Female pseudohermaphroditism with urethral duplication: A delayed presentation in adulthood.

Female pseudohermaphroditism with urethral duplication presenting as urinary retention in adulthood is extremely rare. We report the case of a 26-year-old female who had multiple failed attempts of per urethral catheterization during a planned cesarean section. She had labial fusion and clitoral hypertrophy with a phallic urethra and underwent labial separation with urethral reconstruction.

Delayed presentation of an organized chronic intrapericardial hematoma with diastolic dysfunction.

We describe the case of a 45-year-old man, with a history of blunt trauma to the chest 2 years back, presenting with diastolic dysfunction secondary to the development of a large, organized, intrapericardial hematoma. The case highlights the possibility of extremely delayed presentation in such cases and the importance of cardiac magnetic resonance imaging in making an accurate preoperative diagnosis and guiding optimal management strategies.

Unruptured sinus of valsalva aneurysm in a case of large vessel vasculitis: A diagnostic dilemma.

BACKGROUND: Takayasu arteritis and tuberculous aortitis, both can result in aneurysmal disease of the aorta. The overlapping imaging features in case of large vessel vasculitis can create a diagnostic dilemma. AIM: We present a case of large vessel vasculitis and chronic empyema with unruptured sinus of valsalva aneurysm. METHODS AND RESULTS: A 30-year-old man presented with acute onset shortness of breath, palpitations, and gradually progressing pedal edema. The echocardiography and CT angiogram revealed features of large vessel vasculitis and chronic empyema along with unruptured sinus of valsava aneurysms. Patient underwent emergency Bentall procedure and the histopathology confirmed the diagnosis of takayasu arteritis. DISCUSSION: Tuberculosis being an endemic disease with varied presentations should always be considered a differential diagnosis, whenever appropriate. An unruptured sinus of valsalva aneurysm can be clinically silent or can cause compression symptoms. Although there are no specific guidelines regarding surgical correction, symptomatic and aneurysms of size >5.5cm are usually managed surgically. CONCLUSION: Unruptured sinus of valsalva aneurysms can be seen in Takayasu arteritis, which complicates the methodology and timing of the surgical management.

Anomalous branch of right pulmonary artery supplying the left lung: A "pseudo-pulmonary sling".

We report a case of a 9-month-old boy with supracardiac total anomalous pulmonary venous connection showing a small aberrant vessel arising from the right pulmonary artery and traversing below the left main bronchus to supply the anteromedial segment of the left lower lobe.

A rare pediatric case of bilateral bronchopulmonary vascular malformations and right isomerism.

We present an unusual case of an 18-day-old term neonate with coexistent bilateral bronchopulmonary vascular malformations and right isomerism. This case highlights the importance of computed tomography angiography in depicting such complex anomalies and classifying them according to components involved providing a systematic approach for evaluation of the disease process.

Tetralogy of Fallot, right aortic arch with isolated left subclavian artery: Rare synchronous triple occurrence!!!

We present a rare synchronous occurrence of tetralogy of Fallot, right aortic arch, and isolated left subclavian artery, highlighting potential clinical and therapeutic implications.

Paraneoplastic pemphigus associated with a pericardial ectopic thymoma.

Paraneoplastic Pemphigus (PNP), a rare autoimmune blistering disease, can be accompanied by both benign and malignant neoplasms. The most frequently reported associated malignancies include lymphomatoid and hematologic malignancies, Castleman's disease, carcinoma, thymoma. In a patient suspected of PNP, with no known history of malignancy, an extensive workup is suggested to look for underlying malignancy, which has to be treated to induce PNP remission. In this clinical case report, cross sectional imaging of a young female diagnosed with PNP, unveiled a pericardial mass lesion extending into transverse pericardial sinus. Excisional biopsy was performed. Histopathology revealed pericardial ectopic thymoma.

Characterization of immune regulatory molecules B7-H4 and PD-L1 in low and high grade endometrial tumors.

