A first-in-class inhibitor of HSP110 to potentiate XPO1-targeted therapy in primary mediastinal B-cell lymphoma and classical Hodgkin lymphoma.

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 XPO1wt as well as of XPO1E571K. 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.

[Imaging characteristics and diagnosis of primary middle mediastinal tumors].

Objectives: To investigate the proportion of different histological types and CT enhanced imaging features of primary middle mediastinal lesions in order to improve the understanding of these tumors and the accuracy of preoperative diagnosis. Methods: Retrospective analysis was conducted on 84 patients with primary middle mediastinal lesions and clear histological classifications diagnosed and treated at the Cancer Hospital, Chinese Academy of Medical Sciences from January 2012 to December 2022. Clinical, imaging, and pathological data were collected and classified according to tumor histological classifications. CT imaging manifestations such as tumor location, size, morphology, edge, boundary, internal components, enhancement characteristics, and surrounding tissue invasion were evaluated and recorded. Results: The histological types of the primary middle mediastinal lesions from the 84 patients included mesenchymal tumors, anterior intestinal cysts, giant lymph node hyperplasia, substernal goiter, neuroendocrine carcinoma, lymphohematopoietic system tumors, and mesothelioma, accounting for 28.6%, 27.4%, 14.3%, 3.6%, 11.9%, 9.5%, and 4.8%, respectively. Mesenchymal tumors included peripheral nerve sheath tumors, vascular tumors, adipogenic tumors, solitary fibrous tumors, and synovial sarcoma, accounting for 54.2%, 20.8%, 12.5%, 8.3%, and 4.2%, respectively. The above tumors had diverse imaging manifestations and specific imaging features. Mature fat were found in 3 cases of liposarcoma; Calcification was observed in 2 cases of thyroid nodules and 7 cases of giant lymph node hyperplasia; Enhanced scanning showed significant enhancement in 2 cases of solitary fibrous tumors, 3 cases of thyroid nodules, and 11 cases of giant lymph node hyperplasia; Mediastinal large lymph nodes was observed in 6 cases of lymphoma and 3 cases of mesothelioma; High invasiveness was observed in 4 cases of mesothelioma and 9 cases of neuroendocrine carcinoma. Conclusion: Mediastinal tumors have low incidence rate and rich histological types, and their imaging manifestations are diverse. Preoperative differential diagnosis can be made according to their specific imaging characteristics.

Large atypical lipomatous tumour of the neck with mediastinal extension managed by transcervical excision.

Tumours of adipose tissue origin are relatively rare in the head and neck. Here, we report a case of an unfamiliar lipomatous lesion that involved the neck and mediastinum. A nil-comorbid man in his 40s presented with a slowly progressive anterior neck swelling of 3 years, which was diagnosed as lipoma by histopathological sampling. Computed tomography demonstrated the lesion to be involving parapharyngeal and retropharyngeal spaces with mediastinal extension. The lesion was removed by the transcervical approach. The final histology of the excised specimen, with immunohistochemistry for mouse double minute 2 (MDM2) and p16, suggested an atypical lipomatous tumour (ALT). This report accentuates the occurrence of this rare neoplasm in the neck, which often mimics lipoma clinically. Although radiology can demonstrate suggestive features, histology with MDM2 and/or p16 positivity can confirm the diagnosis of ALT as against the lipoma. A successful transcervical excision, despite the deeper extension of the lesion between the critical structures of the neck and mediastinum, demonstrates the non-infiltrating nature of the tumour.

Sarcoma of the Lung and Mediastinum.

