Clinical significance of MYC family protein expression in surgically resected high-grade neuroendocrine carcinoma of the lung.

OBJECTIVES: MYC family genes including MYC, MYCN, and MYCL are amplified and overexpressed as oncogenic drivers in high-grade neuroendocrine carcinoma of the lung (HGNEC), but little is known about their clinical significance. This study evaluated the prognostic impact of MYC family protein expression in patients with surgically resected HGNEC. METHODS: Immunohistochemical analyses were performed on 83 resected specimens of HGNEC using antibodies against MYC family proteins (c-MYC, n-MYC, and l-MYC). When nuclear staining of any intensity in ≥10% of tumor cells showed immunoreactivity with any one or more of c-MYC, n-MYC, or l-MYC, the specimens were defined as MYC family-positive. RESULTS: A total of 83 patients were analyzed. MYC family-positive status was observed in 33.7% (28 of 83 cases) and was not correlated with clinicopathological factors. The protein expression was mutually exclusive and no duplicate cases were observed. A log-rank test showed that MYC family-positive status was significantly associated with shorter overall survival (OS) (p = 0.003) and recurrence-free survival (RFS) (p = 0.039). According to Cox multivariate analysis, MYC family-positive status had a significant effect on shorter OS (hazard ratio [HR] = 2.217, 95% confidence interval [CI] 1.179-4.169, p = 0.014) and RFS (HR = 1.802, 95% CI 1.014-3.202, p = 0.045). In patients with pathological stage I, MYC family-positive status also showed significantly poor OS (HR = 2.847, 95% CI 1.236-6.557, p = 0.014) and RFS (HR = 2.088, 95% CI 1.006-4.332, p = 0.048) in the multivariate analysis. CONCLUSIONS: MYC family protein expression could be an independent unfavorable prognostic factor in patients with surgically resected HGNEC.

Brain and spinal cord metastases with seminoma: A case report.

Introduction: Brain and spinal cord metastases from testicular cancer occur rarely, and metastases with seminoma are extremely rare. Case presentation: A 42-year-old man who was diagnosed with seminoma and multiple metastases underwent first-line and salvage chemotherapy. Brain metastases were noted; consequently, surgery, third-line chemotherapy, and whole-brain irradiation were performed. Subsequently, paralysis developed, and spinal cord metastases were detected. He received fourth-line chemotherapy but died. Pathological autopsy revealed metastases only in the spinal cord. The cause of death was considered respiratory failure due to cervical spinal cord involvement from spinal metastases. Conclusion: Brain and spinal cord metastases from seminoma are rare. Thus, similar future cases should be treated appropriately.

Early effects of adipose-derived stem cell sheets against detrusor underactivity in a rat cryo-injury model.

AIMS: This study investigated the effects of adipose-derived stem cell sheets on a rat model of detrusor underactivity. MAIN METHODS: Adipose-derived stem cell sheets were prepared from the subcutaneous adipose tissue of male Lewis rats. Female Lewis rats were assigned into four groups: control, sham operation, cryo-injury, and cryo-injury+sheet (n = 8 per group). Rats in the cryo-injury+sheet group were implanted with ASC sheets 3 days after cryo-injury induction and underwent cystometry 7 days later. Subsequently, reverse transcription-polymerase chain reaction (RT-PCR) and histopathological examinations were performed. Cell sheets expressing the green fluorescent protein were prepared and transplanted to confirm the viability and differentiation of the sheets. Fluorescence was confirmed using a fluorescence stereomicroscope on days 3, 7, 14, 21, and 28 after sheet implantation, and tissue immunostaining was performed. KEY FINDINGS: Cystometry showed that sheet implantation improved the maximum intravesical pressure (P = 0.009) and the residual urine volume (P = 0.011). Furthermore, RT-PCR indicated that the mRNA levels of the angiogenic factors vascular endothelial growth factor and hepatocyte growth factor were significantly higher in the cryo-injury+sheet group than in the cryo-injury group (P = 0.045, P = 0.037, respectively). Histologically, sheet implantation resulted in an improvement in inflammation and increased the number of blood vessels. Green fluorescent protein-positive cells fused with von Willebrand factor-positive cells and differentiated into blood vessels 7 days after sheet implantation. SIGNIFICANCE: Adipose-derived stem cell sheets transplanted into the bladder of cryo-injured rats differentiated into blood vessels and restored bladder contractile function 7 days after transplantation.