BACKGROUND: The objective of this investigation was to characterize the expression landscape of immune regulatory molecules programmed death-ligand-1 (PD-L1, B7-H1) and B7-H4 in a cohort of endometrial tumors across the spectrum of grade and histology. MATERIALS AND METHODS: With institutional review board approval, 70 endometrial tumors from patients with known clinical outcomes were identified representing a spectrum of grade and histology. Immunohistochemistry (IHC) was performed for PD-L1 and B7-H4 and scored. Microsatellite instability (MSI) status was assessed for endometrioid tumors using the institutional IHC assay for expression of the mismatch repair (MMR) genes, MLH1, MSH2, MSH6 and PMS2. RNA sequencing data from the Cancer Genome Atlas was queried for expression levels of CD274 (PD-L1 protein) and VTCN1 (B7-H4) across molecular subtypes of endometrial carcinoma and were correlated with a T cell infiltration index. RESULTS: We identified 40 low grade endometrioid tumors and a cohort of 30 high grade tumors. PD-L1 expression was observed in both high and low grade endometrial tumors (56% vs 35%, p=0.07). In the low grade tumors, PD-L1 expression was associated with MSI status (p<0.01). The high grade cohort had similar rates of PD-L1 expression compared to low grade MSI tumor (56% and 62% respectively), and both were distinct from low grade MSS tumors (22%, p<0.05). High (3+) B7-H4 positive cells were observed in both high and low grade carcinomas (33% and 31% respectively). RNA profiling data from confirmed highest CD274 expression in POLE and MSI tumors that was linearly correlated with T cell infiltration, while VTCN1 expression appeared consistent across molecular subtypes. CONCLUSIONS: While PD-L1 expression correlated with MSI and high grade tumors, B7-H4 expression was independent of grade, histology and immune cell infiltration. The development and testing of multi-agent therapeutics targeting PD-L1 and B7-H4 may be a novel strategy for endometrial tumors.

TTLL12 has a potential oncogenic activity, suppression of ligation of nitrotyrosine to the C-terminus of detyrosinated α-tubulin, that can be overcome by molecules identified by screening a compound library.

Tubulin tyrosine ligase 12 (TTLL12) is a promising target for therapeutic intervention since it has been implicated in tumour progression, the innate immune response to viral infection, ciliogenesis and abnormal cell division. It is the most mysterious of a fourteen-member TTL/TTLL family, since, although it is the topmost conserved in evolution, it does not have predicted enzymatic activities. TTLL12 seems to act as a pseudo-enzyme that modulates various processes indirectly. Given the need to target its functions, we initially set out to identify a property of TTLL12 that could be used to develop a reliable high-throughput screening assay. We discovered that TTLL12 suppresses the cell toxicity of nitrotyrosine (3-nitrotyrosine) and its ligation to the C-terminus of detyrosinated α-tubulin (abbreviated to ligated-nitrotyrosine). Nitrotyrosine is produced by oxidative stress and is associated with cancer progression. Ligation of nitrotyrosine has been postulated to be a check-point induced by excessive cell stress. We found that the cytotoxicities of nitrotyrosine and tubulin poisons are independent of one another, suggesting that drugs that increase nitrotyrosination could be complementary to current tubulin-directed therapeutics. TTLL12 suppression of nitrotyrosination of α-tubulin was used to develop a robust cell-based ELISA assay that detects increased nitrotyrosination in cells that overexpress TTLL12 We adapted it to a high throughput format and used it to screen a 10,000 molecule World Biological Diversity SETTM collection of low-molecular weight molecules. Two molecules were identified that robustly activate nitrotyrosine ligation at 1 µM concentration. This is the pioneer screen for molecules that modulate nitrotyrosination of α-tubulin. The molecules from the screen will be useful for the study of TTLL12, as well as leads for the development of drugs to treat cancer and other pathologies that involve nitrotyrosination.

M9657 Is a Bispecific Tumor-Targeted Anti-CD137 Agonist That Induces MSLN-Dependent Antitumor Immunity without Liver Inflammation.

