DORSALIS PEDIS NEUROVASCULAR FLAP, OUR EXPERIENCE.

Objectives: Analyze the donor site morbidity of the dorsalis pedis neurovascular flap in traumatic injuries with hand tissue loss. Material and Methods: The study involved dorsalis pedis neurovascular flaps that were used to reconstruct the hands of eight male patients, between 1983 and 2003, aged between 21 and 53 years (mean 34.6, SD ± 10.5 years). The size of the lesions ranged from 35 to 78 cm2 (mean 53, SD ± 14.4 cm2). Surgical procedures were performed two to 21 days after the injuries had occurred. The patients were followed up for an average of 10.3 years (ranging 8-14, SD ± 2.1 years). Results: Regarding the donor site, in one case there was hematoma formation, which was drained; in another case, the skin graft needed to be reassessed. All patients experienced delayed healing, with complete healing from 2 to 12 months after the surgery (mean 4.3, SD ± 3.2 months). Conclusion: Despite the advantages of the dorsalis pedis neurovascular flap, we consider that the sequelae in the donor site is cosmetically unacceptable. Nowadays, this procedure is only indicated and justified when associated with the second toe transfer. Level of Evidence IV; Case series .

Objetivos: Analisar a morbidade da área doadora do retalho neurovascular do dorso do pé em lesões traumáticas com perda de tecido da mão. Material e métodos: O estudo envolveu retalhos neurovasculares do dorso do pé usados para reconstruir as mãos de oito pacientes do sexo masculino, entre 1983 e 2003, com idades entre 21 e53 anos (média de 34,6, DP ± 10,5 anos). O tamanho das lesões variou de 35 a 78 cm2 (média de 53, DP ± 14,4 cm2). Os procedimentos cirúrgicos foram realizados entre dois a 21 dias após a ocorrência das lesões. Os pacientes foram acompanhados por uma média de10,3 anos (variando de 8 a 14, DP ± 2,1 anos). Resultados: Quanto ao local doador, em um caso houve formação de hematoma, que foi drenado; em outro caso, o enxerto de pele precisou ser reavaliado. Todos os pacientes apresentaram retardo na cicatrização, com cicatrização completa de 2 a 12 meses após a cirurgia (média de 4,3, DP ± 3,2 meses). Conclusão: Apesar das vantagens do retalho neurovascular do dorso do pé, consideramos que as sequelas no local doador são cosmeticamente inaceitáveis. Atualmente, esse procedimento só é indicado e justificado quando associado à transferência do segundo dedo do pé. Nível de evidência IV; Série de casos .

Dorsalis pedis neurovascular flap, our experience / Retalho neurovascular dorsal do pé, nossa experiência

ABSTRACT Objectives: Analyze the donor site morbidity of the dorsalis pedis neurovascular flap in traumatic injuries with hand tissue loss. Material and Methods: The study involved dorsalis pedis neurovascular flaps that were used to reconstruct the hands of eight male patients, between 1983 and 2003, aged between 21 and 53 years (mean 34.6, SD ± 10.5 years). The size of the lesions ranged from 35 to 78 cm2 (mean 53, SD ± 14.4 cm2). Surgical procedures were performed two to 21 days after the injuries had occurred. The patients were followed up for an average of 10.3 years (ranging 8-14, SD ± 2.1 years). Results: Regarding the donor site, in one case there was hematoma formation, which was drained; in another case, the skin graft needed to be reassessed. All patients experienced delayed healing, with complete healing from 2 to 12 months after the surgery (mean 4.3, SD ± 3.2 months). Conclusion: Despite the advantages of the dorsalis pedis neurovascular flap, we consider that the sequelae in the donor site is cosmetically unacceptable. Nowadays, this procedure is only indicated and justified when associated with the second toe transfer. Level of Evidence IV; Case series .

RESUMO Objetivos: Analisar a morbidade da área doadora do retalho neurovascular do dorso do pé em lesões traumáticas com perda de tecido da mão. Material e métodos: O estudo envolveu retalhos neurovasculares do dorso do pé usados para reconstruir as mãos de oito pacientes do sexo masculino, entre 1983 e 2003, com idades entre 21 e53 anos (média de 34,6, DP ± 10,5 anos). O tamanho das lesões variou de 35 a 78 cm2 (média de 53, DP ± 14,4 cm2). Os procedimentos cirúrgicos foram realizados entre dois a 21 dias após a ocorrência das lesões. Os pacientes foram acompanhados por uma média de10,3 anos (variando de 8 a 14, DP ± 2,1 anos). Resultados: Quanto ao local doador, em um caso houve formação de hematoma, que foi drenado; em outro caso, o enxerto de pele precisou ser reavaliado. Todos os pacientes apresentaram retardo na cicatrização, com cicatrização completa de 2 a 12 meses após a cirurgia (média de 4,3, DP ± 3,2 meses). Conclusão: Apesar das vantagens do retalho neurovascular do dorso do pé, consideramos que as sequelas no local doador são cosmeticamente inaceitáveis. Atualmente, esse procedimento só é indicado e justificado quando associado à transferência do segundo dedo do pé. Nível de evidência IV; Série de casos .

OBIF: an omics-based interaction framework to reveal molecular drivers of synergy.