Retroperitoneal paraganglioma with loss of heterozygosity of the von Hippel-Lindau gene: a case report and review of the literature.

Von Hippel-Lindau (VHL) disease is an autosomal dominant disease related to germline mutations in VHL. In VHL disease, pheochromocytoma develops in 10%-20% of patients because of germline mutations and loss of heterozygosity of VHL. However, the rate of paraganglioma associated with VHL is low compared with that of pheochromocytoma, and the reason is unknown. In this study, we performed germline and somatic mutation analyses of retroperitoneal paraganglioma that developed in a patient with clinically diagnosed VHL disease and investigated the tumorigenic mechanism of paraganglioma. The patient was a 25-year-old woman who was considered to have VHL disease on the basis of her family history. She was referred to our clinic to investigate a tumor at the bifurcation of the common iliac artery. The tumor was diagnosed as retroperitoneal paraganglioma by clinical evaluations. A left renal cell carcinoma was also suspected. Polymerase chain reaction direct sequencing analysis and polymorphic microsatellite analysis within the VHL locus suggested that loss of heterozygosity of VHL was associated with paraganglioma and renal cell carcinoma. Multiplex ligation-dependent probe amplification analysis showed a loss of the copy number of VHL exons in paraganglioma. These results suggest that VHL disease contributes to the development of paraganglioma. A literature review showed no reported common missense variants involved in the progression of paraganglioma. The loss of heterozygosity of VHL can be a tumorigenic mechanism of retroperitoneal paraganglioma in VHL disease. However, the low rate of paraganglioma compared with pheochromocytoma is not explained by their genetic background alone.

Is Preoperative Magnetic Resonance Imaging in a Daily Clinical Setting Useful to Evaluate Tumor Invasion Beyond the Pseudocapsule in Renal Cell Carcinoma?

BACKGROUND: We wanted to clarify whether preoperative magnetic resonance imaging (MRI) in the clinical setting can evaluate the pathologic pseudocapsule (PC) morphology with high accuracy in renal cell carcinoma (RCC). METHODS: We retrospectively analyzed 34 consecutive patients who underwent MRI (1.5 or 3.0T, 5 mm slices) prior to partial nephrectomy (PN) for RCC at our institution between January 2010 and December 2019. First, the correlation between PC morphology (complete or incomplete) and tumor infiltration to the renal parenchyma was examined as pathologic validation. Second, the concordance rate of PC morphology between pathologic tissue and preoperative MRI was evaluated as radiologic validation. Third, risk factor for renal parenchymal invasion in RCC was analyzed. RESULTS: In the pathologic validation, parenchymal invasion rates were 11% and 28% in the "complete PC" and "incomplete PC" groups, respectively. In the radiologic validation, pathological PC morphology could be diagnosed on preoperative MRI in 17 patients (50.0%). "None PC" on MRI had the lowest positive predictive value (PPV) (0%), "partial PC" on MRI had a good PPV (76.5%), "complete PC" on MRI had a relatively low PPV (33.3%). Unfortunately, these data were insufficient for diagnostic accuracy. As risk factor for renal parenchymal invasion in RCC, only pathologic subtype (non-clear cell) was found to have significant differences in the multivariate analysis. CONCLUSION: The results of this study suggest that renal tumors with pathologically incomplete PC have a high possibility of renal parenchymal invasion. However, it is currently difficult to accurately evaluate pathologic PC morphology by preoperative MRI in the clinical setting.

BRAF V600E-mutated combined large cell neuroendocrine carcinoma and adenocarcinoma responding to targeted therapy.

We present a case of combined large cell neuroendocrine carcinoma (LCNEC), harbouring a BRAF V600E mutation, which significantly benefited from BRAF-targeted therapy. A 57-year-old woman was referred to our hospital for headache and vomiting. A head MRI showed a large tumour in her brain, and a whole-body CT revealed a tumour in the hilum of the right lung and mediastinal lymphadenopathies. Both the resected brain tumour and the mediastinal lymph node tissue contained LCNEC. Next-generation sequencing revealed a BRAF V600E mutation, and a combination therapy with dabrafenib and trametinib was initiated. The patient had a good response to treatment. Like non-small cell lung cancer patients, LCNEC patients should undergo multiplex somatic mutation testing.