Primary sarcoma of the lung and mediastinum is rare. The diagnosis requires careful exclusion of sarcomatoid carcinoma, sarcomatoid mesothelioma, and metastases from extra-thoracic sites. This review summarizes the key morphologic, immunohistochemical, and molecular characteristics of sarcomas that are encountered in the lung and mediastinum. The tumor types discussed are synovial sarcoma, well-differentiated/dedifferentiated liposarcoma, myxoid pleomorphic liposarcoma, intimal sarcoma of the pulmonary artery, inflammatory myofibroblastic tumor, epithelioid hemangioendothelioma, primary pulmonary myxoid sarcoma, malignant peripheral nerve sheath tumor, Ewing sarcoma, and CIC-rearranged sarcoma. Relevant differential diagnoses are also addressed.

[Malignant melanotic nerve sheath tumor of the posterior mediastinum]. / Tumor maligno melanocítico de la vaina neural en mediastino posterior.

Melanotic schwannoma (MS) is a rare and infrequent subtype of schwannoma characterized by cytoplasmic deposits of melanosomes (melanin). Unlike the other schwannomas, it could have malignant transformation. Due to distinctive characteristics and atypical behavior from classic schwannomas subtypes, MS were renamed and reclassified as "melanocytic malignant neural sheath tumor" in the 5th ed. of the World Health Organization's classification of central nervous system tumors in 2021. We present two cases of MS that underwent complete surgical resection.

El schwannoma melanótico (SM) es una variante rara e infrecuente caracterizada por el depósito citoplasmático de melanosomas (melanina). A diferencia de las otras variantes de schwannomas, tienen capacidad de malignización. Por poseer características y comportamiento distintos al resto de los schwannomas, fue reclasificado como "tumor maligno melanocítico de la vaina neural" en la 5ta edición de la clasificación de los tumores del sistema nervioso central de la Organización Mundial de la Salud en 2021. Presentamos dos casos de SM de ubicación mediastinal en los que se realizó una resección quirúrgica completa.

A rare presentation of primary cardiac myxofibrosarcoma: Case report and literature review.

BACKGROUND: Primary cardiac myxofibrosarcoma is a rare and aggressive malignancy, with the majority of approaching strategies relying on case reports. This article provides insights into its diagnosis and treatment. CASE PRESENTATION: This paper presents the case of a 40-year-old man with sudden onset hemoptysis, leading to the diagnosis of primary cardiac myxofibrosarcoma. Treatment involved open-heart surgery to excise the left atrium tumor, followed by 6 cycles of adjuvant chemotherapy. Unfortunately, brain metastasis developed, leading to the patient's death 1 year after initial diagnosis. CONCLUSION: Primary cardiac myxofibrosarcoma remains a clinical challenge with an unfavorable prognosis. Early diagnosis through advanced imaging is crucial, and research is needed to explore innovative treatments. This case underscores the complexities of managing this rare cardiac malignancy and highlights the necessity for ongoing investigations to enhance patient outcomes.

Spatiotemporal distribution of mediastinal neoplasms: A comprehensive multi-center study.

OBJECTIVES: Mediastinal neoplasms are typical but uncommon thoracic diseases with increasing incidence and unfavorable prognoses. A comprehensive understanding of their spatiotemporal distribution is essential for accurate diagnosis and timely treatment. However, previous studies are limited in scale and data coverage. Therefore, this study aims to elucidate the distribution of mediastinal lesions, offering valuable insights into this disease. MATERIALS AND METHODS: This multi-center, hospital-based observational study included 20 nationwide institutions. A retrospective search of electronic medical records from January 1st, 2009, to December 31st, 2020, was conducted, collecting sociodemographic data, computed tomography images, and pathologic diagnoses. Analysis focused on age, sex, time, location, and geographical region. Comparative assessments were made with global data from a multi-center database. RESULTS: Among 7,765 cases, thymomas (30.7%), benign mediastinal cysts (23.4%), and neurogenic tumors (10.0%) were predominant. Distribution varied across mediastinal compartments, with thymomas (39.6%), benign cysts (28.1%), and neurogenic tumors (51.9%) most prevalent in the prevascular, visceral, and paravertebral mediastinum, respectively. Age-specific variations were notable, with germ cell tumors prominent in patients under 18 and aged 18-29, while thymomas were more common in patients over 30. The composition of mediastinal lesions across different regions of China remained relatively consistent, but it differs from that of the global population. CONCLUSION: This study revealed significant heterogeneity in the spatiotemporal distribution of mediastinal neoplasms. These findings provide useful demographic data when considering the differential diagnosis of mediastinal lesions, and would be beneficial for tailoring disease prevention and control strategies.