Bioactive molecule library screening may empirically identify effective combination therapies, but molecular mechanisms underlying favorable drug-drug interactions often remain unclear, precluding further rational design. In the absence of an accepted systems theory to interrogate synergistic responses, we introduce Omics-Based Interaction Framework (OBIF) to reveal molecular drivers of synergy through integration of statistical and biological interactions in synergistic biological responses. OBIF performs full factorial analysis of feature expression data from single versus dual exposures to identify molecular clusters that reveal synergy-mediating pathways, functions and regulators. As a practical demonstration, OBIF analyzed transcriptomic and proteomic data of a dyad of immunostimulatory molecules that induces synergistic protection against influenza A and revealed unanticipated NF-κB/AP-1 cooperation that is required for antiviral protection. To demonstrate generalizability, OBIF analyzed data from a diverse array of Omics platforms and experimental conditions, successfully identifying the molecular clusters driving their synergistic responses. Hence, unlike existing synergy quantification and prediction methods, OBIF is a phenotype-driven systems model that supports multiplatform interrogation of synergy mechanisms.

Adecuación al flujograma PROA de neumonía aguda comunitaria en la emergencia del Hospital de Clínicas en 2019, Uruguay / Adaptation to the PROA flowchart for community acute pneumonia in the Hospital de Clínicas emergency in 2019, Uruguay / Adaptação ao fluxograma PROA para pneumonia aguda comunitária na emergência do Hospital de Clínicas em 2019, Uruguai

Resumen: Introducción: La resistencia antimicrobiana es uno de los principales problemas de salud pública mundial. Representa una causa importante de morbilidad en la población general y un elevado costo para los sistemas sanitarios. La Neumonía Aguda Comunitaria (NAC) representa una de las principales infecciones bacterianas en nuestro medio. Objetivo general: Evaluar la adecuación al flujograma del Programa de Optimización de Antimicrobianos (PROA) para el manejo de NAC en Departamento de Emergencia del Hospital de Clínicas (HC) entre julio y agosto de 2019. Materiales y métodos: Se realizó un estudio observacional, transversal, en el período de julio-agosto de 2019, en Departamento de Emergencia del Hospital de Clínicas. Se incluyeron pacientes mayores de 18 años, que firmaron el consentimiento informado, diagnosticados con NAC, cumpliendo criterios clínicos e imagenológicos establecidos en el flujograma del PROA del Hospital de Clínicas. Se elaboró una base de datos diseñada a partir del flujograma. Resultados: Se incluyeron 51 pacientes para el análisis. La edad promedio fue 54 años, 28 eran mujeres. Las comorbilidades más prevalentes fueron: tabaquismo, consumo de pasta base de cocaína y alcoholismo, presentes en 51% de la muestra. Treinta y cinco pacientes presentaron criterios de severidad, predominando insuficiencia respiratoria en 71%. Un 43 % presentaron factores de riesgo para microorganismos multirresistentes. Se observó una adecuación al PROA de 41%. Discusión: La adecuación al tratamiento recomendado fue inferior a la descrita en otros trabajos. El principal problema fue una errónea clasificación en los grupos de riesgo propuestos en el flujograma, ocasionando la hospitalización de pacientes que debieron recibir tratamiento ambulatorio, recibiendo antibioticoterapia de mayor espectro. Conclusiones: La existencia de PROA hospitalarios permite realizar monitoreo de prácticas diagnósticas y prescripción de antimicrobianos. Se observó una inadecuada aplicación del flujograma, lo que determinó el uso de antibióticos de mayor espectro con riesgo potencial del desarrollo de resistencia.

Abstract: Introduction: Antimicrobial resistance is one of the main world public health problems. It represents an important cause of morbidity in general population and a high cost for health systems. Community Acquired Pneumonia (CAP) represents one of the main bacterial infections in our midst. Objective: To evaluate the adequacy of the Antimicrobial Stewardship (AMS) in the management of CAP in the Emergency Department of Hospital de Clínicas (HC) between July and August 2019. Materials and methods: An observational, cross-sectional study was conducted from July-August 2019, in the Emergency Department of Hospital de Clínicas. Patients older than 18 years old were included, who signed the informed consent, diagnosed with CAP, fulfilling clinical and imaging criteria established in the flowchart. A database designed from the AMS flow chart of the Hospital de Clínicas was developed. Results: 51 patients were included for the analysis. The average age was 54 years, 28 were women. The most prevalent comorbidities were smoking, consumption of cocaine paste or alcoholism, present in 51% of the sample. Thirty-five patients presented severity criteria, prevailing respiratory failure in 71%. Risk factors for multiresistant microorganisms was 43%. PROA adequacy of 41.2% was observed. Discussion: The adequacy to the recommended treatment was lower than that described in other papers. The main problem was an erroneous classification in the risk groups proposed in the flowchart, causing hospitalization of patients who had to receive treatment at home, receiving broader spectrum antibiotic therapy. Conclusions: The existence of hospital stewardships allows monitoring of diagnostic practices and antimicrobial prescription. Inadequate application of the flow chart was observed, which determined the use of broader spectrum antibiotics with potential risk of developing resistance.

