Recurrent and atypical immune checkpoint inhibitor-induced pneumonitis.

INTRODUCTION: Pembrolizumab (Keytruda) is a monoclonal antibody against the programmed cell death-1 (PD-1) receptor on lymphocytes, which is one of the immune checkpoint inhibitors (ICIs) approved for multiple solid and hematologic malignancies. Although ICIs have proven to be more effective and less toxic compared to chemotherapy, there are reports of adverse side effects with ICIs. For example, pneumonitis is a potentially lethal side effect occurring in 1%-5% of patients who received ICIs in clinical trials, and there are case reports with clinical and radiological features of checkpoint inhibitor-pneumonitis (CIP). CASE REPORT: We report an unusual case of pneumonitis with atypical imaging in a patient who received pembrolizumab for metastatic p16-positive squamous cell carcinoma of the base of the tongue. We discuss the approach to the recognition and management of atypical CIP in patients on pembrolizumab with the intent to standardize workup and increase awareness among healthcare providers in the new era of immunotherapy. MANAGEMENT AND OUTCOME: Serologic workup including laboratory studies for complete blood count (CBC), lactate, procalcitonin, SARS-CoV-2 (COVID-19), Legionella, Cytomegalovirus (CMV), Coccidioides, Coxiella, and viral respiratory panel were negative for infectious processes. Since CIP was suspected, the patient was started on steroid therapy. Interval computed tomography (CT) of the chest without contrast showed a resolution of pneumonitis. DISCUSSION: In this case report, we discuss our workup of CIP and initial testing to rule out other possible causes of the patient's symptoms and radiographic findings, and management of the patient's diagnosis of atypical CIP which led to complete clinical recovery from CIP.

Unveiling the Prognostic Significance of BCL6+/CD10+ Mantle Cell Lymphoma: Meta-Analysis of Individual Patients and Systematic Review.

Mantle cell lymphoma (MCL) is a type of non-Hodgkin lymphoma (NHL) characterized by a hallmark translocation of t (11; 14). CD10 negativity has been used to differentiate MCL from other NHL types; however, recently, there has been an increase in the number of reported cases of CD10-positive MCL. This warrants further investigation into this rarer immunophenotype and its clinical significance. BCL6, which is a master transcription factor for the regulation of cell proliferation and key oncogene in B cell lymphomagenesis, has been reported to have co-expression with CD10 in MCL. The clinical significance of this aberrant antigen expression remains unknown. We conducted a systematic review by searching four databases and selected five retrospective analyses and five case series. Two survival analyses were conducted to determine if BCL6 positivity conferred a survival difference: 1. BCL6+ vs. BCL6- MCL. 2. BCL6+/CD10+ vs. BCL6-/CD10+ MCL. Correlation analysis was conducted to determine if BCL6 positivity correlated with the Ki67 proliferation index (PI). Overall survival (OS) rates were performed by the Kaplan-Meier method and log-rank test. Our analyses revealed that BCL6+ MCL had significantly shorter overall survival (median OS: 14 months vs. 43 months; p = 0.01), BCL6+/CD10+ MCL had an inferior outcome vs. BCL6+/CD10- MCL (median OS: 20 months vs. 55 months p = 0.1828), BCL6+ MCL had significantly higher percentages of Ki67% (Ki67% difference: 24.29; p = 0.0094), and BCL6 positivity had a positive correlation with CD10+ status with an odds ratio 5.11 (2.49, 10.46; p = 0.0000286). Our analysis showed that BCL6 expression is correlated with CD10 positivity in MCL, and BCL6 expression demonstrated an inferior overall survival. The higher Ki67 PI in BCL6+ MCL compared to BCL6- MCL further supports the idea that the BCL6+ immunophenotype may have prognostic value in MCL. MCL management should consider incorporating prognostic scoring systems adjusted for BCL6 expression. Targeted therapies against BCL6 may offer potential therapeutic options for managing MCL with aberrant immunophenotypes.

Comprehensive Review: Unveiling the Pro-Oncogenic Roles of IL-1ß and PD-1/PD-L1 in NSCLC Development and Targeting Their Pathways for Clinical Management.