Posterior mediastinal leiomyosarcoma: Case report and literature review.

BACKGROUND: Posterior mediastinal leiomyosarcoma is an extremely rare malignant mesenchymal tumor with no special clinical symptoms, which is easily confused with some common tumors in the posterior mediastinum, affecting the accuracy of the first diagnosis by clinicians and delaying the treatment of patients. CASE SUMMARY: We report a 59-year-old woman with a space-occupying lesion in the posterior mediastinum. The patient was mistakenly diagnosed with lumbar muscle or vertebral body lesions due to chest and back pain and underwent conservative treatment, but her symptoms did not improve significantly and she gradually developed pain in both lower limbs. Chest computed tomography (CT) scan indicated the left lower lung paraspinal space and underwent standard single-aperture video-assisted thoracoscopic surgery (VATS), which was pathologically confirmed as posterior mediastinal leiomyosarcoma. CONCLUSION: Complete surgical resection of posterior mediastinal leiomyosarcoma can achieve good clinical results.

[Progress in treatment of primary mediastinal large B-cell lymphoma].

Primary mediastinal large B-cell lymphoma (PMBCL) is an aggressive B-cell lymphoma originating from the thymus, which has different clinical and biological characteristics from diffuse large B-cell lymphoma, NOS. PMBCL tends to occur in young women, usually presenting as a large anterior mediastinal mass. Most patients are in stage Ⅰ-Ⅱ at the time of presentation. There is no standard prognostic scoring system for PMBCL. Immunochemotherapy is commonly used in the treatment of PMBCL, but the optimal first-line treatment has not been determined, and the status of radiotherapy is controversial. The value of PET-CT guided therapy needs to be further verified. Relapsed/refractory PMBCL has a poor prognosis, while novel therapies such as PD-1 inhibitors, brentuximab vedotin, and CAR-T can help improve survival in these patients.

Unusual presentation and delayed diagnosis of cardiac angiosarcoma.

BACKGROUND: Primary cardiac angiosarcomas are very rare and present aggressively with high rates of metastasis. Given the poor prognosis, particularly once disease has spread, early diagnosis and multidisciplinary treatment is essential. CASE PRESENTATION: We present the case of a 46-year-old male who presented with chest pain, intermittent fevers, and dyspnea. Workup with computed tomography scan and transesophageal echocardiography demonstrated a right atrial pseudoaneurysm. Given the concern for rupture, the patient was taken to the operating room, where resection of the pseudoaneurysm and repair using a bovine pericardial patch was performed. Histopathology report initially demonstrated perivascular lymphocyte infiltrate. Six weeks later, the patient represented with chest pain and new word finding difficulty. Workup revealed multiple solid lung, pericardial, brain, and bone nodules. Eventual biopsy of a cardiophrenic nodule demonstrated angiosarcoma, and rereview of the original pathology slides confirmed the diagnosis of primary cardiac angiosarcoma. CONCLUSIONS: Primary cardiac angiosarcomas are often misdiagnosed given the rarity of these tumors, but early diagnosis and initiation of treatment is essential. The unique presentation of our case demonstrates that clinical suspicion for cardiac angiosarcoma should be maintained for spontaneous pseudoaneurysm originating from the right atrium.

Axicabtagene ciloleucel treatment is more effective in primary mediastinal large B-cell lymphomas than in diffuse large B-cell lymphomas: the Italian CART-SIE study.

