Clinical Outcomes of Small Cell Carcinoma of the Genitourinary Tract and the Prognostic Significance of the Tumor Immune Microenvironment / Journal of the Korean Cancer Association, 대한암학회지

Purpose@#Small cell carcinoma of the genitourinary tract (GU SCC) is a rare disease with a poor prognosis. There are only limited treatment options due to insufficient understanding of the disease. In this study, we analyzed the clinical outcomes of patients with GU SCC and their association with the tumor immune phenotype. @*Materials and Methods@#Patients diagnosed with GU SCC were included. Survival outcomes according to the primary location (prostate and non-prostate) and stages (limited disease [LD] and extensive disease [ED]) were analyzed. We performed multiplex immunohistochemistry (IHC) in non-prostate SCC patients and analyzed the immune cell population. @*Results@#A total of 77 patients were included in this study. Their median age was 71 years, 67 patients (87.0%) were male, and 48 patients (62.3%) had non-prostate SCC. All patients with ED (n=31, 40.3%) received etoposide plus platinum (EP) as initial treatment and median overall survival (OS) was 9.7 months (95% confidence interval [CI], 7.1 to 18.6). Patients with LD (n=46, 59.7%) received EP followed by radiotherapy or surgery, and 24-months OS rate was 63.6% (95% CI, 49.9 to 81.0). The multiplex IHC analysis of 21 patients with non-prostate SCC showed that patients with a higher density of programmed death-ligand 1–expressing CD68+CD206+ M2-like macrophages had significantly worse OS outcomes with an adjusted hazards ratio of 4.17 (95% CI, 1.25 to 14.29; adjusted p=0.02). @*Conclusion@#Patients with GU SCC had a poor prognosis, even those with localized disease. The tumor immune phenotypes were significantly associated with survival. This finding provides new insights for treating GU SCC.

Spatial Distribution and Prognostic Implications of Tumor-Infiltrating FoxP3- CD4+ T Cells in Biliary Tract Cancer / Journal of the Korean Cancer Association, 대한암학회지

Purpose@#The clinical implications of tumor-infiltrating T cell subsets and their spatial distribution in biliary tract cancer (BTC) patients treated with gemcitabine plus cisplatin were investigated. @*Materials and Methods@#A total of 52 BTC patients treated with palliative gemcitabine plus cisplatin were included. Multiplexed immunohistochemistry was performed on tumor tissues, and immune infiltrates were separately analyzed for the stroma, tumor margin, and tumor core. @*Results@#The density of CD8+ T cells, FoxP3- CD4+ helper T cells, and FoxP3+ CD4+ regulatory T cells was significantly higher in the tumor margin than in the stroma and tumor core. The density of LAG3- or TIM3-expressing CD8+ T cell and FoxP3- CD4+ helper T cell infiltrates was also higher in the tumor margin. In extrahepatic cholangiocarcinoma, there was a higher density of T cell subsets in the tumor core and regulatory T cells in all regions. A high density of FoxP3- CD4+ helper T cells in the tumor margin showed a trend toward better progression-free survival (PFS) (p=0.092) and significantly better overall survival (OS) (p=0.012). In multivariate analyses, a high density of FoxP3- CD4+ helper T cells in the tumor margin was independently associated with favorable PFS and OS. @*Conclusion@#The tumor margin is the major site for the active infiltration of T cell subsets with higher levels of LAG3 and TIM3 expression in BTC. The density of tumor margin-infiltrating FoxP3- CD4+ helper T cells may be associated with clinical outcomes in BTC patients treated with gemcitabine plus cisplatin.

Clinical Significance of CLDN18.2 Expression in Metastatic Diffuse-Type Gastric Cancer

Purpose@#Isoform 2 of tight junction protein claudin-18 (CLDN18.2) is a potential target for gastric cancer treatment. A treatment targeting CLDN18.2 has shown promising results in gastric cancer. We investigated the clinical significance of CLDN18.2 and other cell-adherens junction molecules (Rho GTPase-activating protein [RhoGAP] and E-cadherin) in metastatic diffuse-type gastric cancer (mDGC). @*Materials and Methods@#We evaluated CLDN18.2, RhoGAP, and E-cadherin expression using two-plex immunofluorescence and quantitative data analysis of H-scores of 77 consecutive mDGC patients who received first-line platinum-based chemotherapy between March 2015 and February 2017. @*Results@#CLDN18.2 and E-cadherin expression was significantly lower in patients with peritoneal metastasis (PM) than those without PM at the time of diagnosis (P=0.010 and 0.013, respectively), whereas it was significantly higher in patients who never developed PM from diagnosis to death than in those who did (P=0.001 and 0.003, respectively). Meanwhile, CLDN18.2 and E-cadherin expression levels were significantly higher in patients with bone metastasis than in those without bone metastasis (P=0.010 and 0.001, respectively).Moreover, we identified a positive correlation between the expression of CLDN18.2 and E-cadherin (P<0.001), RhoGAP and CLDN18.2 (P=0.004), and RhoGAP and E-cadherin (P=0.001). Conversely, CLDN18.2, RhoGAP, and E-cadherin expression was not associated with chemotherapy response and survival. @*Conclusions@#CLDN18.2 expression was reduced in patients with PM but significantly intactin those with bone metastasis. Furthermore, CLDN18.2 expression was positively correlated with other adherens junction molecules, which is clinically associated with mDGC and PM pathogenesis.