In the past decade, targeted therapies for solid tumors, including non-small cell lung cancer (NSCLC), have advanced significantly, offering tailored treatment options for patients. However, individuals without targetable mutations pose a clinical challenge, as they may not respond to standard treatments like immune-checkpoint inhibitors (ICIs) and novel targeted therapies. While the mechanism of action of ICIs seems promising, the lack of a robust response limits their widespread use. Although the expression levels of programmed death ligand 1 (PD-L1) on tumor cells are used to predict ICI response, identifying new biomarkers, particularly those associated with the tumor microenvironment (TME), is crucial to address this unmet need. Recently, inflammatory cytokines such as interleukin-1 beta (IL-1ß) have emerged as a key area of focus and hold significant potential implications for future clinical practice. Combinatorial approaches of IL-1ß inhibitors and ICIs may provide a potential therapeutic modality for NSCLC patients without targetable mutations. Recent advancements in our understanding of the intricate relationship between inflammation and oncogenesis, particularly involving the IL-1ß/PD-1/PD-L1 pathway, have shed light on their application in lung cancer development and clinical outcomes of patients. Targeting these pathways in cancers like NSCLC holds immense potential to revolutionize cancer treatment, particularly for patients lacking targetable genetic mutations. However, despite these promising prospects, there remain certain aspects of this pathway that require further investigation, particularly regarding treatment resistance. Therefore, the objective of this review is to delve into the role of IL-1ß in NSCLC, its participation in inflammatory pathways, and its intricate crosstalk with the PD-1/PD-L1 pathway. Additionally, we aim to explore the potential of IL-1ß as a therapeutic target for NSCLC treatment.

Evidence for a functional role of epigenetically regulated midcluster HOXB genes in the development of Barrett esophagus.

Barrett esophagus (BE) is a human metaplastic condition that is the only known precursor to esophageal adenocarcinoma. BE is characterized by a posterior intestinal-like phenotype in an anterior organ and therefore it is reminiscent of homeotic transformations, which can occur in transgenic animal models during embryonic development as a consequence of mutations in HOX genes. In humans, acquired deregulation of HOX genes during adulthood has been linked to carcinogenesis; however, little is known about their role in the pathogenesis of premalignant conditions. We hypothesized that HOX genes may be implicated in the development of BE. We demonstrated that three midcluster HOXB genes (HOXB5, HOXB6, and HOXB7) are overexpressed in BE, compared with the anatomically adjacent normal esophagus and gastric cardia. The midcluster HOXB gene signature in BE is identical to that seen in normal colonic epithelium. Ectopic expression of these three genes in normal squamous esophageal cells in vitro induces markers of intestinal differentiation, such as KRT20, MUC2, and VILLIN. In BE-associated adenocarcinoma, the activation midcluster HOXB gene is associated with loss of H3K27me3 and gain of AcH3, compared with normal esophagus. These changes in histone posttranslational modifications correlate with specific chromatin decompaction at the HOXB locus. We suggest that epigenetically regulated alterations of HOX gene expression can trigger changes in the transcriptional program of adult esophageal cells, with implications for the early stages of carcinogenesis.

Advancing Esophageal Cancer Treatment: Immunotherapy in Neoadjuvant and Adjuvant Settings.

Locally advanced esophageal cancer (LAEC) poses a significant and persistent challenge in terms of effective treatment. Traditionally, the primary strategy for managing LAEC has involved concurrent neoadjuvant chemoradiation followed by surgery. However, achieving a pathologic complete response (pCR) has proven to be inconsistent, and despite treatment, roughly half of patients experience locoregional recurrence or metastasis. Consequently, there has been a paradigm shift towards exploring the potential of immunotherapy in reshaping the landscape of LAEC management. Recent research has particularly focused on immune checkpoint inhibitors, investigating their application in both neoadjuvant and adjuvant settings. These inhibitors, designed to block specific proteins in immune cells, are meant to enhance the immune system's ability to target and combat cancer cells. Emerging evidence from these studies suggests the possibility of a mortality benefit, indicating that immunotherapy may contribute to improved overall survival rates for individuals grappling with esophageal cancer. This manuscript aims to meticulously review the existing literature surrounding neoadjuvant and adjuvant immunotherapy in the context of LAEC management. The intention is to thoroughly examine the methodologies and findings of relevant studies, providing a comprehensive synthesis of the current understanding of the impact of immunotherapy on esophageal cancer.