Axicabtagene ciloleucel showed efficacy for relapsed/refractory large B-cell lymphomas (LBCL), including primary mediastinal B-cell lymphomas (PMBCL); however, only few PMBCLs were reported. Aim was to evaluate efficacy and safety of axicabtagene ciloleucel in patients with PMBCL compared to those with other LBCL, enrolled in the Italian prospective observational CART-SIE study. PMBCLs (n = 70) were younger, with higher percentage of bulky and refractory disease, compared to other LBCLs (n = 190). Median follow-up time for infused patients was 12.17 months (IQR 5.53,22.73). The overall (complete + partial) response rate (ORR,CR + PR) after bridging was 41% for PMBCL and 28% for other LBCL, p = 0.0102. Thirty days ORR was 78% (53/68) with 50% (34) CR in PMBCL, and 75% (141/187) with 53% (100) CR in other LBCL, p = 0.5457. Ninety days ORR was 69% (45/65) with 65% (42) CR in PMBCL, and 54% (87/162) with 47% (76) CR in other LBCL; progressive disease was 21% in PMBCL and 45% in other LBCL, p = 0.0336. Twelve months progression-free survival was 62% (95% CI: 51-75) in PMBCL versus 48% (95% CI: 41-57) in other LBCL, p = 0.0386. Twelve months overall survival was 86% (95% CI: 78-95) in PMBCL versus 71% (95% CI: 64-79) in other LBCL, p = 0.0034. All grade cytokine release syndrome was 88% (228/260); all grade neurotoxicity was 34% (88/260), with 6% of fatal events in PMBCL. Non-relapse mortality was 3%. In conclusion, PMBCLs achieved significantly better response and survival rates than other LBCLs.

Mediastinal Germ-cell Tumors Relapse in a Male With Klinefelter Syndrome. Is Longer Surveillance Needed?

Germ cell tumors (GCTs) are a heterogeneous group of pediatric cancers. In up to one-third of male patients, a primary mediastinal location is associated with the presence of Klinefelter syndrome (KS). We describe a case of mediastinal GCT in a patient, with unacknowledged KS, that presented a relapse 7 years from diagnosis, that is, 2 years after the end of the follow-up program usually recommended for patients with GCT. There are no recommendations for screening for KS in patients with mediastinal GCT and there are no specific guidelines for surveillance of GCT in KS patients. Our experience suggests that KS should be suspected in patients with mediastinal GCT, and a longer follow-up plan should be implemented when GCT occurs in patients with KS.

Survival difference among adult and pediatric mediastinal yolk sac tumors cases: A meta-analysis of case reports.

BACKGROUND: Mediastinal Yolk sac tumors (YST) are rare and highly malignant extragonadal germ cell tumors with rapid growth and early metastases. We sought to conduct a meta-analysis of published case reports/case series to compare differences in survival, demographics, and treatment modalities between adult and pediatric patients with YST. METHODS: Ovid Embase, Cochrane, and Ovid Medline databases were searched for primary mediastinal pure YST cases. The primary outcome was overall survival (OS). Log-rank and Cox regression were used. This study is registered on PROSPERO (CRD42022367586). RESULTS: Among 846 studies, 87 met our inclusion criteria including 130 patients (Adults: 90 and Pediatrics: 40). About 41.5% of the patients were from the United States. The median age was 23.0 (Q1-Q3: 17.0-30.0), 88.5% were males, and (32.3%) were Asian. Stage II represented almost 40%. AFP was elevated in 96.9%. Respiratory distress was the presenting symptom in 65.4%. Chemotherapy, radiotherapy, and surgery were utilized in 84.6, 23.1, and 64.7% respectively. Median OS was 24 months (Adults: 23 months, Pediatrics: 25 months, P = 0.89). 3- and 5-year OS were 34.4% and 22.9% in adults and 41.5% and 41.5% in pediatrics, respectively. On multivariate analysis, anterior location of tumors, receipt of chemotherapy, and undergoing surgery were associated with better OS. CONCLUSION: Primary mediastinal YSTs are rare, but lethal neoplasms. Our meta-analysis showed that mediastinal YSTs mimic other non-seminomatous mediastinal GCTs in terms of clinical characteristics and available treatment options. Early diagnosis, neoadjuvant chemotherapy, and surgical resection are the key points for effective management and improved outcomes.

