Prediction of homologous recombination deficiency from Oncomine Comprehensive Assay Plus correlating with SOPHiA DDM HRD Solution.

OBJECTIVE: Poly(ADP-ribose) polymerase (PARP) inhibitors are used for targeted therapy for ovarian cancer with homologous recombination deficiency (HRD). In this study, we aimed to develop a homologous recombination deficiency prediction model to predict the genomic integrity (GI) index of the SOPHiA DDM HRD Solution from the Oncomine Comprehensive Assay (OCA) Plus. We also tried to a find cut-off value of the genomic instability metric (GIM) of the OCA Plus that correlates with the GI index of the SOPHiA DDM HRD Solution. METHODS: We included 87 cases with high-grade ovarian serous carcinoma from five tertiary referral hospitals in Republic of Korea. We developed an HRD prediction model to predict the GI index of the SOPHiA DDM HRD Solution. As predictor variables in the model, we used the HRD score, which included percent loss of heterozygosity (%LOH), percent telomeric allelic imbalance (%TAI), percent large-scale state transitions (%LST), and the genomic instability metric (GIM). To build the model, we employed a penalized logistic regression technique. RESULTS: The final model equation is -21.77 + 0.200 × GIM + 0.102 × %LOH + 0.037 × %TAI + 0.261 × %LST. To improve the performance of the prediction model, we added a borderline result category to the GI results. The accuracy of our HRD status prediction model was 0.958 for the test set. The accuracy of HRD status using GIM with a cut-off value of 16 was 0.911. CONCLUSION: The Oncomine Comprehensive Assay Plus provides a reliable biomarker for homologous recombination deficiency.

Altered tumor signature and T-cell profile after chemotherapy reveal new therapeutic opportunities in high-grade serous ovarian carcinoma.

Chemotherapy combined with debulking surgery is the standard treatment protocol for high-grade serous ovarian carcinoma (HGSOC). Nonetheless, a significant number of patients encounter relapse due to the development of chemotherapy resistance. To better understand and address this resistance, we conducted a comprehensive study investigating the transcriptional alterations at the single-cell resolution in tissue samples from patients with HGSOC, using single-cell RNA sequencing and T-cell receptor sequencing techniques. Our analyses unveiled notable changes in the tumor signatures after chemotherapy, including those associated with epithelial-mesenchymal transition and cell cycle arrest. Within the immune compartment, we observed alterations in the T-cell profiles, characterized by naïve or pre-exhausted populations following chemotherapy. This phenotypic change was further supported by the examination of adjoining T-cell receptor clonotypes in paired longitudinal samples. These findings underscore the profound impact of chemotherapy on reshaping the tumor landscape and the immune microenvironment. This knowledge may provide clues for the development of future therapeutic strategies to combat treatment resistance in HGSOC.

Dramatic Response to Cabozantinib in a Patient with Refractory Hepatocellular Carcinoma with c-MET Amplification.

We report a case of a patient with c-MET amplified hepatocellular carcinoma (HCC) who had a dramatic response to cabozantinib despite being refractory to four previous lines of systemic therapy. The patient had previously received regorafenib plus nivolumab as first-line treatment, lenvatinib as second-line, sorafenib as third-line, and ipilimumab plus nivolumab as fourth-line treatment in sequence. However, all regimens showed early progression within 2 months. The patient's HCC was well-controlled, with a partial response (PR) of over 9 months after beginning cabozantinib treatment. Although there were mild adverse events such as diarrhea and elevated liver enzymes, they were tolerable. Next-generation sequencing (NGS) of the patient's previous surgical specimen indicated amplification of c-MET genes. Although it is well known that cabozantinib has excellent effectiveness for inhibiting c-MET at the preclinical level, to the best of our knowledge this is the first case of dramatic response to cabozantinib in a patient with advanced HCC with c-MET amplification.

Predictive biomarkers for the responsiveness of recurrent glioblastomas to activated killer cell immunotherapy.