Resumo: Introdução: A resistência antimicrobiana é um dos principais problemas de saúde pública global. Representa uma das principais causas de morbidade na população em geral e um alto custo para os sistemas de saúde. A Pneumonia Aguda Comunitária (PAC) representa uma das principais infecções bacterianas em nosso meio. Objetivo: Avaliar a adequação do fluxograma do Programa de Otimização de Antimicrobianos (PROA) para o gerenciamento do PAC no Pronto Atendimento do Hospital de Clínicas (HC) entre julho e agosto de 2019. Materiais e métodos: Foi realizado um estudo observacional, transversal, no período de julho a agosto de 2019, no Pronto-Socorro do Hospital de Clínicas. Foram incluídos pacientes maiores de 18 anos, que assinaram o termo de consentimento livre e esclarecido, com diagnóstico de PAC, que preenchessem os critérios clínicos e de imagem estabelecidos no fluxograma do PROA do Hospital de Clínicas. Um banco de dados projetado a partir do fluxograma foi desenvolvido. Resultados: 51 pacientes foram incluídos para análise. A idade média era de 54 anos, 28 eram mulheres. As comorbidades mais prevalentes foram: tabagismo, consumo de pasta base de cocaína e etilismo, presentes em 51% da amostra. Trinta e cinco pacientes apresentaram critérios de gravidade, predominando insuficiência respiratória em 71%. 43% apresentaram fatores de risco para microrganismos multirresistentes. Observou-se adequação ao PROA de 41%. Discussão: A adequação ao tratamento recomendado foi inferior ao descrito em outros estudos. O principal problema era uma classificação errônea nos grupos de risco propostos no fluxograma, ocasionando a internação de pacientes que precisavam receber tratamento ambulatorial, recebendo antibioticoterapia de maior espectro. Conclusões: A existência de PROAs hospitalares permite o monitoramento das práticas diagnósticas e prescrição de antimicrobianos. Observou-se uma aplicação inadequada do fluxograma, que determinou o uso de antibióticos de maior espectro e com potencial risco de desenvolvimento de resistência.

Anatomical Study of the Motor Branches of the Radial Nerve in the Forearm.

Objective To analyze the anatomical variations of the motor branches of the radial nerve in the elbow region. The origin, course, length, branches, motor points and relationships with neighboring structures were evaluated. Materials and Methods Thirty limbs from15 adult cadavers were dissected and prepared by intra-arterial injection of a 10% glycerin and formaldehyde solution. Results The first branch of the radial nerve in the forearm went to the brachioradialis muscle (BR), originating proximally to the division of the radial nerve into superficial branch of the radial nerve (SBRN) and posterior interosseous nerve (PIN) in all limbs. The branches to the extensor carpi radialis longus muscle (ECRL) detached from the proximal radial nerve to its division into 26 limbs, in 2, at the dividing points, in other 2, from the PIN. In six limbs, the branches to the BR and ECRL muscles originated from a common trunk. We identified the origin of the branch to the extensor carpi radialis brevis muscle (ECRB) in the PIN in 14 limbs, in the SBRN in 12, and in the radial nerve in only 4. The branch to the supinator muscle originated from the PIN in all limbs. Conclusion Knowledge of the anatomy of the motor branches of the radial nerve is important when performing surgical procedures in the region (such as the approach of the proximal third and the head of the radius, release of compressive syndromes of the posterior interosseous nerve and radial tunnel, and distal nerve transfers) in order to understand the order of recovery of muscle function after a nerve injury.

Anatomical Study of the Motor Branches of the Radial Nerve in the Forearm / Estudo anatômico dos ramos motores do nervo radial no antebraço

Abstract Objective To analyze the anatomical variations of the motor branches of the radial nerve in the elbow region. The origin, course, length, branches, motor points and relationships with neighboring structures were evaluated. Materials and Methods Thirty limbs from15 adult cadavers were dissected and prepared by intra-arterial injection of a 10% glycerin and formaldehyde solution. Results The first branch of the radial nerve in the forearm went to the brachioradialis muscle (BR), originating proximally to the division of the radial nerve into superficial branch of the radial nerve (SBRN) and posterior interosseous nerve (PIN) in all limbs. The branches to the extensor carpi radialis longus muscle (ECRL) detached from the proximal radial nerve to its division into 26 limbs, in 2, at the dividing points, in other 2, from the PIN. In six limbs, the branches to the BR and ECRL muscles originated from a common trunk. We identified the origin of the branch to the extensor carpi radialis brevis muscle (ECRB) in the PIN in 14 limbs, in the SBRN in 12, and in the radial nerve in only 4. The branch to the supinator muscle originated from the PIN in all limbs. Conclusion Knowledge of the anatomy of the motor branches of the radial nerve is important when performing surgical procedures in the region (such as the approach of the proximal third and the head of the radius, release of compressive syndromes of the posterior interosseous nerve and radial tunnel, and distal nerve transfers) in order to understand the order of recovery of muscle function after a nerve injury.

Resumo Objetivo Analisar as variações anatômicas dos ramos motores do nervo radial na região do cotovelo. Foram avaliadas a origem, curso, comprimento, ramificações, pontos motores e relações com estruturas vizinhas. Materiais e Métodos Foram dissecados 30 membros de 15 cadáveres adultos, preparados por injeção intra-arterial de uma solução de glicerina e formol a 10%. Resultados O primeiro ramo do nervo radial no antebraço foi para o músculo braquiorradial (BR), que se origina proximalmente à divisão do nervo radial em ramo superficial do nervo radial (RSNR) e nervo interósseo posterior (NIP) em todos os membros. Os ramos para o músculo extensor radial longo do carpo (ERLC) se desprenderam do nervo radial proximalmente à sua divisão em 26 membros, em 2, nos pontos de divisão, em outros 2, do NIP. Em seis, os ramos para os músculos BR e ERLC originavam-se de um tronco comum. Identificamos a origem do ramo para o músculo extensor radial curto do carpo (ERCC) no NIP em 14 membros, no RSNR em 12, e no nervo radial em apenas 4. O ramo para o músculo supinador originou-se do NIP em todos os membros. Conclusão O conhecimento da anatomia dos ramos motores do nervo radial é importante quando se realizam procedimentos cirúrgicos na região, como a abordagem do terço proximal e da cabeça do rádio, a liberação das síndromes compressivas do nervo interósseo posterior e do túnel radial, as transferências nervosas distais, e para entender a ordem de recuperação da função muscular após uma lesão nervosa.