Portal vein thrombosis as the presenting manifestation of JAK2 positive myeloproliferative neoplasm.

Deep venous thrombosis (DVT) is a complication of myeloproliferative neoplasms (MPNs). However, DVTs in unusual sites such as portal vein thrombosis (PVT) are rare and may be the first clinical manifestation of occult MPNs. There is a need for increasing awareness of such manifestations; so, here we discuss a patient who presented with new portal vein thrombosis, underwent further studies, was ultimately diagnosed with JAK2 positive MPN, and started on appropriate treatment with improvement of thrombosis and controlled hematocrit.

Perianal basosquamous carcinoma treated with radiation therapy, a case report.

Background: Perianal basal cell carcinoma (BCC) is very rare and estimated to account for 0.08% of all BCC and 0.02% of all anorectal neoplasms. Perianal lesions are more likely to be squamous cell carcinoma (SCC) as BCC usually develops on areas of skin exposed to ultraviolet (UV) light such as the face and arms. Proper diagnosis with the assistance of immunohistochemistry (IHC) stains to distinguish the two entities can help inform the suitable course of treatment. Case Description: Our case is an 82-year-old male with a history of cutaneous BCC on the arms and trunk presenting with a symptomatic perianal lesion. Initial biopsy demonstrated BCC with subsequent IHC studies differentiating from basaloid SCC. Standard treatment includes wide local excision (WLE) but given his poor performance status, radiation only was recommended. He was successfully treated and tolerated 30 Gy in 5 daily fractions. Conclusions: Radiation only is a unique and feasible non-surgical treatment for basosquamous carcinoma of the anus.

Leukostasis With Isolated Central Nervous System Involvement in Chronic Phase of Chronic Myelogenous Leukemia.

Chronic myelogenous leukemia (CML) is a hematologic malignancy with unique significance to the field of hematology and oncology, specifically due to the development of tyrosine kinase inhibitors (TKIs). CML often presents with nonspecific symptoms, and the quality of life in patients with CML has drastically improved as a result of TKIs. However, complications of CML including the risk of transforming into life-threatening blast crises continue to exist. Further, as most patients are asymptomatic in the chronic phase, patients often present with serious complications associated with noncompliance to TKIs. For example, central nervous system (CNS) manifestations of CML have been reported, both as the initial presentation of undiagnosed CML and as known complication of uncontrolled CML. Hyperleukocytosis is a manifestation of uncontrolled CML and leukostasis is a complication, occurring in cases of acute myeloid leukemia (AML). Here we present a rare case of leukostasis in a patient with known CML presenting on computed tomography (CT) as intracranial masses in the chronic phase. Our goal is to discuss this rare case of leukostasis in adult CML and describe its management.

Medullary carcinoma of the duodenum treated with pembrolizumab: a case report.

Background: Medullary carcinoma (MC) is a recognized histologic subtype of colorectal cancer characterized by poor glandular differentiation and intraepithelial lymphocytic infiltrate. However, MC originating from the small intestine is exceedingly rare, with only nine cases described in the literature. Based on previous cases, surgical resection is currently the mainstay of treatment for those with localized disease. We report the first case of a patient who presented with unresectable microsatellite instability-high (MSI-H) MC of the duodenum and was instead treated with pembrolizumab. Case Description: A 50-year-old man with history of adenocarcinoma of the proximal descending colon status post hemicolectomy and adjuvant treatment with chemotherapy and family history of Lynch syndrome presented with abdominal pain for two weeks. Computed tomography (CT) abdomen/pelvis revealed a 10.7 cm by 4.3 cm mass in the mid-portion of the duodenum abutting against the pancreatic head. Esophagogastroduodenoscopy (EGD) demonstrated circumferential, partially obstructing, intrinsic stenosis of the duodenum with ampullary involvement and likely invasion into the pancreatic head and common bile duct. Endoscopic biopsy of the primary tumor revealed poorly differentiated MC. Immunohistochemical staining showed loss of MLH1 and PMS2 expression. Staging with CT chest showed no evidence of disease. Positron emission tomography (PET) scan redemonstrated circumferential duodenal wall thickening and hypermetabolic activity with standardized uptake value (SUV) max of 26.4, as well as PET-avid epigastric, retroperitoneal, and periaortic lymphadenopathy suggestive of metastasis. He was started on pembrolizumab and found to have stable disease on repeat imaging along with significant improvement in symptoms and performance status. Conclusions: Due to the rarity of the tumor, there is no standardized approach to treatment. All patients in previously published cases underwent surgical resection. However, our patient was deemed a poor surgical candidate. Given his previous history of colon cancer and treatment with platinum-based therapy, he qualified for pembrolizumab as first line therapy for his MSI-H tumor. To our knowledge, this is the first report of MC of the duodenum as well as the first MC to be treated with pembrolizumab in the first line setting. In order to corroborate the use of immune checkpoint inhibitors as a treatment option for MC of the colon or small intestine, the aggregation of existing and future case data in this unique patient group is certainly warranted.