BACKGROUND: Recurrent glioblastoma multiforme (GBM) is a highly aggressive primary malignant brain tumor that is resistant to existing treatments. Recently, we reported that activated autologous natural killer (NK) cell therapeutics induced a marked increase in survival of some patients with recurrent GBM. METHODS: To identify biomarkers that predict responsiveness to NK cell therapeutics, we examined immune profiles in tumor tissues using NanoString nCounter analysis and compared the profiles between 5 responders and 7 non-responders. Through a three-step data analysis, we identified three candidate biomarkers (TNFRSF18, TNFSF4, and IL12RB2) and performed validation with qRT-PCR. We also performed immunohistochemistry and a NK cell migration assay to assess the function of these genes. RESULTS: Responders had higher expression of many immune-signaling genes compared with non-responders, which suggests an immune-active tumor microenvironment in responders. The random forest model that identified TNFRSF18, TNFSF4, and IL12RB2 showed a 100% accuracy (95% CI 73.5-100%) for predicting the response to NK cell therapeutics. The expression levels of these three genes by qRT-PCR were highly correlated with the NanoString levels, with high Pearson's correlation coefficients (0.419 (TNFRSF18), 0.700 (TNFSF4), and 0.502 (IL12RB2)); their prediction performance also showed 100% accuracy (95% CI 73.54-100%) by logistic regression modeling. We also demonstrated that these genes were related to cytotoxic T cell infiltration and NK cell migration in the tumor microenvironment. CONCLUSION: We identified TNFRSF18, TNFSF4, and IL12RB2 as biomarkers that predict response to NK cell therapeutics in recurrent GBM, which might provide a new treatment strategy for this highly aggressive tumor.

miR-22-3p and miR-30e-5p Are Associated with Prognosis in Cervical Squamous Cell Carcinoma.

Alteration in expression of miRNAs can cause various malignant changes and the metastatic process. Our aim was to identify the miRNAs involved in cervical squamous cell carcinoma (SqCC) and metastasis, and to test their utility as indicators of metastasis and survival. Using microarray technology, we performed miRNA expression profiling on primary cervical SqCC tissue (n = 6) compared with normal control (NC) tissue and compared SqCC that had (SqC-M; n = 3) and had not (SqC-NM; n = 3) metastasized. Four miRNAs were selected for validation by qRT-PCR on 29 SqC-NM and 27 SqC-M samples, and nine metastatic lesions (ML-SqC), from a total of 56 patients. Correlation of miRNA expression and clinicopathological parameters was analyzed to evaluate the clinical impact of candidate miRNAs. We found 40 miRNAs differentially altered in cervical SqCC tissue: 21 miRNAs were upregulated and 19 were downregulated (≥2-fold, p < 0.05). Eight were differentially altered in SqC-M compared with SqC-NM samples: four were upregulated (miR-494, miR-92a-3p, miR-205-5p, and miR-221-3p), and four were downregulated (miR-574-3p, miR-4769-3p, miR-1281, and miR-1825) (≥1.5-fold, p < 0.05). MiR-22-3p might be a metastamiR, which was gradually further downregulated in SqC-NM > SqC-M > ML-SqC. Downregulation of miR-30e-5p significantly correlated with high stage, lymph node metastasis, and low survival rate, suggesting an independent poor prognostic factor.

p53 Immunohistochemistry and Mutation Types Mismatching in High-Grade Serous Ovarian Cancer.

High-grade serous carcinoma (HGSCa) of the ovary is featured by TP53 gene mutation. Missense or nonsense mutation types accompany most cases of HGSCa that correlate well with immunohistochemical (IHC) staining results-an all (missense) or none (nonsense) pattern. However, some IHCs produce subclonal or mosaic patterns from which TP53 mutation types, including the wild type of the gene, cannot be clearly deduced. We analyzed a total of 236 cases of ovarian HGSCa and tumors of other histology by matching the results of p53 IHC staining and targeted next-generation sequencing (TruSight Tumor 170 panel). Ambiguous IHCs that do not belong to the conventional "all or none" groups were reviewed to distinguish the true wild type (WT) from potentially pathogenic subclonal or mosaic patterns. There were about 9% of sequencing-IHC mismatching cases, which were enriched by the p53 c-terminal encoding nuclear localization signal and oligomerization domain, in which the subcellular locations of p53 protein were affected. Indeed, mutations in the oligomerization domain of the p53 protein frequently revealed an unmatched signal or cytosolic staining (L289Ffs*57 (Ins), and R342*). We conclude that both mutation types and IHC patterns of p53 are important sources of information to provide a precise diagnosis of HGSCa.

