça operatória permitiu o diagnóstico de CASTLE. O doente efetuou radioterapia e quimioterapia e obteve resposta mínima. Pretende-se discutir o diagnóstico anatomopatológico diferencial e a abordagem terapêutica mais adequada de uma patologia com prognóstico favorável, mas de natureza recidivante, que exige seguimento rigoroso a longo prazo.

Carcinoma with thymus-like differentiation (CASTLE) is a rare malignant epithelial tumor wich arises on soft tissue of the neck or thyroid gland. It is important to differentiate CASTLE from primary or metastatic squamous cell carcinoma of head and neck, and from squamous cell thyroid carcinoma, because it has a different prognosis. CD5 immunoreactivity might be helpful in CASTLE diagnosis. CASTLE behaves generally in an indolent fashion, even though it has a high relapse rate, while the other have a dismal prognosis due its high dissemination rate. Treatment includes surgical excision and radiotherapy. Chemotherapy can be offered, although its efficacy is not clear. Authors present a case of a 52 year-old male that complaints with cough, disphony, asthenia, and thyroid mass. Thyroidectomy was performed and the pathology revealed a CASTLE. After radiotherapy and chemotherapy, minimal response was obtained. The authors intend to discuss the differential pathologic diagnosis and the best therapy of this indolent but recurrent neoplasm, that demands strict long term follow-up.

Embedded spectroscopic fiber sensor for on-line arc-welding analysis.

A new fiber sensor system designed for spectroscopic analysis and on-line quality assurance of arc-welding processes is presented here. Although several different approaches have been considered for the optical capture of plasma emission in arc-welding processes, they tend to be invasive and make use of optical devices such as collimators or photodiodes. The solution proposed here is based on the arrangement of an optical fiber, which is used at the same time as the optical capturing device and also to deliver the optical information to a spectrometer, embedded within an arc-welding torch. It will be demonstrated that, by using the shielding gas as a protection for the fiber end, the plasma light emission is efficiently collected, forming a sensor system completely transparent and noninvasive for the welding operator. The feasibility of the proposed sensor designed to be used as the input optics of a welding quality-assurance system based on plasma spectroscopy will be demonstrated by means of several welding tests.

Interrogation unit for fiber Bragg grating sensors that uses a slanted fiber grating.

A novel interrogation technique for fiber Bragg gratings is presented. It is based on measuring the characteristics of the outgoing near-field radiation from a tilted fiber grating. This scheme was experimentally checked and was found to offer a wide wavelength interrogation range as well as a good linearity, stability, and wavelength resolution.

Interrogation of interferometric sensors with a tilted fiber Bragg grating.

This paper describes the interrogation of interferometer-based transducers with a technique that involves the use of a tilted fiber Bragg grating. The interrogation process will be analyzed both from the conceptual and experimental points of view. Simultaneous interrogation of multiplexed interferometric transducers is successfully checked using this technique.