CT-guided percutaneous transthoracic needle biopsy for anterior mediastinal lymphoma: the role of PET/CT.

BACKGROUND: Computed tomography (CT)-guided percutaneous transthoracic needle biopsy (PTNB) is not recommended as the diagnostic modality of choice for anterior mediastinal lymphoma, despite its advantages of minimal invasiveness and easy accessibility. PURPOSE: To identify the modifiable risk factors for non-diagnostic results from CT-guided PTNB for anterior mediastinal lymphoma. MATERIAL AND METHODS: This retrospective study identified CT-guided PTNB for anterior mediastinal lesions diagnosed as lymphoma between May 2007 and December 2021. The diagnostic sensitivity and complications were investigated. The appropriateness of PTNB targeting was evaluated using positron emission tomography (PET)/CT and images from intra-procedural CT-guided PTNB. Targeting was considered inappropriate when the supposed trajectory of the cutting needle was within a region of abnormally low metabolism. The risk factors for non-diagnostic results were determined using logistic regression analysis. RESULTS: A total of 67 PTNBs in 60 patients were included. The diagnostic sensitivity for lymphoma was 76.1% (51/67), with an immediate complication rate of 4.5% (3/67). According to the PET/CT images, PTNB targeting was inappropriate in 10/14 (71.4%) of the non-diagnostic PTNBs but appropriate in all diagnostic PTNBs (P <0.001). Inappropriate targeting was the only significant risk factor for non-diagnostic results (odds ratio = 203.69; 95% confidence interval = 8.17-999.99; P = 0.001). The number of specimen acquisitions was not associated with non-diagnostic results (P = 0.40). CONCLUSIONS: Only inappropriate targeting of the non-viable portion according to PET/CT was an independent risk factor for non-diagnostic results. Acquiring PET/CT scans before biopsy and targeting the viable portion on PET/CT may help improve the diagnostic sensitivity of PTNB.

Surgical management of mediastinal mature cystic teratoma of the elderly remaining asymptomatic.

BACKGROUND: Mediastinal teratoma is an uncommon disease, nevertheless they represent the most common mediastinal germ cell tumors. It may grow silently for several years and remain undiagnosed until the occurrence of a complication. AIM: The main aim of this article is to illustrate the silent evolution of an anterior mediastinal teratoma for over 70 years without presenting any notable complications. CASE PRESENTATION: We present the case of a 70-year-old female, treated for hypertension referred to our department for managing a voluminous mediastinal mass, discovered fortuitously by a general practitioner in a chest X-ray. The anamnesis didn't relate any chest pain, cough, dyspnea nor hemoptysis. The clinical examination, in particular pleuropulmonary, was unremarkable. The workup (Chest X-Ray and CT scan) demonstrated a voluminous pleural mass at the expense of the right mediastinal pleura, rounded in shape, with calcified wall and fluid content. Blood tests did not demonstrate eosinophilia, and hydatid IgG serology was negative. serum human chorionic gonadotropin (hCG) and alpha fetoprotein (AFP) levels were found to be normal. The patient subsequently underwent a right posterolateral thoracotomy with resection of the lesion. The mass was dissected very carefully and then resected in toto. The macroscopic and microscopic histological examination demonstrated a mature cystic teratoma. Surgical resection was an adequate treatment and the prognosis was excellent for the patient. CONCLUSION: Cystic mature teratomas are rare thoracic tumors, often recognized by radiological examination. This article relates the silent evolution that a teratoma could have, and the late appearance of symptoms that it could have.