Low-dose radiation treatment enhances systemic antitumor immune responses by overcoming the inhibitory stroma.

BACKGROUND: Despite some successes with checkpoint inhibitors for treating cancer, most patients remain refractory to treatment, possibly due to the inhibitory nature of the tumor stroma that impedes the function and entry of effector cells. We devised a new technique of combining immunotherapy with radiotherapy (XRT), more specifically low-dose XRT, to overcome the stroma and maximize systemic outcomes. METHODS: We bilaterally established 344SQ lung adenocarcinoma tumors in 129Sv/Ev mice. Primary and secondary tumors were irradiated with either high-dose or low-dose of XRT with systemic anti-programmed cell death protein 1 and anti-cytotoxic T-lymphocyte associated protein 4 administration. Survival and tumor growth were monitored for the various groups, and secondary tumors were phenotyped by flow cytometry for immune populations. Tumor growth factor-beta (TGF-ß) cytokine levels were assessed locally after low-dose XRT, and specific immune-cell depletion experiments were conducted to identify the major contributors to the observed systemic antitumor effect. RESULTS: Through our preclinical and clinical studies, we observed that when tumor burden was high, there was a necessity of combining high-dose XRT to 'prime' T cells at the primary tumor site, with low-dose XRT directed to secondary (metastatic) tumors to 'modulate the stroma'. Low-dose XRT improved the antitumor outcomes of checkpoint inhibitors by favoring M1 macrophage polarization, enhancing natural killer (NK) cell infiltration, and reducing TGF-ß levels. Depletion of CD4+ T cells and NK cells abrogated the observed antitumor effect. CONCLUSION: Our data extend the benefits of low-dose XRT to reprogram the tumor environment and improve the infiltration and function of effector immune cells into secondary tumors.

Author Correction: Bone morphogenetic protein 7 promotes resistance to immunotherapy.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Bone morphogenetic protein 7 promotes resistance to immunotherapy.

Immunotherapies revolutionized cancer treatment by harnessing the immune system to target cancer cells. However, most patients are resistant to immunotherapies and the mechanisms underlying this resistant is still poorly understood. Here, we report that overexpression of BMP7, a member of the TGFB superfamily, represents a mechanism for resistance to anti-PD1 therapy in preclinical models and in patients with disease progression while on immunotherapies. BMP7 secreted by tumor cells acts on macrophages and CD4+ T cells in the tumor microenvironment, inhibiting MAPK14 expression and impairing pro-inflammatory responses. Knockdown of BMP7 or its neutralization via follistatin in combination with anti-PD1 re-sensitizes resistant tumors to immunotherapies. Thus, we identify the BMP7 signaling pathway as a potential immunotherapeutic target in cancer.

Interplay between estrogen and Stat3/NF-κB-driven immunomodulation in lung cancer.

K-ras mutant lung adenocarcinoma (LUAD) is the most common type of lung cancer, displays abysmal prognosis and is tightly linked to tumor-promoting inflammation, which is increasingly recognized as a target for therapeutic intervention. We have recently shown a gender-specific role for epithelial Stat3 signaling in the pathogenesis of K-ras mutant LUAD. The absence of epithelial Stat3 in male K-ras mutant mice (LR/Stat3Δ/Δ mice) promoted tumorigenesis and induced a nuclear factor-kappaB (NF-κB)-driven pro-tumor immune response while reducing tumorigenesis and enhancing anti-tumor immunity in female counterparts. In the present study, we manipulated estrogen and NF-κB signaling to study the mechanisms underlying this intriguing gender-disparity. In LR/Stat3Δ/Δ females, estrogen deprivation by bilateral oophorectomy resulted in higher tumor burden, an induction of NF-κB-driven immunosuppressive response, and reduced anti-tumor cytotoxicity, whereas estrogen replacement reversed these changes. On the other hand, exogenous estrogen in males successfully inhibited tumorigenesis, attenuated NF-κB-driven immunosuppression and boosted anti-tumor immunity. Mechanistically, genetic targeting of epithelial NF-κB activity resulted in reduced tumorigenesis and enhanced the anti-tumor immune response in LR/Stat3Δ/Δ males, but not females. Our data suggest that estrogen exerts a context-specific anti-tumor effect through inhibiting NF-κB-driven tumor-promoting inflammation and provide insights into developing novel personalized therapeutic strategies for K-ras mutant LUAD.

Anatomical Study of Radial Tunnel and its Clinical Implications in Compressive Syndromes.

Objective The purpose of the present study was to analyze the structures in the radial tunnel that can cause posterior interosseous nerve entrapment. Methods A total of 30 members of 15 adult cadavers prepared by intra-arterial injection of a 10% solution of glycerol and formalin were dissected. All were male, belonging to the laboratory of anatomy of this institution. Results The branch for the supinator muscle originated from the posterior interosseous nerve in all limbs. We identified the Frohse arcade with a well-developed fibrous constitution in 22 of the 30 dissected limbs (73%) and of muscular constitution in 8 (27%). The distal margin of the supinator muscle presented fibrous consistency in 7 of the 30 limbs (23.5%) and muscular appearance in 23 (76.5%). In the proximal margin of the extensor carpi radialis brevis muscle, we identified the fibrous arch in 18 limbs (60%); in 9 (30%) we noticed the arcade of muscular constitution; in 3 (10%) there was only the radial insertion, so that it did not form the arcade. Conclusion The Frohse arcade and the arcade formed by the origins of the extensor carpi radialis brevis are normal anatomical structures in adult cadavers. However, from the clinical point of view, these structures have the potential to cause entrapment of the posterior interosseous nerve.