Impact of positive surgical margin status in predicting early biochemical recurrence after robot-assisted radical prostatectomy.

BACKGROUND: We investigated the association between positive surgical margin (PSM) status and biochemical recurrence (BCR) after robot-assisted radical prostatectomy (RARP) to develop a prognostic factor-based risk stratification model for BCR. METHODS: We analyzed the data of 483 patients who underwent RARP at our hospital between October 2010 and April 2019; 435 patients without neoadjuvant therapy were finally included. The BCR-free survival rate was determined using Kaplan-Meier analysis. Effects of the PSM status, including the number of PSMs, Gleason score (GS) at a PSM, and the maximum PSM length for BCR, were investigated using Cox regression analysis. RESULTS: BCR was confirmed after RARP in 61 patients (14.0%), and PSM was confirmed in 74 patients (17.0%); PSM was a significant predictor of BCR (p < 0.001). The median number of PSMs was 2 (1-6), and the median maximum length of PSM was 6.0 (2.0-17.0) mm. Multivariable analysis showed lymph node invasion (p < 0.001), GS of ≥ 7 at a PSM (p = 0.022) and a maximum PSM length of > 6.0 mm (p = 0.003) were significant predictors of BCR. We classified the patients without lymph node invasion into good-, intermediate-, and poor-risk groups according to the other two risk factors (presence of 0, 1, and 2 factors, respectively) and rates of 1-year BCR-free survival (100.0, 72.7, and 48.1%, respectively). CONCLUSION: Higher GS at PSM and greater length of PSM were significant predictors of BCR after RARP, and console surgeons should be careful to prevent PSM during RARP.

A rare case of combined thymoma and a multilocular thymic cyst discovered due to chest pain.

BACKGROUND: A thymoma with chest pain and multilocular thymic cysts (MTCs) is very rare. CASE PRESENTATION: A 49-year-old man presented to another hospital complaining of an anterior chest pain. Chest computed tomography (CT) showed an anterior mediastinal tumor 60 × 30 × 55 mm in size. The boundary with the pericardium or left brachiocephalic vein seemed to be partially unclear while enhanced by the contrast medium, and so the tumor could have invaded them. No definitive diagnosis of myasthenia gravis was made although the serum anti-acetylcholine receptor antibody count was high. We performed an extended thymectomy with combined partial resection of left brachiocephalic vein, left upper lobe, and left phrenic nerve. He was discharged with no chest pain and no complications post-surgery. The tumor was pathologically type B2 thymoma with hemorrhage necrosis and MTCs, and we diagnosed Masaoka stage II because of no histological infiltration to the organs. CONCLUSIONS: We speculated that hemorrhagic necrosis due to infarction in tumor caused the inflammation to spread to the surrounding organs, which was related to the chest pain and the development of MTCs.

Upregulation of glucose and amino acid transporters in micropapillary carcinoma.

Micropapillary carcinoma (MPC), a relatively rare histologic carcinoma observed in various organs, is associated with vascular invasion, nodal metastasis, and poor prognosis. MPC is different from papillary carcinoma as it has no fibrovascular core and is thus considered essentially hypovascular. MPCs are known to upregulate glucose transporter 1 (GLUT1) via the activation of a transcription factor, hypoxia-inducible factor (HIF)-1. Here we evaluated the expression of nutrient transporters in MPCs to gain a better understanding of the system used by MPCs to compensate for their intrinsic poor vascularity. We immunohistochemically evaluated 29 MPCs including breast (n=14), lung (n=8), gastrointestinal tract (n=5), and urinary tract cancers (n=2), and compared them with non-micropapillary control cancers (n=32) regarding the expression of amino acid (ASCT1, ASCT2, LAT1, and SNAT1) and glucose (GLUT1, GLUT2) transporters. Each section was scored by the staining intensity (0-3) multiplied by the occupying area (0-10), with a possible range 0-30. The average scores of the MPC and control groups were compared by Student's or Welch's t-test according to the homoscedasticity. The MPC group showed significantly higher scores for ASCT1 (p=0.007), ASCT2 (p=0.001), GLUT1 (p<0.001), and GLUT2 (p<0.001), whereas no significant scores were noted for LAT1 and SNAT1. In conclusion, MPC could be associated with the upregulation of several nutrient transporters, which may contribute to the malignant potential by supporting the survival of cancer cells.