USP19 and RPL23 as Candidate Prognostic Markers for Advanced-Stage High-Grade Serous Ovarian Carcinoma.

Ovarian cancer is one of the leading causes of deaths among patients with gynecological malignancies worldwide. In order to identify prognostic markers for ovarian cancer, we performed RNA-sequencing and analyzed the transcriptome data from 51 patients who received conventional therapies for high-grade serous ovarian carcinoma (HGSC). Patients with early-stage (I or II) HGSC exhibited higher immune gene expression than patients with advanced stage (III or IV) HGSC. In order to predict the prognosis of patients with HGSC, we created machine learning-based models and identified USP19 and RPL23 as candidate prognostic markers. Specifically, patients with lower USP19 mRNA levels and those with higher RPL23 mRNA levels had worse prognoses. This model was then used to analyze the data of patients with HGSC hosted on The Cancer Genome Atlas; this analysis validated the prognostic abilities of these two genes with respect to patient survival. Taken together, the transcriptome profiles of USP19 and RPL23 determined using a machine-learning model could serve as prognostic markers for patients with HGSC receiving conventional therapy.

Colonic Perforation After Treatment With Nivolumab in Esophageal Cancer: A Case Report.

With the advent of checkpoint inhibitors, it has opened up opportunities for numerous cancer patients. However, as is the case with every treatment, complications need to be weighed. Gastrointestinal adverse effects, such as diarrhea and colitis are well-known complications for checkpoint inhibitors. In severe cases, colitis-induced colonic perforation may occur with an estimation of 1.0% to 1.5% in anti-CTLA-4 antibodies. However, only a handful of cases of such devastating complications have been reported in anti-PD-1 antibodies such as pembrolizumab and nivolumab. We here report a case of intestinal perforation in a patient treated with nivolumab.

Clinical Impact of Somatic Variants in Homologous Recombination Repair-Related Genes in Ovarian High-Grade Serous Carcinoma.

PURPOSE: In this study, we investigated the frequencies of mutations in DNA damage repair genes including BRCA1, BRCA2, homologous recombination genes and TP53 gene in ovarian high-grade serous carcinoma, alongside those of germline and somatic BRCA mutations, with the aim of improving the identification of patients suitable for treatment with poly(ADP-ribose) polymerase inhibitors. MATERIALS AND METHODS: Tissue samples from 77 Korean patients with ovarian high-grade serous carcinoma were subjected to next-generation sequencing. Pathogenic alterations of 38 DNA damage repair genes and TP53 gene and their relationships with patient survival were examined. Additionally, we analyzed BRCA germline variants in blood samples from 47 of the patients for comparison. RESULTS: BRCA1, BRCA2, and TP53 mutations were detected in 28.6%, 5.2%, and 80.5% of the 77 patients, respectively. Alterations in RAD50, ATR, MSH6, MSH2, and FANCA were also identified. At least one mutation in a DNA damage repair gene was detected in 40.3% of patients (31/77). Germline and somatic BRCA mutations were found in 20 of 47 patients (42.6%), and four patients had only somatic mutations without germline mutations (8.5%, 4/47). Patients with DNA damage repair gene alterations with or without TP53mutation, exhibited better disease-free survival than those with TP53 mutation alone. CONCLUSION: DNA damage repair genes were mutated in 40.3% of patients with high-grade serous carcinoma, with somatic BRCA mutations in the absence of germline mutation in 8.5%. Somatic variant examination, along with germline testing of DNA damage repair genes, has potential to detect additional candidates for PARP inhibitor treatment.

Immune gene signatures for predicting durable clinical benefit of anti-PD-1 immunotherapy in patients with non-small cell lung cancer.

Immune checkpoint blockade is promising for treating non-small-cell lung cancer (NSCLC). We used multipanel markers to predict the response to immune checkpoint inhibitors (ICIs) by characterizing gene expression signatures or individual genes in patients who showed durable clinical benefit to ICIs. Twenty-one patients with NSCLC treated with single-agent anti-programmed cell death protein (PD)-1 antibody were analyzed and their clinicopathological characteristics and response to ICIs were characterized. Nine (43%) showed a durable clinical benefit (DCB), while the remaining 12 (57%) patients showed non-durable benefit (NDB). The M1 and peripheral T cell signatures showed the best performance for discriminating DCB from NDB (sensitivity, specificity, accuracy = 0.89, 1.0, 0.95, respectively). Progression-free survival (PFS) was significantly longer in patients with high M1 signature or high peripheral T cell signature scores. CD137 and PSMB9 mRNA expression was higher in the DCB group than in the NDB group. Patients with high PSMB9 expression showed longer PFS. M1 signature, peripheral T cell signature and high mRNA expression level of CD137 and PSMB9 showed better predictive performance than known biomarkers, such as PD-L1 immunohistochemistry, tumor mutation burden, or tumor-infiltrating lymphocytes.

