Rare Subtype Research Articles

Managing crawling-type gastric adenocarcinoma with endoscopic techniques and postoperative monitoring

Crawling-type gastric adenocarcinoma is a rare subtype of gastric cancer with diagnostic and therapeutic challenges due to its flat, ill-defined lesions. Advanced diagnostic techniques, such as narrow-band imaging and linear endoscopic ultrasonography, improve detection, but endoscopic submucosal dissection poses a risk of incomplete resection. Despite negative resection margins, vigilant postoperative monitoring is crucial due to the potential for recurrence. This letter highlights the importance of refined diagnostic criteria, individualized treatment approaches, and continuous follow-up to optimize management of this unique gastric cancer subtype.

Pitfalls of frozen section diagnosis in ureter margin evaluation of plasmacytoid urothelial carcinoma of urinary bladder.

Plasmacytoid urothelial carcinoma (PUC) is a rare and aggressive subtype that often presents at advanced stages with poor prognosis. This study investigated tumor invasion to better understand tumor behavior and potentially to improve management strategies by comparing the clinicopathologic characteristics of PUC with positive ureter resection margin (+ URM) with PUC with negative URMs (-URM). This retrospective analysis used pathology reports from 2017 to 2023 for cases diagnosed with PUC during radical cystectomy (RC). All applicable H&E slides of RC specimens were reviewed. Cases with a plasmacytoid component greater than 25% in the RC specimens were analyzed. Frozen section analyses (FSAs) and permanent section analyses (PSAs) of ureter resection margins were performed. Fifteen patients with a plasmacytoid component greater than 25% in their RC specimens were identified. Compared with -URM PUC cases, +URM PUC cases were located more frequently at the trigone or bladder neck, and all + URM cases exhibited ureter orifice involvement. Among 6 PSA-positive cases, three (50%) cases showed discrepancies with FSA. Three + URM cases exhibited PUC tumor cells along the submucosa and muscularis propria layer, and the 3 remaining cases showed PUC tumor cells along the adventitia. We observed a consistent adventitia invasion in all the discordant cases, with sectioning errors and misinterpretation identified as the primary causal factors. To the best of our knowledge, this is the first study to demonstrate two separate patterns of tumor infiltration along the ureter and to discuss the significance of comparing FSA with PSA in PUC. The significance of comprehensive management strategies for PUC patients, including a thorough evaluation of ureteral margins and accurate interpretation of periureteral fat tissue, is highlighted. Large, well-designed studies are needed to strengthen the evidence and to establish optimal management strategies for patients with PUC.

Cytologic hallmarks and differential diagnosis of papillary thyroid carcinoma subtypes

Papillary thyroid carcinoma (PTC) is the most common thyroid malignancy, characterized by a range of subtypes that differ in their cytologic features, clinical behavior, and prognosis. Accurate cytologic evaluation of PTC using fine-needle aspiration is essential but can be challenging due to the morphologic diversity among subtypes. This review focuses on the distinct cytologic characteristics of various PTC subtypes, including the classic type, follicular variant, tall cell, columnar cell, hobnail, diffuse sclerosing, Warthin-like, solid/trabecular, and oncocytic PTCs. Each subtype demonstrates unique nuclear features, architectural patterns, and background elements essential for diagnosis and differentiation from other thyroid lesions. Recognizing these distinct cytologic patterns is essential for identifying aggressive subtypes like tall cell, hobnail, and columnar cell PTCs, which have a higher risk of recurrence, metastasis, and poorer clinical outcomes. Additionally, rare subtypes such as diffuse sclerosing and Warthin-like PTCs present unique cytologic profiles that must be carefully interpreted to avoid diagnostic errors. The review also highlights the cytologic indicators of lymph node metastasis and high-grade features, such as differentiated high-grade thyroid carcinoma. The integration of molecular testing can further refine subtype diagnosis by identifying specific genetic mutations. A thorough understanding of these subtype-specific cytologic features and molecular profiles is vital for accurate diagnosis, risk stratification, and personalized management of PTC patients. Future improvements in diagnostic techniques and standardization are needed to enhance cytologic evaluation and clinical decision-making in thyroid cancer.