The costimulatory receptor CD137 (also known as TNFRSF9 or 4-1BB) sustains effective cytotoxic T-cell responses. Agonistic anti-CD137 cancer immunotherapies are being investigated in clinical trials. Development of the first-generation CD137-agonist monotherapies utomilumab and urelumab was unsuccessful due to low antitumor efficacy mediated by the epitope recognized on CD137 or hepatotoxicity mediated by Fcγ receptors (FcγR) ligand-dependent CD137 activation, respectively. M9657 was engineered as a tetravalent bispecific antibody (mAb2) in a human IgG1 backbone with LALA mutations to reduce binding to FCγRs. Here, we report that M9657 selectively binds to mesothelin (MSLN) and CD137 with similar affinity in humans and cynomolgus monkeys. In a cellular functional assay, M9657 enhanced CD8+ T cell-mediated cytotoxicity and cytokine release in the presence of tumor cells, which was dependent on both MSLN expression and T-cell receptor/CD3 activation. Both FS122m, a murine surrogate with the same protein structure as M9657, and chimeric M9657, a modified M9657 antibody with the Fab portion replaced with an anti-murine MSLN motif, demonstrated in vivo antitumor efficacy against various tumors in wild-type and human CD137 knock-in mice, and this was accompanied by activated CD8+ T-cell infiltration in the tumor microenvironment. The antitumor immunity of M9657 and FS122m depended on MSLN expression density and the mAb2 structure. Compared with 3H3, a murine surrogate of urelumab, FS122m and chimeric M9657 displayed significantly lower on-target/off-tumor toxicity. Taken together, M9657 exhibits a promising profile for development as a tumor-targeting immune agonist with potent anticancer activity without systemic immune activation and associated hepatotoxicity.

MYTX-011: a pH-dependent anti-cMET antibody-drug conjugate designed for enhanced payload delivery to cMET expressing tumor cells.

Advances in linker payload technology and target selection have been at the forefront of recent improvements in antibody-drug conjugate (ADC) design, leading to several approvals over the last decade. In contrast, the potential of novel ADC technologies to enhance payload delivery to tumors is relatively underexplored. We demonstrate that incorporation of pH-dependent binding in the antibody component of a cMET targeting ADC (MYTX-011) can overcome the requirement for high cMET expression on tumors, an innovation that has the potential to benefit a broader population of patients with lower cMET levels. MYTX-011 drove four-fold higher net internalization than a non-pH engineered parent ADC in non-small cell lung cancer (NSCLC) cells and showed increased cytotoxicity against a panel of cell lines from various solid tumors. A single dose of MYTX-011 showed at least three-fold higher efficacy than a benchmark ADC in mouse xenograft models of NSCLC ranging from low to high cMET expression. Moreover, MYTX-011 showed improved pharmacokinetics over parent and benchmark ADCs. In a repeat dose toxicology study, MYTX-011 exhibited a toxicity profile similar to other MMAE-based ADCs. These results highlight the potential of MYTX-011 for treating a broader range of NSCLC patients with cMET expression than other cMET targeting ADCs. A first in human study is ongoing to determine the safety, tolerability, and preliminary efficacy of MYTX-011 in patients with NSCLC (NCT05652868).

MYTX-011: A pH-Dependent Anti-c-MET Antibody-Drug Conjugate Designed for Enhanced Payload Delivery to c-MET-Expressing Tumor Cells.

Advances in linker payload technology and target selection have been at the forefront of recent improvements in antibody-drug conjugate (ADC) design, leading to several approvals over the last decade. In contrast, the potential of novel ADC technologies to enhance payload delivery to tumors is relatively underexplored. We demonstrate that incorporation of pH-dependent binding in the antibody component of a c-mesenchymal-epithelial transition (MET)-targeting ADC (MYTX-011) can overcome the requirement for high c-MET expression on tumors, an innovation that has the potential to benefit a broader population of patients with lower c-MET levels. MYTX-011 drove fourfold higher net internalization than a non-pH-engineered parent ADC in non-small cell lung cancer (NSCLC) cells and showed increased cytotoxicity against a panel of cell lines from various solid tumors. A single dose of MYTX-011 showed at least threefold higher efficacy than a benchmark ADC in mouse xenograft models of NSCLC ranging from low to high c-MET expression. Moreover, MYTX-011 showed improved pharmacokinetics over parent and benchmark ADCs. In a repeat dose toxicology study, MYTX-011 exhibited a toxicity profile similar to other monomethyl auristatin E-based ADCs. These results highlight the potential of MYTX-011 for treating a broader range of patients with NSCLC with c-MET expression than other c-MET-targeting ADCs. A first-in-human study is ongoing to determine the safety, tolerability, and preliminary efficacy of MYTX-011 in patients with NSCLC (NCT05652868).

CDK6 kinase activity is required for thymocyte development.