Giant angioleiomyoma of the sacral foramina: an unusual location.

Angioleiomyoma is a benign, vascular smooth muscle tumor originating from the tunica media of the vessel wall. In general, it typically arises in the cutaneous, subcutaneous tissue or fascia of the lower extremities in middle-aged women and is less than 2 cm in diameter. We report an unusual case of an angioleiomyoma of the sacral foramina in an 82-year-old man. MRI revealed a well-defined irregular-shaped deep-seated mass in the sacral foramina, showing branching pattern of growth associated with pressure bony erosion of the adjacent bones, with isointense to hypointense signal on T2-weighted images. Surgical excision was performed and the mass was diagnosed as angioleiomyoma on pathological examination. To the best of our knowledge, there has been no report of an angioleiomyoma involving the sacral foramina.

Intraarticular calcifying aponeurotic fibroma of the wrist: mimicking gout or calcium pyrophosphate dihydrate deposition disease.

Calcifying aponeurotic fibroma is a rare, benign fibroblastic tumor that typically occurs in the palms of the hands and soles of the feet in children and adolescents. We report an unusual case of a calcifying aponeurotic fibroma with diffuse intra-articular involvement of the carpal joints in a 59-year-old female. Radiographs and computed tomography scans revealed a large lobulated soft tissue mass with multiple stippled calcifications around the carpal joints and numerous erosions of the second to fifth carpometacarpal and intercarpal joints. Magnetic resonance imaging showed diffuse multinodular synovial proliferation with inhomogeneous hypo- to isointense signal intensity on T1-weighted images, inhomogeneous hypointense to hyperintense signal intensity on T2-weighted images, and inhomogeneous intense enhancement on fat-suppressed contrast-enhanced T1-weighted images. Radiologic diagnosis included gout, calcium pyrophosphate dihydrate deposition disease, and tenosynovial giant cell tumor. Surgical excision was performed, and the mass was diagnosed on pathologic examination as a calcifying aponeurotic fibroma. There has been no reported case of a calcifying aponeurotic fibroma with diffuse intra-articular involvement of the carpal joints in the literature.

Fascin expression is inversely correlated with breast cancer metastasis suppressor 1 and predicts a worse survival outcome in node-negative breast cancer patients.

Background: Fascin is an actin-bundling protein that promotes cancer cell migration and invasion. By contrast, breast cancer metastasis suppressor 1 (BRMS1) inhibits cancer metastasis by targeting multiple steps of the metastatic cascade. We evaluated whether expression patterns of fascin and BRMS1 correlate with clinicopathological features and patient outcome. Methods: Immunohistochemistry for fascin and BRMS1 was performed using a tissue microarray constructed from 183 human breast cancer tissues. Fascin expression determined by the proportion of stained tumor cells (0: 0-5%, 1: 6-25%, 2: 26-50%, 3: 51-75%, or 4: >75%) and staining intensity (0: negative, 1: weak, 2: moderate, or 3: strong) were multiplied and defined as negative (0-3) or positive (4-12). BRMS1 expression was scored separately based on nuclear and cytoplasmic staining intensity (0: negative, 1: weak, 2: moderate, 3: strong). We obtained the BRMS1 H score by summing the nuclear and cytoplasmic scores and defined it as negative (0-2) or positive (3-6). Results: Expression of BRMS1 showed a significant inverse correlation with that of fascin. Fascin+ tumors were significantly associated with no lymph node metastasis, higher histological and higher nuclear grade, ER/PR/HER2 negativity, and triple-negative subtype (all ps < 0.05). These clinicopathological differences showed the same trend in a comparison of fascin-/BRMS1+ and fascin+/BRMS1- tumors. Negative or weak BRMS1 cytoplasmic expression was significantly associated with shorter disease-free survival (DFS; p = 0.043). Fascin positivity was significantly associated with shorter DFS (p = 0.005) and overall survival (p = 0.020) when analyses were confined to node-negative patients. Conclusions: This study confirms an inverse correlation between expression of fascin and expression of BRMS1 using a quite large cohort of human breast cancer tissues. Fascin alone or combined with BRMS1 was a worse prognostic marker, particularly in node-negative breast cancer patients.