Case series of pure mucinous breast carcinoma: A rare histopathological subtype

Pure mucinous breast carcinoma (PMBC) is even rarer and accounts for about 2% of all primary breast carcinoma. It is composed entirely of tumour cells with abundant extracellular mucin and without admixing of infiltrating ductal carcinoma. We studied a total of ten cases of Pure Mucinous Breast Carcinoma. Here we describes each case of demographic features and histopathological features of PMBC. The results of immunohistochemistry of Estrogen receptor (ER), Progesterone receptor (PR), Human epidermal growth factor receptor 2(HER-2neu) were also noted in this case series. All the cases were female and above 50 years of age. Out of 10 cases, 6 cases have the tumour’s location on the left side of the breast and 4 cases have the tumour’s location on the right side of the breast. All the cases belong to the lower grading and staging of the tumour. Only one case had positive lymph node status.Hormone receptor status of all the cases has ER & PR positive expression, HER-2neu negative expression and low Ki 67 labelling index. To conclude, PMBC was associated with lower-grade tumours, lower-stage, infrequent lymph node metastasis and luminal type A hormonal receptor status. These favourable findings suggest that PMBC has a better prognosis and may give a better response to hormonal therapy.

Myxoid Solitary Fibrous Tumor of the Nasal Vestibule: An Unusual Histological Subtype in the Head and Neck Region.

Solitary fibrous tumors (SFTs) are mesenchymal neoplasms associated with the characteristic NAB2::STAT6 gene fusion. They frequently occur in extra-thoracic sites and are not uncommon in the head and neck (HN) region. Myxoid SFT is a rare morphological subtype of SFT, the features of which overlap with those of other myxoid-appearing tumors, making the diagnosis challenging. We describe the distinctive histopathological and immunohistochemical features of myxoid SFT that occurred in a 32-year-old man with a recurrent swelling in the nasal vestibule. Histological examination showed a nodular tumor composed of short spindle-shaped cells in an abundant myxoid stroma. Nuclei were ovoid, with minimal pleomorphism. Occasional intervening slender vascular channels were present; staghorn vasculature was absent. Tumor cells were diffusely immunopositive for STAT6, CD34, and BCL2, while S100, SOX10, EMA, ER, and CD10 were negative, confirming the diagnosis of myxoid SFT. Thus, myxoid SFTs are unusual in the HN, with potential for misdiagnosis. Due to their propensity for local recurrence if incompletely excised, a high index of suspicion is required to include them in differential diagnosis of myxoid mesenchymal neoplasms occurring at this location. STAT6 is a reliable immunohistochemical marker that aids in diagnosis, reducing the necessity for molecular testing.

Improved identification of clinically relevant Acute Leukemia subtypes using standardized EuroFlow panels versus non-standardized approach.

Rare acute leukemia (AL) components or subtypes such as blastic plasmacytoid dendritic cell neoplasm (BPDCN) or early T-cell precursor acute Lymphoblastic Leukemia (ETP-ALL) can be difficult to detect by routine flow cytometry due to their immunophenotypes overlapping with other poorly differentiated AL. We hypothesized that using standardized EuroFlow™ Consortium approach could better diagnose such entities among cases that previously classified as acute myeloid leukemia (AML)-M0, AML with minimal differentiation, AML with myelodysplasia-related changes without further lineage differentiation, and AL of ambiguous lineage. In order to confirm this hypothesis and assess whether these AL subtypes such as BPDCN and ETP-ALL had previously gone undetected, we reanalyzed 49 banked cryopreserved sample cases using standardized EuroFlow™ Consortium panels. We also performed target sequencing to capture the mutational commonalities between these AL subtypes. Reanalysis led to revised or refined diagnoses for 23 cases (47%). Of these, five diagnoses were modified, uncovering 3 ETP-ALL and 2 typical BPDCN cases. In 12 AML cases, a variable proportion of immature plasmacytoid dendritic cell and/or monocytic component was newly identified. In one AML case, we have identified a megakaryoblastic differentiation. Finally, in five acute lymphoblastic leukemia (ALL) cases, we were able to more precisely determine the maturation stage. The application of standardized EuroFlow flow cytometry immunophenotyping improves the diagnostic accuracy of ALs and could impact treatment decisions.

Characteristics and therapeutic outcomes of subcutaneous panniculitis-like T-cell lymphoma with and without germline HAVCR2 mutations in Thai children and adolescents.

Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare subtype of non-Hodgkin lymphoma associated with hemophagocytic lymphohistiocytosis (HLH)/HLH-like systemic illnesses and germline HAVCR2 mutations. Although previous studies suggested successful treatment of SPTCL with immunosuppressive therapy (IST) without chemotherapy, IST data in pediatric SPTCL remain scarce. To explore characteristics and therapeutic outcomes, comparing IST-based and chemotherapy-based regimens in pediatric SPTCL, in this retrospective cohort study, patients with SPTCL diagnosed at age ≤20 years during 2007-2023 were enrolled from 6 hematology/oncology centers in Thailand. HAVCR2 exon 2 sequencing was performed using DNA extracted from peripheral blood or bone marrow. Presence of HLH/HLH-like systemic illnesses, treatment outcomes, and adverse events (AEs) were reviewed and analyzed. Of 22 patients with SPTCL (median age at diagnosis, 11.5 years [range, 6.0-19.0]; 63.6% males), 86.4% harbored germline HAVCR2 mutation, either homozygous (77.3%) or heterozygous (9.1%) p.Y82C variant, while 68.2% developed HLH/HLH-like systemic illnesses. Overall, 36.4% received IST as first-line treatment. Durable complete remission (CR) was achieved in 71.4% and 50.0% after first-line chemotherapy and IST, respectively (P=0.45); however, chemotherapy tended to increase any AEs compared to IST (57.1% vs. 12.5%; P=0.07). The most common AEs were hypertension (27.3%), febrile neutropenia (18.2%), and fungal infection (13.6%). Among the relapsed cases, 71.4% could reach CR after subsequent-line therapy. Fatality (4.5%) only occurred in the chemotherapy group. Pediatric SPTCL in Thailand frequently involves germline HAVCR2 mutations and/or HLH/HLH-like systemic illnesses. With comparable response and modest therapy-related toxicity, IST-based regimens may alternatively be considered as first-line treatment for pediatric SPTCL.

Warthin-like Papillary Thyroid Carcinoma: A Case Report and Review of the Literature.

Warthin-like subtype of papillary thyroid carcinoma (WLPTC) is a rare subtype of papillary thyroid carcinoma. This PTC subtype shows some pattern resemblance to Warthin tumors of the salivary gland, which confers its name but is a not genetically similar to salivary Warthin tumor, with the most frequent genetic change in WLPTC being BRAF p.V600E, the most frequent genetic driver of PTC. Warthin-like subtype of papillary thyroid carcinoma is found to have a favorable prognosis. We report a 44-year-old woman who presented with anterior neck swelling and elevated levels of antithyroid peroxidase antibodies. Fine-needle aspiration cytology showed features of papillary thyroid carcinoma and lymphocytic thyroiditis. On histopathological examination, thyroid follicular cells have oncocytic cytoplasm with infiltration of the tumor and fibrovascular cores by a dense lymphoplasmacytic infiltrate. Numerous multinucleated giant cells in the tumor are a notable feature. The final diagnosis is Warthin-like papillary thyroid carcinoma arising in association with chronic lymphocytic (Hashimoto) thyroiditis. Along with this case report, we perform a literature review of WLPTC between 2010 and 2024.

Challenging clinical management of a patient with Gaucher disease type IIIC homozygous for the D409H mutation, aortic valve calcification and porcelain aorta

Background. Gaucher disease is a rare lysosomal storage disorder caused by glucocerebrosidase enzyme deficiency resulting in the cumulative deposition of glucocerebroside in macrophages, predominantly effecting bone marrow, liver and spleen. Gaucher disease type IIIC is a rare subtype that is characterized by cardiovascular involvement, eye-movement disorders, and late-onset neurological symptoms. Case presentation. We present a 14-year-old adolescent boy diagnosed with Gaucher disease type IIIC at age four with a homozygous D409H mutation who developed severe aortic valve stenosis, extensive aortic calcification and a porcelain aorta despite enzyme replacement treatment since the diagnosis. Despite the challenges during the cardiac surgery, we successfully performed transcatheter aortic valve implantation (TAVI). The patient developed a complete atrioventricular block and required a pacemaker after the TAVI. He experienced further complications during the follow-up. Conclusion. The case presents the challenges in the treatment of cardiovascular complications in patients with Gaucher disease and demonstrates the importance of individualized treatment approaches, as well as the potential advantages and complications of TAVI in difficult situations like this.

