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Journal of Experimental & Clinical... May 2024Primary mediastinal B-cell lymphoma (PMBL) and classical Hodgkin lymphoma (cHL) are distinct hematological malignancies of B-cell origin that share many biological,...
BACKGROUND
Primary mediastinal B-cell lymphoma (PMBL) and classical Hodgkin lymphoma (cHL) are distinct hematological malignancies of B-cell origin that share many biological, molecular, and clinical characteristics. In particular, the JAK/STAT signaling pathway is a driver of tumor development due to multiple recurrent mutations, particularly in STAT6. Furthermore, the XPO1 gene that encodes exportin 1 (XPO1) shows a frequent point mutation (E571K) resulting in an altered export of hundreds of cargo proteins, which may impact the success of future therapies in PMBL and cHL. Therefore, targeted therapies have been envisioned for these signaling pathways and mutations.
METHODS
To identify novel molecular targets that could overcome the treatment resistance that occurs in PMBL and cHL patients, we have explored the efficacy of a first-in-class HSP110 inhibitor (iHSP110-33) alone and in combination with selinexor, a XPO1 specific inhibitor, both in vitro and in vivo.
RESULTS
We show that iHSP110-33 decreased the survival of several PMBL and cHL cell lines and the size of tumor xenografts. We demonstrate that HSP110 is a cargo of XPO1 as well as of XPO1. Using immunoprecipitation, proximity ligation, thermophoresis and kinase assays, we showed that HSP110 directly interacts with STAT6 and favors its phosphorylation. The combination of iHSP110-33 and selinexor induces a synergistic reduction of STAT6 phosphorylation and of lymphoma cell growth in vitro and in vivo. In biopsies from PMBL patients, we show a correlation between HSP110 and STAT6 phosphorylation levels.
CONCLUSIONS
These findings suggest that HSP110 could be proposed as a novel target in PMBL and cHL therapy.
Topics: Humans; Exportin 1 Protein; Karyopherins; Receptors, Cytoplasmic and Nuclear; Animals; Mice; Hodgkin Disease; Lymphoma, B-Cell; HSP110 Heat-Shock Proteins; Cell Line, Tumor; Mediastinal Neoplasms; Xenograft Model Antitumor Assays; Triazoles; Hydrazines; Female; STAT6 Transcription Factor; Molecular Targeted Therapy
PubMed: 38773631
DOI: 10.1186/s13046-024-03068-x -
Surgical Case Reports May 2024Mediastinal paragangliomas are rare. Their dangerousness may unfold during surgery, especially if hormonal activity was previously unknown. We report our experience with...
BACKGROUND
Mediastinal paragangliomas are rare. Their dangerousness may unfold during surgery, especially if hormonal activity was previously unknown. We report our experience with this case in context to the incidence and localization of atypically located mediastinal paragangliomas in the literature.
CASE PRESENTATION
A 69-year-old female patient who was scheduled for thoracoscopic resection due to a posterior mediastinal tumor that had been progressing in size for several years and increasing symptoms. The induction of anesthesia, the ventilation of the lungs and the gas exchange after lung separation was uneventful. After initially stable circulatory conditions, there was a sudden increase in blood pressure up to 300/130 mmHg and tachycardia up to 130/min. This hypertensive phase was difficult to influence and required a rapid and consistent use of antihypertensive medication to bring down the blood pressure to reasonable values. The patient stabilized after tumor resection. The postoperative course was unremarkable. During the intraoperative blood pressure crisis, blood was drawn for analysis. These samples showed elevated concentrations of normetanephrine and metanephrine. The tumor subsequently presented as a catecholamine-secreting paraganglioma.
CONCLUSION
In order to avoid life-threatening blood pressure crises, hormone activity should be ruled out preoperatively in the case of mediastinal tumor, in which a paraganglioma could be considered in the differential diagnosis, especially if there are indications of hypertension in the medical history. Robotic-assisted thoracoscopic resection of the posterior mediastinal tumor was a feasible surgical method, even in the case of unexpected functional paraganglioma.
PubMed: 38772971
DOI: 10.1186/s40792-024-01930-w -
Cancer May 2024Patients with relapsed primary mediastinal nonseminomatous germ cell tumor have low cure rates with salvage chemotherapy or surgery. The authors report survival outcomes...
High-dose chemotherapy and peripheral blood stem cell transplantation as salvage therapy in primary mediastinal nonseminomatous germ cell tumors: The Indiana University experience.