miR-150 enhances apoptotic and anti-tumor effects of paclitaxel in paclitaxel-resistant ovarian cancer cells by targeting Notch3.

Tumor recurrence by obtaining chemoresistance is a major obstacle to treating ovarian cancer. By TargetScan database and a luciferase reporter assay, we identified miR-150 directly targets Notch3, which is a key oncogene in ovarian cancer. We, therefore, investigated the role of miR-150 in ovarian cancer cells, and the usefulness of miR-150 as a therapeutic target in chemoresistant ovarian cancer, through examining miR-150 expression by qRT-PCR in ovarian cancer cell lines and tissues, and assessing the gain-of-function effect by WST, colony forming, TUNEL, wound healing and angiogenesis assays. Western blotting was performed to evaluate its downstream targets. The miR-150 expression was significantly downregulated in ovarian cancers. Treatment with pre-miR-150 significantly inhibited cancer cell proliferation, and induced apoptosis in PTX (paclitaxel) -resistant SKpac cells, which was not seen by PTX only treatment. On spheroid forming assay, an additional pre-miR-150 treatment with PTX decreased cancer stem cell activation in PTX-resistant SKpac cells. An experimental upregulation of miR-150 also decreased cancer cell migration and angiogenesis in SKpac cells. The Notch3 downstream proteins(NICD3 and HEY2), and cell cycle-related proteins (cyclinD3, pS6, and NF-kB), and apoptosis-related proteins (BCL-2 and BCL-W) were significantly downregulated by pre-miR-150 transfection. Taken together, miR-150 is related with PTX-resistance in ovarian cancer, and treatment with pre-miR-150 resensitizes cancer cells to PTX. Therefore, it may be a promising treatment strategy in chemoresistant and recurrent ovarian cancer.

Solitary myofibroma of the lumbar vertebra in young adult: A case report with 4-year follow-up of postoperative CT or MRI.

BACKGROUND: Solitary myofibroma of the spine is extremely rare, particularly among adults. To the best of our knowledge, only 3 cases affecting lumbar vertebrae have been reported in the English language literature. Of them, only 1 case was an adult case of solitary myofibroma affecting the L1 vertebra. METHODS: We report a case of solitary myofibroma affecting the L5 vertebra in an 18-year-old man and the postoperative imaging of solitary myofibroma for the first time. Conventional radiographs demonstrated an expansile osteolytic lesion with thinned cortex and marginal sclerosis. Computed tomography (CT) showed a purely osteolytic expansile lesion with partial disappearance of thinned cortex. MRI of the lesion revealed an isointense signal on T1-weighted images, an inhomogeneous slightly hyperintense signal on T2-weighed images, and homogeneous avid enhancement with gadolinium. RESULTS: Surgical excision was performed and the lesion was diagnosed as solitary myofibroma on pathological examination. One-year follow-up postoperative CT demonstrated decreased size of the osteolytic lesion with sclerotic change. Four-year follow-up postoperative MRI revealed complete resolution of the lesion replaced by normal fatty marrow. CONCLUSION: If a benign-looking expansile osteolytic lesion reveals a homogeneously isointense signal on T1-weighted image, inhomogeneous slightly hyperintense signal on T2-weighted image, and homogeneous avid enhancement with gadolinium, solitary myofibroma should be considered in the differential diagnosis of spine bone tumors. It can be resolved completely.

Presternal subcutaneous bronchogenic cyst in adolescence: A case report and unusual ultrasonographic findings.