INNV-14. OUTCOMES OF PATIENTS WITH ISOCITRATE DEHYDROGENASE-MUTANT WHO GRADE 4 ASTROCYTOMA TREATED WITH TUMOR TREATING FIELDS (TTFIELDS) THERAPY: A REAL-WORLD ANALYSIS

Abstract BACKGROUND Tumor Treating Fields (TTFields) therapy is approved for the treatment of patients with newly diagnosed glioblastoma, based on the EF-14 study which demonstrated improvement in progression free survival and overall survival (OS). EF-14 included patients with the isocitrate dehydrogenase (IDH) mutation (IDHmut), which has since been reclassified as IDHmut WHO grade 4 astrocytoma (Astrocytoma IDHmut/G4) and confers a more favorable prognosis than IDH wild type. However, large real-world datasets are lacking. Here, we report real-world outcomes of patients with Astrocytoma IDHmut/G4 treated with TTFields in the US. METHODS Utilizing electronic health records from the xCures real-world data platform, patients with newly diagnosed Astrocytoma IDHmut/G4 receiving TTFields in the US from January 1 to December 31, 2019 were analyzed and IDH-mut status was confirmed. Survival was analyzed based on IDH-mut status and TTFields usage, with patients categorized into 2 usage groups (minimum 30 days treatment): high (≥50%) and low (<50%) usage. RESULTS Among 1285 patients with known IDH status, 82 had an IDH-mut and were included. The median (range) age of patients was 40.6 (21–75) years, with the majority being men (n=58/71%) and with methylguanine-methyltransferase-promoter methylation (n=48/59%). Median TTFields therapy duration and usage were 9.4 months and 76.8%, respectively. OS at 2 and 4 years was 66% (95% CI: 56–77%) and 44% (34–57%), respectively. Patients with high TTFields usage had increased OS compared to low usage (HR: 0.53 [0.28–1.02], P=0.057, n=80). Among 22 patients with a minimum 4 years of survival, 5 were still on therapy as of the data cutoff. CONCLUSIONS These findings demonstrate the utility of the xCures platform in systematically assessing outcomes for a rare glioma subtype in the real-world setting, and suggests that patients with Astrocytoma IDHmut/G4 may benefit from TTFields therapy. Additional patient follow-up and correlative data will be presented.

TMOD-17. FOXR2-ACTIVATED CNS NEUROBLASTOMA ORIGINATES FROM THE MEDIAL GANGLIONIC EMINENCE LINEAGE

Abstract FOXR2-activated CNS neuroblastoma is a rare subtype of pediatric brain tumor characterized by the elevated expression of the transcription factor FOXR2 due to genomic rearrangement. However, the precise pathogenic mechanisms, including the cell type of origin and the function of FOXR2, are not fully understood. An expression profile analysis of patient tumors showed increased expression of the marker genes associated with the Medial Ganglionic Eminence (MGE) in the ventral forebrain such as NKX2.1 and SOX6. Based on this result, we hypothesized that FOXR2-activated CNS neuroblastoma originates from the MGE lineage. To test this hypothesis, we overexpressed FOXR2 in human embryonic stem cell-derived MGE progenitors and, as a control cell type, cortical progenitors. Our data showed that FOXR2 overexpression resulted in a significantly increased proliferation in the MGE progenitors but not in the cortical progenitors, indicating a cell-type-specific effect of FOXR2. When injected into the brain of immunodeficient mice, FOXR2-expressing MGE progenitors formed tumors that molecularly resemble patient tumors, while FOXR2-expressing cortical progenitors did not. To further dissect the underlying molecular mechanisms, we conducted an RNA-seq experiment and found that FOXR2 overexpression activated the MEK/ERK signaling pathway through a suppression of the endogenous RAS inhibitor DIRAS3. Moreover, the FDA-approved MEK inhibitor trametinib significantly suppressed the proliferation and induced cell death in FOXR2-expressing MGE progenitors in vitro with the IC50 value of 30 nM. Collectively, our study has revealed the cell type of origin of FOXR2-activated CNS neuroblastoma and identified the MEK/ERK pathway as a critical downstream of FOXR2 that can be targeted therapeutically.