Anatomical Study of Radial Tunnel and its Clinical Implications in Compressive Syndromes / Estudo anatômico do túnel radial e suas implicações nas síndromes compressivas

Abstract Objective The purpose of the present study was to analyze the structures in the radial tunnel that can cause posterior interosseous nerve entrapment. Methods A total of 30 members of 15 adult cadavers prepared by intra-arterial injection of a 10% solution of glycerol and formalin were dissected. All were male, belonging to the laboratory of anatomy of this institution. Results The branch for the supinator muscle originated from the posterior interosseous nerve in all limbs. We identified the Frohse arcade with a well-developed fibrous constitution in 22 of the 30 dissected limbs (73%) and of muscular constitution in 8 (27%). The distal margin of the supinator muscle presented fibrous consistency in 7 of the 30 limbs (23.5%) and muscular appearance in 23 (76.5%). In the proximal margin of the extensor carpi radialis brevis muscle, we identified the fibrous arch in 18 limbs (60%); in 9 (30%) we noticed the arcade of muscular constitution; in 3 (10%) there was only the radial insertion, so that it did not form the arcade. Conclusion The Frohse arcade and the arcade formed by the origins of the extensor carpi radialis brevis are normal anatomical structures in adult cadavers. However, from the clinical point of view, these structures have the potential to cause entrapment of the posterior interosseous nerve.

Resumo Objetivo O objetivo do presente estudo foi analisar as estruturas contidas no túnel radial que podem causar neuropatia compressiva do nervo interósseo posterior. Métodos Foram dissecados 30 membros de 15 cadáveres adultos, preparados por injeção intra-arterial de uma solução de glicerina e formol a 10%. Todos do sexo masculino, pertencentes ao laboratório de anatomia desta instituição. Resultados O ramo para o músculo supinador originou-se do nervo interósseo posterior em todos os membros. Identificamos a arcada de Frohse com uma constituição fibrosa bem desenvolvida em 22 dos 30 membros dissecados (73%) e de constituição muscular em 8 (23%) A margem distal do músculo supinador apresentou consistência fibrosa em 7 dos 30 membros (23,5%) e uma aparência muscular em 23 (76,5%). Na margem proximal do músculo extensor radial curto do carpo, identificamos a arcada fibrosa em 18 membros (60%); em 9 (30%), notamos a arcada de constituição muscular; e em três (10%) havia apenas a inserção radial, de maneira que não formava a arcada. Conclusão A arcada de Frohse e a arcada formada pelas origens do músculo extensor radial curto do carpo são estruturas anatômicas normais em cadáveres adultos. No entanto, sob o ponto de vista clínico, essas estruturas têm potencial para causar a compressão do nervo interósseo posterior.

Riché-Cannieu Anastomosis: Structure, Function, and Clinical Significance.

Objective To define the anatomy pattern and the incidence of Riché-Cannieu anastomosis, that is, median and ulnar communication in the palmar aspect of the hand. Materials Methods A total of 80 anatomical dissections were performed on 60 hands of 30 cadavers from 1979 to 1982, and on 20 hands from 2012 to 2015. All of these procedures were performed at the Department of Anatomy of our institution. The incidence of Riché-Cannieu anastomosis and the innervation of the thenar muscles were studied. Results Riché-Cannieu anastomosis was identified in every dissected hand (100%). The extramuscular Riché-Cannieu anastomosis was recorded in 57 hands, and the intramuscular, in 19 hands. The association of extra- and intramuscular Riché-Cannieu anastomoses occurred in four hands. The ulnar component always originated from the deep branch. The anastomotic branch arising from the median nerve originated from the motor thenar branch (recurrent branch) of the median nerve in most of the observations. The median-ulnar double innervation only to the deep head of the flexor pollicis brevis was identified in 29 of 80 hands. The double innervation only of the superficial head of the flexor pollicis brevis was found in 13 hands. In 12 hands, the deep head of the flexor pollicis brevis was absent. The double innervation of the superficial and deep heads of the flexor pollicis brevis occurred in 14 hands. The oblique head of the adductor pollicis received double innervation in 12 hands. The deep head of the flexor pollicis brevis and the oblique head of adductor pollicis were doubly-innervated in nine hands. The transverse head of the adductor pollicis received double innervation in two hands. Double innervation of the deep head of the flexor pollicis brevis and the transverse head of the adductor pollicis were found in one hand. Conclusion According to the present study, Riché-Cannieu anastomosis should be considered a normal anatomical neural connection, not an anatomical variation. Knowledge of this anastomosis is essential because the presence of such neural communication may result in confusing clinical, surgical, and electromyographic findings in cases of median or ulnar damage or entrapment.