Subcutaneous bronchogenic cysts have been described rarely, particularly among adolescents. Only a few reports have described the ultrasonographic features of bronchogenic cysts, characterizing them as nonspecific cystic masses with or without internal echogenic foci or debris. Therefore, it is hard to differentiate subcutaneous bronchogenic cysts from other subcutaneous cystic tumors ultrasonographically.We report a case of presternal subcutaneous bronchogenic cyst in an 18-year-old man with unusual ultrasonographic findings. Ultrasonography revealed a small, oval, cystic mass containing a well-circumscribed, heterogeneously hypoechoic, egg-shaped lesion in the dependent portion of the mass within the subcutaneous fat layer overlying the sternum.Surgical excision was performed, and the cystic mass was diagnosed as a bronchogenic cyst. On pathological examination, the internal, heterogeneously hypoechoic, ball-like lesion was found to be mucous material within the cyst. To our knowledge, this is the first reported case of a presternal subcutaneous bronchogenic cyst presenting with a ball-like lesion inside of the cyst. This unusual ultrasonographic feature can be a clue to the diagnosis of subcutaneous bronchogenic cyst.In conclusion, if an anechoic cyst containing an internal, well-circumscribed, hypoechoic ball-like lesion is seen in the presternal subcutaneous fat layer, subcutaneous bronchogenic cyst should be considered in the differential diagnosis of subcutaneous cystic masses.

MicroRNA-136 inhibits cancer stem cell activity and enhances the anti-tumor effect of paclitaxel against chemoresistant ovarian cancer cells by targeting Notch3.

To identify microRNAs (miRNAs) regulating Notch3 expression in association with paclitaxel resistance, candidate miRNAs targeting Notch3 were predicted using TargetScan. We found that miR-136 directly targets Notch3, and miR-136 was significantly downregulated in OSC tissues relative to normal control tissues, and low expression of miR-136 correlated with poor overall in ovarian cancer patients. Artificial miR-136 overexpression significantly reduced cell viability, proliferation, Cancer stem cell (CSC) spheroid formation, and angiogenesis, and increased apoptosis in paclitaxel-resistant SKpac cells compared with the effects of paclitaxel alone. miR-136 overexpression downregulated cell survival- (survivin, DNA-PK, pS6, S6) and cell cycle- (Cyclin D1, NF-κB) related proteins, and anti-apoptotic proteins (BCL2, and BCL-XL), and upregulated pro-apoptotic proteins (Bim, Bid, and Bax). Taken together, miR-136 targets the Notch3 oncogene and functions as a tumor suppressor. miR-136 overexpression resensitized paclitaxel-resistant ovarian cancer cells and reduced CSC activities, suggesting a promising new target for the treatment of chemoresistant ovarian cancers.

Sox10 expression in ovarian epithelial tumors is associated with poor overall survival.

Sox10 is a transcription factor regulating the development of several cell lineages and is involved in tumor development. However, the clinicopathological relevance of Sox10 expression in ovarian cancer has not been examined. We assessed expression of Sox10 in ovarian epithelial tumors by immunohistochemistry and assessed its prognostic value by analyzing the correlation between its expression and clinicopathological factors. We used tissue microarrays including 244 ovarian epithelial tumors. Sox10 staining was found in the cytoplasm or nucleus of tumor cells. Malignant serous, mucinous, and endometrioid tumors were significantly more likely to express Sox10 than benign and borderline tumors. Expression patterns in adenocarcinomas were different for histologic subtypes: nuclear Sox10 staining was common in clear-cell adenocarcinomas and serous adenocarcinomas, whereas all cases of mucinous and endometrioid tumors were negative for nuclear staining. Nuclear Sox10 staining was also associated with chemoresistance and shorter overall survival in ovarian adenocarcinomas, notably in high-grade serous adenocarcinoma. Sox10 is expressed in many ovarian carcinomas, suggesting that it might be involved in oncogenesis of ovarian carcinoma. Expression pattern of Sox10 differs between histological subtypes. Nuclear Sox10 expression is an independent indicator of poor prognosis in ovarian adenocarcinomas, notably in high-grade serous adenocarcinomas.

Spermatic Cord Paraganglioma With Histologically Malignant Features.

Paragangliomas occur extremely rarely in the spermatic cord. A 40-year-old man presented with a scrotal mass that was diagnosed as spermatic cord paraganglioma with malignant histological features. To our knowledge, this is the first case of spermatic cord paraganglioma presented with malignant histological features evaluated by histological scoring. Careful evaluation of histological features and systematic evaluation should be considered for patients with spermatic cord paragangliomas.