BACKGROUND
Patients with relapsed primary mediastinal nonseminomatous germ cell tumor have low cure rates with salvage chemotherapy or surgery. The authors report survival outcomes of patients who received high-dose chemotherapy (HDCT) and peripheral blood stem cell transplantation (PBSCT) at Indiana University.
METHODS
The prospectively maintained Indiana University germ cell tumor database identified 32 patients with primary mediastinal nonseminomatous germ cell tumor who progressed after first-line cisplatin-based combination chemotherapy and received HDCT and PBSCT between 2006 and 2021. Therapy included two consecutive courses of HDCT consisting of 700 mg/m carboplatin and 750 mg/m etoposide, each for 3 consecutive days, and each followed by PBSCT. A second course was not given if the patient experienced progressive disease or prohibitive toxicity. Progression-free survival and overall survival were analyzed using the Kaplan-Meier method. Medians with 95% confidence intervals were also calculated along with 2-year probabilities.
RESULTS
The median age at HDCT was 30 years (range, 18-61 years). With a median follow-up of 4.7 years (range, 1-14 years), the 2-year progression-free survival rate was 31% (95% confidence interval, 16%-47%), and the 2-year overall survival rate was 35% (95% confidence interval, 19%-52%). At last follow-up, nine patients (28%) remained without evidence of disease, including two platinum-refractory patients and two patients who were receiving HDCT as third-line therapy. There were three treatment-related deaths.
CONCLUSIONS
Salvage HDCT and PBSCT is an active combination in patients who have relapsed primary mediastinal nonseminomatous germ cell tumor with curative potential and prolonged survival, including in platinum-refractory and third-line settings. The authors recommend this approach for initial salvage chemotherapy in this patient population.
PubMed: 38768296
DOI: 10.1002/cncr.35375 -
Frontiers in Immunology 2024Corticosteroid therapy is the mainstay of immune effector cell-associated neurotoxicity syndrome (ICANS) management, although its use has been associated with worse...
Corticosteroid therapy is the mainstay of immune effector cell-associated neurotoxicity syndrome (ICANS) management, although its use has been associated with worse overall survival (OS) and progression-free survival (PFS) after chimeric antigen receptor T-cell (CAR-T cell) therapy. Many options are being investigated for prophylaxis and management. Accumulating evidence supports the use of intrathecal (IT) chemotherapy for the management of high-grade ICANS. Here, we describe a case of a patient with stage IV Primary mediastinal B-cell lymphoma (PMBCL) successfully treated with IT methotrexate, cytarabine, and dexamethasone as first-line therapy for CD19 CAR-T cell-associated grade IV ICANS. The stable and rapid resolution of ICANS to grade 0 allowed us to discontinue systemic corticosteroid use, avoiding CAR-T cells ablation and ensuring preservation of CAR-T cell function. The described patient achieved a complete radiologic and clinical response to CD19 CAR-T cell therapy and remains disease-free after 9 months. This case demonstrates a promising example of how IT chemotherapy could be used as first-line treatment for the management of high-grade ICANS.
Topics: Humans; Dexamethasone; Injections, Spinal; Methotrexate; Cytarabine; Antineoplastic Combined Chemotherapy Protocols; Male; Neurotoxicity Syndromes; Middle Aged; Treatment Outcome; Immunotherapy, Adoptive; Lymphoma, B-Cell; Female
PubMed: 38765003
DOI: 10.3389/fimmu.2024.1380451 -
Diseases of the Esophagus : Official... May 2024A high risk of complications still accompanies gastric conduit reconstruction after esophagectomy. In this narrative review, we summarize the technological progress and...
A high risk of complications still accompanies gastric conduit reconstruction after esophagectomy. In this narrative review, we summarize the technological progress and the problems of gastric conduit reconstruction after esophagectomy. Several types of gastric conduits exist, including the whole stomach and the narrow gastric tube. The clinical outcomes are similar between the two types of conduits. Sufficient blood supply to the conduit is mandatory for a successful esophageal reconstruction. Recently, due to the availability of equipment and its convenience, indocyanine green angiography has been rapidly spreading. When the blood perfusion of the planning anastomotic site is insufficient, several techniques, such as the Kocher maneuver, pedunculated gastric tube with duodenal transection, and additional microvascular anastomosis, exist to decrease the risk of anastomotic failure. There are two different anastomotic sites, cervical and thoracic, and mainly two reconstructive routes, retrosternal and posterior mediastinal routes. Meta-analyses showed no significant difference in outcomes between the anastomotic sites as well as the reconstructive routes. Anastomotic techniques include hand-sewn, circular, and linear stapling. Anastomoses using linear stapling is advantageous in decreasing anastomosis-related complications. Arteriosclerosis and poorly controlled diabetes are the risk factors for anastomotic leakage, while a narrow upper mediastinal space and a damaged stomach predict leakage. Although standardization among the institutional team members is essential to decrease anastomotic complications, surgeons should learn several technical options for predictable or unpredictable intraoperative situations.