Primary hepatic alpha-fetoprotein-producing neuroendocrine neoplasm harboring FGFR2 and TP53 mutations: a case report and literature review.

This report presents a rare case of a 45-year-old man diagnosed with a primary hepatic alpha-fetoprotein-producing neuroendocrine neoplasm, a condition rarely reported in the literature. The patient presented with initial symptoms of back and epigastric pain, after which multiple liver lesions were discovered on contrast-enhanced computed tomography, suggesting intrahepatic cholangiocarcinoma. Histopathological and immunohistochemical analyses confirmed the diagnosis of alpha-fetoprotein-producing neuroendocrine neoplasm that was further supported by genetic testing, which revealed FGFR2 and TP53 mutations commonly encountered in intrahepatic cholangiocarcinoma. Despite receiving various chemotherapeutic regimens, the patient exhibited a progressive disease. This case underscores the importance of accurate differential diagnosis from hepatocellular carcinoma and intrahepatic cholangiocarcinoma due to differences in treatment approaches and prognoses and highlights the necessity for increased awareness of AFP-producing primary hepatic neuroendocrine neoplasms among clinicians and pathologists. It emphasizes the significance of comprehensive histopathological evaluation, immunohistochemical profiling, and genetic analysis for precise diagnosis and tailored therapeutic strategies. Further research is warranted to elucidate the molecular mechanisms underlying this rare liver tumor subtype and develop targeted treatments.

The histologic diagnosis and the management of cystic neutrophilic granulomatous mastitis: a case report

BackgroundCystic neutrophilic granulomatous mastitis is a rare subtype of inflammatory mastitis characterized by a distinct histopathologic pattern, often associated with Corynebacterium species. This entity has been recently distinguished and should be differentiated from other types of chronic idiopathic mastitis due to its specific treatment.Case presentationA 44-year-old North African female patient, gravida 2, para 2, with no significant past medical history, presented with a 4-month history of a painful palpable mass in her left breast, with no history of trauma. Ultrasound imaging showed three lesions in the lower quadrant of the left breast, communicating with a superficial areolar abscess collection, creating a fistulous path to the skin. This ultrasound appearance was suspicious for suppurative mastitis; although, a necrotic tumor could not be ruled out. An ultrasound-guided needle biopsy revealed inflammatory and abscess features of the breast parenchyma without histological signs of malignancy. Steroid therapy and empirical antimicrobial treatment were started, and surgical excision was performed. Histologic features confirmed the diagnosis of cystic neutrophilic granulomatous mastitis. The patient recovered and was discharged due to clinical improvement.ConclusionCystic neutrophilic granulomatous mastitis is a recently defined entity, and its association with infection by Corynebacterium species can be detected by Gram stain and/or microbiological culture. Various treatment modalities are suggested, but the optimal treatment still requires further investigation.

Successful delivery in a cornual pregnancy after expectant management with traditional Chinese medicine and low-molecular-weight heparin: A case report.

Horn pregnancy is a rare subtype of ectopic pregnancy that presents a diagnosis and treatment challenge due to its nonspecific symptoms and high risk of rupture. A 32-year-old woman without vaginal pregnancy with history of right corner who presented with painless vaginal bleeding. A transvaginal ultrasound revealed a pregnancy sac implanted in the left corner of the uterus, confirming the diagnosis of a cornual pregnancy. Treatment options include pharmacological or surgical interventions, and anticipatory treatment is rarely recommended. Conservative treatment was chosen after extensive consultation, and the patient was treated with low molecular weight heparin and traditional Chinese medicine. Subsequent ultrasound tests showed stable fetal development and a successful cesarean section. This case highlights the success of combining low molecular weight heparin with traditional Chinese medicine in the treatment of cornual pregnancy. Factors affecting horn pregnancy, diagnostic challenges, and treatment considerations are discussed. Further research is necessary to determine the best management strategy and to ensure safe delivery for patients with impaired fertility but a strong desire to conceive.

Large inferior vena cava thrombosis in a 25-year-old female patient: A case report.