Leukemic infiltration of the optic nerve in chronic lymphocytic leukemia: A case report and review of literature.

Ophthalmic and neurologic involvement are rare complications of CLL, with few cases reported in the literature. We report a case of CLL with leukemic infiltration of the optic nerve and review of literature focusing on management and outcomes. A patient with heavily pretreated CLL presented to our hospital with progressive eye pain and was found to have infiltrative optic neuritis. CSF analysis confirmed involvement with CLL. After systemic treatment with R-CHOP and high-dose methotrexate, along with intrathecal cytarabine and hydrocortisone, she experienced significant improvement and was discharged home. Given the rarity of ophthalmic involvement in CLL, we reviewed all 15 previously reported cases of CLL with optic neuropathy as the first manifestation of CNS involvement and discussed the range of treatment options used and their respective outcomes.

Implante de células mononucleares en la osteonecrosis de cabeza femoral / Implant of mononuclear cells in femoral head osteonecrosis

La necrosis aséptica de la cabeza femoral (NACF) es la muerte de tejido óseo en la cabeza del fémur debido a inadecuado riego sanguíneo, la misma se ha asociado a diversas causas. En la osteonecrosis el grado de destrucción tanto de la arquitectura ósea como de la red de aporte sanguíneo a la cabeza del fémur se afecta en extremo y en muchos casos es necesaria la cirugía como las osteotomías valguizantes, varizantes, Sugioka y otras). En este estudio se utilizó la descompresión central asociada a la terapia celular. Se presenta un paciente masculino de 46 años, con antecedentes de Diabetes Mellitus, bebedor habitual, al cual se le diagnosticó de NACF de cadera izquierda mediante tomografía computarizada, y posteriormente se le realizó cirugía con perforaciones por vía lateral trocantérica (Descompresión Central) y administración de células mononucleares autólogas. El paciente fue dado de alta a las 48 h de operado, con limitación del apoyo los primeros 10 días, y después deambulación asistida. Se le realizaron radiografías a los 6 meses del implante. Después de un año de operado se le da alta y se indica la reincorporación del paciente a sus actividades sociales habituales, no constatando progresión de la osteonecrosis, y logrando así la deambulación sin asistencia(AU)

Aseptic necrosis of the femoral head (AVN-FH) is the death of bone tissue in the femoral head because of inadequate blood supply; it has been associated with various causes. The degree of destruction of bone architecture and the blood supply network to the femoral head is extremely affected. In many cases, surgery is necessary as valgus osteotomies, varus, Sugioka and others. Core decompression associated with cell therapy was used in this study. A male patient aged 46 is presented here. this patient has history of Diabetes Mellitus, regular alcohol consumption, he was diagnosed with aseptic necrosis of the femoral head left hip with CT scan, and he subsequently underwent surgery by perforated lateral approach trochanteric (Central Decompression) and administration of autologous mononuclear cells. The patient was discharged 48 hours after surgery, with limited support during the first 10 days, and then assisted ambulation. Radiographs were performed at 6 months after implantation. After a year of surgery the patient is discharged and he is instructed to return to his usual social activities, noting no progression of osteonecrosis, thus, non-assisted ambulation is achieved(AU)

Las plaquetas con fines terapéuticos en lesiones del Sistema osteomioarticular / Platelets for therapeutic purposes in SOMA injuries

La utilización de las plaquetas con fines terapéuticos ha cobrado gran interés en los últimos años por las grandes propiedades que presentan como reparadoras de tejidos. Además de su papel en la coagulación y la hemostasia, las plaquetas contienen gránulos alfa con varias moléculas (factores de crecimiento) que son secretadas tras su activación. Se realizó una revisión bibliográfica, donde se exponen las principales propiedades y funciones de las plaquetas que le confieren propiedades terapéuticas en diferentes lesiones del sistema osteomioarticular. Se presentan además sus componentes y funciones. Se llega a conclusiones destacando la utilidad de las plaquetas con fines terapéuticos en pacientes con afecciones ortopédicas.