PubMed: 38762331
DOI: 10.1093/dote/doae045 -
Acta Tropica Aug 2024Bovine tuberculosis (bTB) is a chronic infectious-contagious disease with worldwide distribution, caused by the zoonotic pathogen Mycobacterium bovis. It is believed...
Bovine tuberculosis (bTB) is a chronic infectious-contagious disease with worldwide distribution, caused by the zoonotic pathogen Mycobacterium bovis. It is believed that the existence of wild cycles may hamper the success of bTB control strategies worldwide, where wildlife species could be reservoirs of this bacterial agent across their native (e.g., European badgers, wild boars) or non-indigenous (e.g., brushtail possum in New Zealand) ranges. However, further studies are required to understand the potential risk posed by non-native wildlife in becoming carriers of M. bovis in other neglected latitudes, such as the Southern Cone of South America. In this study, we performed a specific M. bovis-RD4 real-time PCR (qPCR) assay to detect bacterial DNA in tissues from the invasive American mink (Neogale vison) in Los Ríos region, Chile. We detected M. bovis DNA in blood samples collected from 13 out of 186 (7 %) minks with known sex and age. We did not find any significant differences in bacterial DNA detection according to mink sex and age. We found that 92 % (12/13) of specimens were positive in lung, 39 % (5/13) in mediastinal lymph node, and 15 % (2/13) in mesenteric lymph node, which suggest that both respiratory and digestive pathways as possible routes of transmission between infected hosts and minks. Our study is the first report on M. bovis molecular detection in invasive minks in an area where the largest cattle population in the country is located. Furthermore, this area is characterized by a low within-herd prevalence of M. bovis infection in cattle, with a relatively low number of infected herds, and so far, no attempts at eradicating the disease have been successful.
Topics: Animals; Mycobacterium bovis; Mink; Chile; Female; Male; Real-Time Polymerase Chain Reaction; Tuberculosis; DNA, Bacterial; Carrier State; Disease Reservoirs; Lung
PubMed: 38761833
DOI: 10.1016/j.actatropica.2024.107257 -
Therapeutic Advances in Medical Oncology 2024Intimal sarcoma (InS) is an ultra-rare and aggressive subtype of soft tissue sarcoma (STS). It usually arises in large mediastinal arteries and the heart. In the...
Intimal sarcoma (InS) is an ultra-rare and aggressive subtype of soft tissue sarcoma (STS). It usually arises in large mediastinal arteries and the heart. In the advanced setting, sequential cytotoxic chemotherapy is often used, mainly based on retrospective studies and case series but with modest benefit. The use of immune checkpoint inhibitors is a promising strategy for some STS, but identifying biomarkers of response remains challenging due to disease rarity and heterogeneity. A reactive and pro-inflammatory tumor microenvironment (TME) is believed to be associated with better outcomes for patients receiving anti-PD-1-based regimens, generating the rationale to explore this strategy in malignancies with this characteristic, such as InS. We report three cases of advanced InS patients experiencing partial response to pembrolizumab-based therapy despite low tumor mutational burden and absence of mismatch-repair deficiency. We hypothesize that TME-related characteristics such as PD-L1 expression and the presence of tertiary lymphoid structures might explain this phenomenon.
PubMed: 38745586
DOI: 10.1177/17588359241250158 -
Cureus Apr 2024Lemierre-like syndrome is a rare, systemic sequelae following a persistent oropharyngeal infection, leading to septic thrombophlebitis of the internal jugular vein...
Lemierre-like syndrome is a rare, systemic sequelae following a persistent oropharyngeal infection, leading to septic thrombophlebitis of the internal jugular vein (IJV). Lemierre syndrome is caused by the obligate anaerobic organism , innate to the oropharyngeal tract. Lemierre-like syndrome is due to infections caused by other organisms, including methicillin-resistant (MRSA). We are reporting a case of a five-month-old male who presented with one week of fever that was not alleviated by acetaminophen, bilateral otitis media, and left-sided cervical lymphadenopathy not alleviated with medical therapy. The patient's clinical course continued to deteriorate as he developed respiratory distress that progressed to acute respiratory failure requiring mechanical ventilation support. Extensive laboratory investigation ruled out the causes of primary and secondary immunodeficiencies. Blood cultures were positive for MRSA, and he was treated initially with vancomycin, then switched to linezolid per ENT recommendations, and ultimately needed daptomycin and ceftaroline therapy. A computed tomography (CT) scan of the neck and chest showed deep neck space infection, bilateral loculated pleural empyema, and mediastinitis. The patient required a decortication video-assisted thoracoscopic surgery (VATS), multiple drains, and a mediastinal washout to control the MRSA infection. This report emphasizes that the rapid progression and spread of septic thrombus can become detrimental to a patient's recovery and survival; therefore, it should be recognized early and treated promptly.