The incidence of venous thromboembolism is increasing, and it is more common in older than in younger patients. Inferior vena cava (IVC) thrombosis is a rare subtype of deep vein thrombosis, and it is associated with a high incidence of arterial and venous thrombosis in patients with systemic lupus erythematosus (SLE). We present the case of a 25-year-old female patient with a large IVC thrombosis caused by SLE that was intractable to thrombolytic therapy. A 25-year-old previously healthy female patient presented to the emergency department with a 5-day history of fever. Her computed tomography revealed a large thrombus with an approximate length 25 cm extending from the suprarenal IVC to the right common iliac vein and the left external and internal iliac veins. We decided to perform intravenous thrombolysis (alteplase 65 mg) because of the massive thrombus burden followed by an infusion of intravenous heparin. However, the size of the thrombus did not showed reduction 3 days after treatment. For the next step, the catheter-directed thrombolysis (CDT) was performed; however, no changes were observed. She was diagnosed with SLE, and the large IVC thrombus gradually improved after primary treatment for SLE, including immunosuppressive drugs combined with anticoagulant. We found a large IVC thrombus secondary to SLE in a young female patient. In this case, systemic thrombolysis or CDT did not improve the thrombus. The thrombus only improved after immunosuppressive treatment for SLE. Our case highlights the importance of treatment for etiologic disease in an intractable thrombosis developed by provoked cause.

Spitz tumours and mimickers.

Since their initial description in 1948, Spitz tumours have always been a challenge in the field of dermatopathology and paediatric pathology. Advances in molecular pathology have confirmed they are associated with specific anomalies, mainly gene fusions. They display a wide range of clinical presentations and histological subtypes. Most cases are Spitz nevi and very few lesions match the criteria to be diagnosed as atypical Spitz tumours. Even fewer are labelled as Spitz melanomas. Follow-up studies of genetically characterized cases have repeatedly confirmed that, even if the regional lymph node is involved, the overall outcome remains favourable. The aims of this review are to cover the variety of morphological presentations of Spitz tumours and illustrate the most rare subtypes. When possible, we have pointed out the potential trends between some unusual morphological features and the frequently associated genetic drivers. Spitz tumours have many differential diagnoses, the main being superficial spreading melanoma, with overlapping morphological features in early lesions. Essential clues to discriminate Spitz from mimickers have been listed and illustrated.

Ballooning and Bursting of Barrels and Pipes: A Rare Case of Suspected Vascular Ehlers–Danlos Disease

Vascular Ehler–Danlos disease (vEDS), a rare subtype of a rare disease, is a life-threatening disease, with an increased risk for spontaneous vascular or visceral rupture. These patients have fatal complications ranging from vascular aneurysms, dissection, and rupture of systemic vessels to frequent thromboembolic events, the common causes of death in these individuals with a shortened life span. In the present case, a 28-year-old male with history of shoulder dislocations and spontaneous colon perforation presented to the primary care clinic with right lower extremity swelling and pain. His history includes presentation to the emergency department with left lower leg swelling with compartment syndrome one year prior. A CT angiogram of lower extremities and abdomen revealed acute arterial extravasation of the left posterior tibial artery, indicating a ruptured aneurysm along with aneurysms of the splenic artery and left common iliac artery. He was treated with a saphenous vein graft, but was associated with post-operative complications that necessitated below-knee amputation. CT angiogram of his right leg revealed occlusion of the anterior tibial and peroneal arteries with aneurysms, and, ultimately, he was referred to a tertiary care center for aneurysm embolization. This case report emphasizes the frequent vascular complications encountered in vascular EDS patients, and thus advocates for close and regular monitoring for early referral and surgical management of their vascular anomalies. Finally, genetic counseling and screening of asymptomatic family members should be routinely implemented in these patients.

Extradigital Symplastic Glomus Tumor and Review of the Literature.

Symplastic glomus tumors are a rare subtype of glomus tumor defined by nuclear atypia without additional markers of malignancy such as large size, deep location, or atypical/prevalent mitotic figures. Glomus tumors, including the symplastic subtype, most commonly present in the subungual area with rarer extradigital presentation. To our knowledge, there have been less than 25 cases of symplastic glomus tumors described in the literature. Herein, we present a case of extradigital symplastic glomus tumor with review of the literature.