Cyclin-dependent kinase-6 (CDK6) is required for early thymocyte development and tumorigenesis. To mechanistically dissect the role of CDK6 in thymocyte development, we generated and analyzed mutant knock-in mice and found that mice expressing a kinase-dead Cdk6 allele (Cdk6(K43M)) had a pronounced reduction in thymocytes and hematopoietic stem cells and progenitor cells (Lin⁻Sca-1⁺c-Kit⁺ [LSK]). In contrast, mice expressing the INK4-insensitive, hyperactive Cdk6(R31C) allele displayed excess proliferation in LSK and thymocytes. However, this is countered at least in part by increased apoptosis, which may limit progenitor and thymocyte expansion in the absence of other genetic events. Our mechanistic studies demonstrate that CDK6 kinase activity contributes to Notch signaling because inactive CDK6 kinase disrupts Notch-dependent survival, proliferation, and differentiation of LSK, with concomitant alteration of Notch target gene expression, such as massive up-regulation of CD25. Further, knockout of CD25 in Cdk6(K43M) mice rescued most defects observed in young mice. These results illustrate an important role for CDK6 kinase activity in thymocyte development that operates partially through modulating Notch target gene expression. This role of CDK6 as a downstream mediator of Notch identifies CDK6 kinase activity as a potential therapeutic target in human lymphoid malignancies.

Catheters in vascular interventional radiology: an illustrated review.

The past five decades have seen significant developments in the knowledge and practice of interventional radiology. Advancements in angiographic equipment have made interventional radiology a safe, minimally invasive preferred option in the treatment of a variety of diseases. Today, a range of catheters are available in the armamentarium of the interventional radiologist to suit different needs when conducting diagnostic angiograms or performing interventions in various vascular territories. The hardware required for interventions includes needles, wires, catheters, balloons, and stents. Catheters, in particular, are an invaluable tool for interventionists. The purpose of this review is to describe the identification characteristics, properties, and uses of the common angiographic catheters used in interventional radiology, with a special focus on peripheral vascular interventions (excluding neurointerventions).

Periaortic air in native and post-operative aorta on computed tomography.

Periaortic air can be seen in various conditions which can be a benign imaging finding or harbinger of a catastrophic event. The causes vary in native aorta and post-operative aorta. A radiologist has an important part in the management process of these patients, as the treatment varies from conservative to radical surgery based on the aetiology. The presence of periaortic air seen in the light of various clinical, laboratory and radiological findings can guide the radiologist towards a particular aetiology. Cross-sectional imaging, mainly computed tomography, is an indispensable tool in recognising ectopic periaortic air and to identify the associated findings and eventually make an accurate diagnosis. We present a pictorial review of various causes of the periaortic air in native and postoperative aorta, the salient features and management of the described conditions.

Stent-Graft Migration Post-Endovascular Repair of Thoracic Aorta: A Retrospective Cohort Study.

Background Migration of the stent-graft post-thoracic endovascular aortic repair (TEVAR) is not uncommon; however, it is sparsely reported. The objective of this study was to assess the incidence, risk factors, and complications of stent-graft migration post-TEVAR. Materials and Methods Thirty-one patients who underwent TEVAR were retrospectively analyzed. The demographic, anatomical, and procedure-related factors were assessed. The measurements were done along the greater curvature of aorta around two fixed anatomic landmarks, that is, left common carotid artery or neoinnominate artery (hybrid repair) proximally and celiac artery distally. Aortic elongation and migration at proximal, distal, as well as at overlapping zone were measured. More than 10 mm of migration was considered significant. Results Significant migration was observed in six (19%) patients. No significant migration was observed in the overlapping zone. The proximal landing zone 3 (odds ratio [OR] 12.78, p 0.01) was a significant risk factor, whereas landing zone 2 was a protective factor against the migration (OR 0.08, p 0.02). The odds for migration were more in segments I/3 and II/3 compared with I/2 and II/2, respectively, as per Modified Arch Landing Areas Nomenclature. A single complication was seen in the migration group which was treated by an overlapping stent graft. Conclusion The stent-graft migration after TEVAR is not uncommon. Type 3 proximal landing zone was a significant risk factor for migration with an increased risk toward I/3 and II/3. Proximal landing zone 2 as well as adequate overlapping distance in multiple stent grafts can prevent migration. Ethical Approval No IECPG-227/24.06.2020.