Riché-Cannieu Anastomosis: Structure, Function, and Clinical Significance / Anastomose de Riché-Cannieu: estrutura, função e significância clínica

Abstract Objective To define the anatomy pattern and the incidence of Riché-Cannieu anastomosis, that is, median and ulnar communication in the palmar aspect of the hand. Materials Methods A total of 80 anatomical dissections were performed on 60 hands of 30 cadavers from 1979 to 1982, and on 20 hands from 2012 to 2015. All of these procedures were performed at the Department of Anatomy of our institution. The incidence of Riché-Cannieu anastomosis and the innervation of the thenar muscles were studied. Results Riché-Cannieu anastomosis was identified in every dissected hand (100%). The extramuscular Riché-Cannieu anastomosis was recorded in 57 hands, and the intramuscular, in 19 hands. The association of extra- and intramuscular Riché-Cannieu anastomoses occurred in four hands. The ulnar component always originated from the deep branch. The anastomotic branch arising from the median nerve originated from the motor thenar branch (recurrent branch) of the median nerve in most of the observations. The median-ulnar double innervation only to the deep head of the flexor pollicis brevis was identified in 29 of 80 hands. The double innervation only of the superficial head of the flexor pollicis brevis was found in 13 hands. In 12 hands, the deep head of the flexor pollicis brevis was absent. The double innervation of the superficial and deep heads of the flexor pollicis brevis occurred in 14 hands. The oblique head of the adductor pollicis received double innervation in 12 hands. The deep head of the flexor pollicis brevis and the oblique head of adductor pollicis were doubly-innervated in nine hands. The transverse head of the adductor pollicis received double innervation in two hands. Double innervation of the deep head of the flexor pollicis brevis and the transverse head of the adductor pollicis were found in one hand. Conclusion According to the present study, Riché-Cannieu anastomosis should be considered a normal anatomical neural connection, not an anatomical variation. Knowledge of this anastomosis is essential because the presence of such neural communication may result in confusing clinical, surgical, and electromyographic findings in cases of median or ulnar damage or entrapment.

Resumo Objetivo Definir a anatomia e a incidência da anastomose de Riché-Cannieu, ou seja, a comunicação entre os nervos medianos e ulnar na palma da mão. Materiais e Métodos Foram dissecadas 60 mãos de 30 cadáveres frescos de adultos, entre 1979 a 1982, e 20 mãos entre 2011 e 2015, num total de 80 mãos, no Departamento de Anatomia da nossa instituição. A incidência da anastomose de Riché-Cannieu e a inervação dos músculos da região do tênar foram estudadas. Resultados A anastomose de Riché-Cannieu foi identificada em todas as mãos dissecadas (100%). A anastomose de Riché-Cannieu extramuscular foi registrada em 57 mãos, e a intramuscular, em 19, e a associação das anastomoses extra e intramuscular, em 4 mãos. O componente ulnar da anastomose de Riché-Cannieu foi sempre do seu ramo profundo. O ramo anastomótico oriundo do nervo originava-se do ramo recorrente do nervo mediano na maioria das observações. A dupla inervação mediano-ulnar apenas da cabeça profunda do músculo flexor curto do polegar foi identificada em 29 de 80 mãos. Observou-se dupla inervação apenas da cabeça superficial do músculo flexor curto do polegar em 13 mãos. Foi observada dupla inervação das cabeças superficial e profunda do flexor curto do polegar em 14 mãos. A cabeça oblíqua do adutor do polegar recebeu inervação dupla em 12 mãos. A cabeça profunda do músculo flexor curto do polegar e a cabeça oblíqua do adutor do polegar foram inervadas duplamente em nove mãos. A cabeça transversa do adutor do polegar recebeu inervação dupla em duas mãos. A inervação dupla da cabeça profunda do flexor curto do polegar e da cabeça transversa do adutor do polegar foi observada em uma mão. Conclusão De acordo com o presente estudo, a anastomose de Riché-Cannieu deve ser considerada uma conexão nervosa normal, e não uma variação anatômica. O conhecimento dessa anastomose é essencial, pois a presença dessa comunicação neural pode resultar em achados clínicos, cirúrgicos e eletromiográficos confusos em casos de lesões ou síndromes compressivas dos nervos mediano ou ulnar.

Triple Therapy with MerTK and PD1 Inhibition Plus Radiotherapy Promotes Abscopal Antitumor Immune Responses.

PURPOSE: Radiotherapy (RT) traditionally has been used for local tumor control in the treatment of cancer. The recent discovery that radiotherapy can have anticancer effects on the immune system has led to recognition of its ability to sensitize the tumor microenvironment to immunotherapy. However, radiation can also prompt adverse immunosuppressive effects that block aspects of systemic response at other tumor sites. Our hypothesis was that inhibition of the MER proto-oncogene tyrosine kinase (MerTK) in combination with anti-programmed cell death-1 (α-PD1) checkpoint blockade will enhance immune-mediated responses to radiotherapy. EXPERIMENTAL DESIGN: We tested the efficacy of this triple therapy (Radiation + α-PD1 + α-MerTK mAbs) in 129Sv/Ev mice with bilateral lung adenocarcinoma xenografts. Primary tumors were treated with stereotactic radiotherapy (36 Gy in 3 12-Gy fractions), and tumors were monitored for response. RESULTS: The triple therapy significantly delayed abscopal tumor growth, improved survival rates, and reduced numbers of lung metastases. We further found that the triple therapy increased the activated CD8+ and NK cells populations measured by granzyme B expression with upregulation of CD8+CD103+ tissue-resident memory cells (TRM) within the abscopal tumor microenvironment relative to radiation only. CONCLUSIONS: The addition of α-PD1 + α-MerTK mAbs to radiotherapy could alter the cell death to be more immunogenic and generate adaptive immune response via increasing the retention of TRM cells in the tumor islets of the abscopal tumors which was proven to play a major role in survival of non-small cell lung cancer patients.