High-affinity T cell receptor ImmTAC® bispecific efficiently redirects T cells to kill tumor cells expressing the cancer testis antigen PRAME

Abstract PRAME (Preferentially expressed Antigen in Melanoma) is a cancer testis antigen expressed in several tumor indications, representing an attractive anti-cancer target. However, its intracellular location limits targeting by traditional methods. PRAME peptides are presented on the surface of tumor cells by human leukocyte antigen (HLA) molecules, indicating that a T cell receptor (TCR)-based strategy that redirects T cells to kill PRAME+ tumors could be a novel immunotherapeutic option. We confirm that PRAME protein is expressed in cutaneous melanoma, including rare subtypes with limited treatment options, as well as primary and metastatic lung, breast, endometrial and ovarian tumors. Furthermore, PRAME is expressed homogeneously across tumors with distinct oncogenic mutations, mutation burden, PD-L1 expression, immune infiltration and features of immune checkpoint resistance. Immunopeptidomic analysis of primary tumors detected HLA class I-restricted PRAME peptides. A TCR recognizing PRAME peptide SLLQHLIGL was engineered to high affinity and fused to a CD3 engaging domain to create a TCRxCD3 bispecific molecule (Immune mobilizing monoclonal TCR Against Cancer, ImmTAC®) with the ability to redirect polyclonal T cells to efficiently kill PRAME+ cells. The degree of T cell activation was positively correlated with peptide-HLA abundance, with as few as 10 epitopes per cell sufficient for target cell killing. Impaired ImmTAC®-redirected cytotoxicity of exhausted T cells was rescued using an anti-PD-1 antibody, supporting the use of a combination strategy to treat tumors with active PDL1-PD1 axes. Our data demonstrate selective and efficient T cell activation and killing by a PRAME-directed TCRxCD3 bispecific, supporting further investigation in multiple cancer indications.

Biological and clinical characteristics of non-small cell lung cancer non-specific subtype

BackgroundNon-small cell lung cancer-not otherwise specified (NSCLC-NOS) is a rare subtype of NSCLC that cannot be classified specifically based on morphology and/or special staining. This study aimed to explore the clinical features, biological and pathological characteristics, treatment, and prognosis of NSCLC-NOS. MethodsThis retrospective study included NSCLC-NOS patients diagnosed and treated between 2010 and 2022. Clinical features, gene expression, first-line treatment, and prognosis were analyzed. Kaplan-Meier methods were calculated and log-rank tests and univariable and multivariable Cox regression analyses were performed to determine the relationship between prognostic factors and survival. ResultsOf 105 NSCLC-NOS patients, most were male (92.4%), smokers (78.1%), with a median age of 64 years, and advanced stage (IIIc-IV, 72.4%). Immunohistochemical analysis showed minimal expression of p40, NapsinA, and TTF-1, whereas cytokeratin (CK) was expressed in 100% of cases. 20.5% of 39 patients who underwent genetic testing had driver gene mutations, including EGFR, KRAS, and ROS1. Among 69 patients with complete treatment information, 58 received platinum-based chemotherapy, with paclitaxel being the most commonly used combination chemotherapy drug (n=25), followed by pemetrexed (n=21). The objective response rate (ORR) of paclitaxel was found to be higher compared to pemetrexed (83.3% vs. 54.5%, P=0.296). Furthermore, the combination of paclitaxel with immunotherapy demonstrated superior benefits in comparison to pemetrexed (76.9% vs. 50.0%, P=0.367). The median progression-free survival (PFS) for patients treated with monotherapy paclitaxel, the paclitaxel-immunotherapy combination, and the pemetrexed-immunotherapy combination were 6.6 months (95% CI: 1.508-11.692; P=0.017), 15.7 months (95% CI: 14.071-17.329; P=0.017), and 11.8 months (95% CI: 10.279-13.321; P=0.324), respectively. The median overall survival (OS) was 13.6 months. Anatomic location (P=0.026) and immunotherapy use (P=0.003) were associated with OS. Multivariate analysis confirmed that anatomical location and immunotherapy use were factors influencing the prognosis. ConclusionNSCLC-NOS is common in male smokers and often diagnosed at an advanced stage with low mutation rate. Paclitaxel with immunotherapy may have better benefits as a first-line treatment. Anatomic location and immunotherapy use are prognostic factors.