PubMed: 38741847
DOI: 10.7759/cureus.58192 -
Fetal Diagnosis and Therapy May 2024Fetal thoracoamniotic shunts are common lifesaving interventions but frequently require replacement. Needle fetal thoracoscopy is a technique that uses standard...
INTRODUCTION
Fetal thoracoamniotic shunts are common lifesaving interventions but frequently require replacement. Needle fetal thoracoscopy is a technique that uses standard thoracoamniotic shunt introducer sheaths to permit direct visualization and even instrument manipulation during shunt deployment to facilitate optimal positioning and primary shunt function in the most challenging cases.
CASE PRESENTATION
In this study, 5 patients who underwent needle fetal thoracoscopy-assisted thoracoamniotic shunt placement were reviewed. Three patients with large, macrocystic congenital pulmonary airway malformations (CPAMs) with evidence of worsening mediastinal shift and/or hydrops and 2 patients with large chylothorax with fetal hydrops were treated. Four cases had previous shunts that failed due to poor sonographic visualization during initial placement, cyst septations, shunt obstruction, or dislodgment. Needle fetal thoracoscopy was used to disrupt cyst walls and septations, clear hematoma, and confirm the optimal initial position of the shunt. In this series, 1 severe CPAM patient with a short cervix developed preterm labor postoperatively resulting in neonatal demise. The remaining 4 patients experienced resolution of hydrops and progressed to successful delivery with excellent neonatal outcomes.
CONCLUSION
Needle fetal thoracoscopy is a procedure that may be selectively deployed in challenging thoracoamniotic shunt cases impacted by recurrent failure, poor sonographic windows, and challenging fetal positioning.
PubMed: 38740011
DOI: 10.1159/000539274 -
Journal of Thoracic Disease Apr 2024As a culture-independent method, metagenomic next-generation sequencing (mNGS) is widely used in microbiological diagnosis with advantages in identifying potential...
BACKGROUND
As a culture-independent method, metagenomic next-generation sequencing (mNGS) is widely used in microbiological diagnosis with advantages in identifying potential pathogens, guiding antibiotic therapy, and improving clinical prognosis, especially in culture-negative cases. () mediastinitis is a rare and severe disease for which etiological diagnosis is important but challenging. The application of mNGS in the etiological diagnosis of mediastinitis has seldom been studied.
METHODS
By searching the electronic medical history retrieval system with "" and "mediastinitis", seven patients diagnosed with mediastinitis were reviewed in Zhongshan Hospital, Fudan University, Shanghai from 9 December 2020 to 14 February 2023. Microbiological cultures and mNGS were conducted for blood, abscess, and/or mediastinal fluid. Adjustment of the antibiotic therapy due to mNGS was assessed. A literature review was conducted in the PubMed database beginning in 1970 for infection and mediastinitis.
RESULTS
For the seven patients, cultures of blood, abscess, and mediastinal fluid were negative whereas mNGS identified in serum, abscess, and/or mediastinal fluid and was used to guide specific antibiotic therapy. The stringent mapped reads number of genera (SMRNG), stringent mapped reads number of species (SMRN), and coverage rate of detection by mNGS were significantly higher in body fluid (abscess or mediastinal fluid) than in serum. All seven patients had underlying heart diseases and underwent previous cardiac surgery. The most common symptoms were fever and sternal pain. After detection of , antibiotics were adjusted to quinolones or doxycycline except for one patient, whose diagnosis was clarified after death. Two patients died. Literature review since 1970 identified 30 cases of extra-genital infection caused by . Including our seven new cases, 2 (5.4%) were neonates and 35 (94.6%) were adults. Thirty (81.1%) cases were postoperative infection and 15 (40.5%) had implanted devices. Five patients (13.5%) died.
CONCLUSIONS
mNGS might be a promising technology in the detection of fastidious pathogens such as . Accurate etiological diagnosis by mNGS could guide antibiotic therapy and facilitate clinical management.
PubMed: 38738251
DOI: 10.21037/jtd-24-286