Anatomical Study of Innervation of the Supinator Muscle to Reinnervate the Posterior Interosseous Nerve.

Objective The purpose of this anatomical study was to analyze the possibility of transferring radial nerve branches to the supinator muscle to reinnervate the posterior interosseous nerve (PIN) originating from the C7-T1 roots. Methods Thirty members of 15 cadavers, all male, prepared with an intra-arterial glycerol and formaldehyde solution injection, were dissected. Results All dissected limbs presented at least one branch intended for the superficial and the deep heads of the supinator muscle. These branches originated from the PIN. A branch to the supinator muscle, proximal to the arcade of Frohse, was identified in six members. In addition, 2 and 3 branches to the supinator muscle were found in 11 and 4 members, respectively. In two limbs, only one branch detached from the PIN, but it duplicated itself proximal to the arcade of Frohse. Seven limbs had no branches to the supinator muscle at the region proximal to the arcade of Frohse. The branches destined for the supinator muscle were sectioned at the neuromuscular junction for connection with no tension to the PIN. The combined diameter of the branches for the supinator muscle corresponded, on average, to 53.5% of the PIN diameter. Conclusion The radial nerve branches intended for the supinator muscle can be transferred, with no tension, directly to the PIN to restore thumb and finger extension in patients with C7-T1 brachial plexus lesions.

Anatomical Study of Innervation of the Supinator Muscle to Reinnervate the Posterior Interosseous Nerve / Estudo anatômico da inervação do músculo supinador para reinervar o nervo interósseo posterior

Abstract Objective The purpose of this anatomical study was to analyze the possibility of transferring radial nerve branches to the supinator muscle to reinnervate the posterior interosseous nerve (PIN) originating from the C7-T1 roots. Methods Thirty members of 15 cadavers, all male, prepared with an intra-arterial glycerol and formaldehyde solution injection, were dissected. Results All dissected limbs presented at least one branch intended for the superficial and the deep heads of the supinatormuscle. These branches originated fromthe PIN. A branch to the supinator muscle, proximal to the arcade of Frohse, was identified in six members. In addition, 2 and 3 branches to the supinator muscle were found in 11 and 4 members, respectively. In two limbs, only one branch detached from the PIN, but it duplicated itself proximal to the arcade of Frohse. Seven limbs had no branches to the supinatormuscle at the region proximal to the arcade of Frohse. The branches destined for the supinator muscle were sectioned at the neuromuscular junction for connection with no tension to the PIN. The combined diameter of the branches for the supinator muscle corresponded, on average, to 53.5% of the PIN diameter. Conclusion The radial nerve branches intended for the supinator muscle can be transferred, with no tension, directly to the PIN to restore thumb and finger extension in patients with C7-T1 brachial plexus lesions.

Resumo Objetivo O objetivo deste estudo anatômico, foi analisar a possibilidade de transferir os ramos do nervo radial destinados ao músculo supinador para reinervar o nervo interósseo posterior (NIP), que se origina das raízes C7-T1. Métodos Foram dissecados 30 membros de 15 cadáveres, todos do sexo masculino, preparados por injeção intra-arterial de uma solução de glicerina e formol a 10%. Resultados Em todos os membros dissecados, encontramos pelo menos um ramo destinado a cada uma das cabeças - superficial e profunda - do músculo supinador. Esses tiveram origem no NIP. Identificamos, proximal à arcada de Frohse, umramo para o supinador em seis membros; 2 ramos para o supinador em 11 membros e 3 ramos em 4 membros. Em dois membros, apenas um ramo desprendia-se do NIP, mas se duplicava proximalmente à arcada de Frohse. Em sete membros, não identificamos ramos para o supinador proximal à arcada de Frohse. Os ramos destinados ao músculo supinador foram seccionados na junção neuromuscular, podendo ser conectados sem tensão ao NIP. O diâmetro somado dos ramos destinados ao músculo supinador correspondeu, em média, a 53,5% do diâmetro do NIP. Conclusão Este estudo anatômico mostra que ramos do nervo radial destinados ao músculo supinador podem ser transferidos diretamente para o NIP semtensão para restaurar a extensão do polegar e dos dedos em pacientes com lesões de plexo braquial C7-T1.

Anatomical study of the branch of the palmaris longus muscle for its transfer to the posterior interosseous nerve / Estudio anatómico del ramo del músculo palmar largo para su transferencia al nervio interóseo posterior

The objective of the study was to evaluate the anatomical characteristics and variations of the palmaris longus nerve branch and define the feasibility of transferring this branch to the posterior interosseous nerve without tension. Thirty arms from 15 adult male cadavers were dissected after preparation with 20 % glycerin and formaldehyde intra-arterial injection. The palmaris longus muscle (PL) received exclusive innervation of the median nerve in all limbs. In most it was the second muscle of the forearm to be innervated by the median nerve. In 5 limbs the PL muscle was absent. In 5 limbs we identified a branch without sharing branches with other muscles. In 4 limbs it shared origin with the pronator teres (PT), in 8 with the flexor carpi radialis (FCR), in 2 with flexor digitorum superficialis (FDS), in 4 shared branches for the PT and FCR and in two with PT, FCR, FDS. The mean length was (4.0 ± 1.2) and the thickness (1.4 ± 0.6). We investigated whether the branch for PL was long enough to be transferred to the posterior interosseous nerve (PIN). The branch diameter for PL corresponds to 46 % of the PIN. The PL muscle branch presented great variability. The PL branch could be transferred to the PIN proximally to the Froshe arcade without tension in all specimens even with full range of motion of the forearm. In 13 limbs was possible the tensionless transfer to PIN distal to the branches of the supinator muscle.