The use of platelets for therapeutic purposes has gained great interest in recent years by their large properties as tissue repair. Besides its role in clotting and hemostasis, platelet alpha granules contain several molecules (growth factors) that are secreted upon activation. A literature review was performed to present the main features and functions of platelets that give them therapeutic properties in different injuries of the osteomioarticular system. Its components and functions are also presented here. Platelets usefulness for therapeutic purposes in patients with orthopedic conditions is highlighted.

Factores de crecimiento aportados por el lisado plaquetario en el tratamiento tópico de úlceras posflebíticas / Platelet lysate-derived growth factors for topical treatment of postphlebitis ulcers

Introducción: los factores de crecimiento plaquetario son proteínas bioactivas que se sintetizan y almacenan en las plaquetas. Objetivo: evaluar la efectividad de los factores de crecimiento aportados por el lisado plaquetario alogénico en el tratamiento tópico de úlceras posflebíticas Métodos: se realizó un estudio cuasi-experimental con control simultáneo en la consulta de medicina regenerativa, Hospital General Docente "Comandante Pinares", entre enero de 2008 y diciembre de 2012. Se evaluaron 135 pacientes con el diagnóstico de úlceras posflebíticas con inadecuada respuesta al tratamiento convencional y ausencia de otras enfermedades de base que impidieran una respuesta a la terapia regenerativa. Los pacientes se dividieron en dos grupos: 90 recibieron tratamiento con la aplicación local del lisado plaquetario obtenido de las plaquetas alogénicas ABO compatibles y 45 mantuvieron el tratamiento convencional (grupo control). El tiempo de respuesta fue la característica distintiva para medir la eficacia entre ambos tratamientos. Resultados: predominó el sexo femenino y edad de más de 50 años. Los síntomas cardinales del síndrome posflebítico, estuvieron presentes en un mayor número de pacientes del grupo tratado con el lisado plaquetario, sin embargo, a los 30 días, se constató una mejoría de los mismos así como una disminución significativa del área promedio de las úlceras. En el grupo tratado con lisado, 86 pacientes remitieron sus síntomas en menos de seis semanas, frente a solo ocho en el mismo tiempo en el grupo convencional. Conclusiones: el uso de factores de crecimiento aportados por el lisado plaquetario alogénico fue efectivo en el tratamiento tópico de úlceras posflebíticas(AU)

Introduction: platelet-derived growth factors are bio-active proteins that are synthesized and stored in the platelets. Objective: to evaluate the effectiveness of allogenic platelet lysate-derived growth factors in the topical treatment of postphlebitis ulcers. Methods: a quasi-experimental study with simultaneous control was conducted from January 2008 through December 2012 in the regenerative medicine service of "Comandante Pinares" general teaching hospital located in San Cristobal, Artemisa province, Cuba. One hundred and thirty five patients with diagnosis of postphlebitis ulcers, inadequate response to the conventional treatment and absence of other illnesses that could hinder such response to regenerative therapy were evaluated. The patients were divided into two groups: 90 treated with local use of compatible ABO allogenic platelet-derived platelet lysate and 45 kept under the conventional treatment (control group). The reaction time was the distinctive characteristic to measure the effectiveness of both treatments. Results: females and over 50 years-old age predominated. The main symptoms of the posphlebitic syndrome were present in a high number of patients in the group treated with the platelet lysate. Thirty days later, these symptoms significantly improved and the average ulcer area dramatically decreased. There was observed symptoms remission in eighty six patients in less than six weeks in contrast with only eight in the conventional group during this period. Conclusions: the use of allogenic platelet lysate-derived growth factors was effective in the topical treatment of postphlebitis ulcers(AU)