El objetivo de este estudio fue evaluar las características anatómicas y las variaciones del ramo del músculo palmar largo y definir la posibilidad de transferir este ramo al nervio interóseo posterior sin tensión. Se disecaron 30 miembros superiores de 15 cadáveres de hombres adultos después de su preparación con 20 % de glicerina y formaldehído, inyectados por vía intraarterial. En todos los miembros el músculo palmar largo (PL) recibió inervación exclusiva del nervio mediano. En la mayoría de los casos, fue el segundo músculo del antebrazo inervado por el nervio mediano. En 5 miembros estaba ausente el músculo. En 5 miembros identificamos un ramo sin compartir ramos con otros músculos. En 4 miembros, compartió el origen con el músculo pronador redondo (PR), en 8 con el músculo flexor radial del carpo (FRC), en 2 con el músculo flexor superficial de los dedos (FCSD), en 4 ramos compartidos para el PR y FRC y en dos con PR, FRC, FCSD. La longitud media fue (4,0±1,2 cm) y el grosor (1,4±0,6 cm). Investigamos si el ramo del PL era lo suficientemente largo para ser transferido al nervio interóseo posterior (NIP). El diámetro del ramo para el PL corresponde al 46 % del NIP. El ramo del músculo PL presentó una gran variabilidad. El ramo del PL podría transferirse al NIP proximalmente a la «arcada de Frohse¼, sin tensión, en todas las muestras, incluso con el rango completo de movimiento del antebrazo. En 13 miembros fue posible la transferencia sin tensión al NIP distal a los ramos del músculo supinador.

IDO1 Inhibition Overcomes Radiation-Induced "Rebound Immune Suppression" by Reducing Numbers of IDO1-Expressing Myeloid-Derived Suppressor Cells in the Tumor Microenvironment.

PURPOSE: The limitation of hypofractionated radiation efficacy is due partly to the immunosuppressive tumor microenvironment. Indoleamine 2,3-dioxygenase 1 (IDO1) is an important regulator of tumor immune suppression. We evaluated the effects of IDO1 in hypofractionated radiation using a Lewis lung carcinoma (LLC) mouse model and tested whether IDO1 inhibition could sensitize those tumors to hypofractionated radiation. METHODS AND MATERIALS: Bilateral LLC tumors were established in C57BL/6 mice. Primary tumors were treated with 3 fractions of either 12 Gy or 6 Gy, and the IDO1 inhibitor INCB023843 was given starting on the first day of radiation. Plasma tryptophan and kynurenine levels were quantified by liquid chromatography and tandem mass spectrometry. Tumor-infiltrating immune cells were isolated from the tumors, stained, and quantified by flow cytometry. RESULTS: The combination of INCB023843 and three 12-Gy fractions led to better tumor control and survival than radiation alone; INCB023843 plus three 6-Gy fractions had no benefit. IDO1 expression by tumor-infiltrating immune cells was increased by three 12-Gy doses and inhibited by the addition of INCB023843. Nearly all IDO1+ immune cells were also F4/80+. Percentages of IDO1+F4/80+ immune cells were drastically increased by three 12-Gy fractions and by three 6-Gy fractions, but only INCB023843 combined with three 12-Gy fractions reduced those percentages. IDO1+F4/80+ immune cells were further found to be CD11b+, Gr1-intermediate-expressing, CD206-, and CD11c- (ie, myeloid-derived suppressor cells). Three 12-Gy fractions also increased the percentages of tumor-infiltrating T regulatory cells and CD8+ T cells, but adding INCB023843 did not affect those percentages. CONCLUSIONS: In addition to its immune activation effects, hypofractionated radiation induced "rebound immune suppression" in the tumor microenvironment by activating and recruiting IDO1-expressing myeloid-derived suppressor cells in a dose-dependent manner. Adding an IDO1 inhibitor to hypofractionated radiation reduced the percentages of these cells, overcame the immune suppression, and sensitized LLC tumors to hypofractionated radiation.

Altered cancer metabolism in mechanisms of immunotherapy resistance.

Many metabolic alterations, including the Warburg effect, occur in cancer cells that influence the tumor microenvironment, including switching to glycolysis from oxidative phosphorylation, using opportunistic modes of nutrient acquisition, and increasing lipid biosynthesis. The altered metabolic landscape of the tumor microenvironment can suppress the infiltration of immune cells and other functions of antitumor immunity through the production of immune-suppressive metabolites. Metabolic dysregulation in cancer cells further affects the expression of cell surface markers, which interferes with immune surveillance. Immune checkpoint therapies have revolutionized the standard of care for some patients with cancer, but disease in many others is resistant to immunotherapy. Specific metabolic pathways involved in immunotherapy resistance include PI3K-Akt-mTOR, hypoxia-inducible factor (HIF), adenosine, JAK/STAT, and Wnt/Beta-catenin. Depletion of essential amino acids such as glutamine and tryptophan and production of metabolites like kynurenine in the tumor microenvironment also blunt immune cell function. Targeted therapies against metabolic checkpoints could work in synergy with immune checkpoint therapy. This combined strategy could be refined by profiling patients' mutation status before treatment and identifying the optimal sequencing of therapies. This personalized combinatorial approach, which has yet to be explored, may well pave the way for overcoming resistance to immunotherapy.