Clinical Significance of CLDN18.2 Expression in Metastatic Diffuse-Type Gastric Cancer

Purpose@#Isoform 2 of tight junction protein claudin-18 (CLDN18.2) is a potential target for gastric cancer treatment. A treatment targeting CLDN18.2 has shown promising results in gastric cancer. We investigated the clinical significance of CLDN18.2 and other cell-adherens junction molecules (Rho GTPase-activating protein [RhoGAP] and E-cadherin) in metastatic diffuse-type gastric cancer (mDGC). @*Materials and Methods@#We evaluated CLDN18.2, RhoGAP, and E-cadherin expression using two-plex immunofluorescence and quantitative data analysis of H-scores of 77 consecutive mDGC patients who received first-line platinum-based chemotherapy between March 2015 and February 2017. @*Results@#CLDN18.2 and E-cadherin expression was significantly lower in patients with peritoneal metastasis (PM) than those without PM at the time of diagnosis (P=0.010 and 0.013, respectively), whereas it was significantly higher in patients who never developed PM from diagnosis to death than in those who did (P=0.001 and 0.003, respectively). Meanwhile, CLDN18.2 and E-cadherin expression levels were significantly higher in patients with bone metastasis than in those without bone metastasis (P=0.010 and 0.001, respectively).Moreover, we identified a positive correlation between the expression of CLDN18.2 and E-cadherin (P<0.001), RhoGAP and CLDN18.2 (P=0.004), and RhoGAP and E-cadherin (P=0.001). Conversely, CLDN18.2, RhoGAP, and E-cadherin expression was not associated with chemotherapy response and survival. @*Conclusions@#CLDN18.2 expression was reduced in patients with PM but significantly intactin those with bone metastasis. Furthermore, CLDN18.2 expression was positively correlated with other adherens junction molecules, which is clinically associated with mDGC and PM pathogenesis.

Clinical experience of immune checkpoint inhibitor for a metastatic jejunal cancer patient with a high tumor mutational burden and low expression of programmed death-ligand 1

Recent data showed that DNA mismatch repair deficiency can be a predictive biomarker for a favorable response of immune checkpoint inhibitors regardless of tumor type due to give rise to high tumor mutational burden (TMB) and microsatellite instability (MSI). Loss-of-function mutations of a specific tumor suppressor gene can also lead to good response to immunotherapy. Herein, we report a case exhibiting good response to pembrolizumab in a jejunal adenocarcinoma patient with low programmed death-ligand 1 (PD-L1) expression. A 67-yearold man underwent surgical resection followed by adjuvant chemotherapy. After 10 months, he was treated with palliative chemotherapy due to hepatic and pulmonary metastases. However, palliative chemotherapy did not have any effect whatsoever. Based on genetic testing results of high TMB and high MSI in the resected primary tumor, pembrolizumab treatment was performed. After the three cycles of treatment, all metastatic lesions shrank remarkably. Considering the mechanism of immune checkpoint inhibitors, this case establishes the importance of genetic markers as TMB and MSI rather than PD-L1 expression by the prediction of their anti-tumor activities.

Autophagy Regulates Formation of Primary Cilia in Mefloquine-Treated Cells

Primary cilia have critical roles in coordinating multiple cellular signaling pathways. Dysregulation of primary cilia is implicated in various ciliopathies. To identify specific regulators of autophagy, we screened chemical libraries and identified mefloquine, an anti-malaria medicine, as a potent regulator of primary cilia in human retinal pigmented epithelial (RPE) cells. Not only ciliated cells but also primary cilium length was increased in mefloquine-treated RPE cells. Treatment with mefloquine strongly induced the elongation of primary cilia by blocking disassembly of primary cilium. In addition, we found that autophagy was increased in mefloquine-treated cells by enhancing autophagic flux. Both chemical and genetic inhibition of autophagy suppressed ciliogenesis in mefloquine-treated RPE cells. Taken together, these results suggest that autophagy induced by mefloquine positively regulates the elongation of primary cilia in RPE cells.

Optical Molecular Imaging for Diagnosing Intestinal Diseases

Real-time visualization of the molecular signature of cells can be achieved with advanced targeted imaging techniques using molecular probes and fluorescence endoscopy. This molecular optical imaging in gastrointestinal endoscopy is promising for improving the detection of neoplastic lesions, their characterization for patient stratification, and the assessment of their response to molecular targeted therapy and radiotherapy. In inflammatory bowel disease, this method can be used to detect dysplasia in the presence of background inflammation and to visualize inflammatory molecular targets for assessing disease severity and prognosis. Several preclinical and clinical trials have applied this method in endoscopy; however, this field has just started to evolve. Hence, many problems have yet to be solved to enable the clinical application of this novel method.

Normative data of penile length in Korean newborns / 소아과

PURPOSE: As modern society has became more open, interest in healthy internal and external growth has increased, including that pertaining to penile length in children. A micropenis is defined as one where penile length is more than 2 SD (standard deviation) below the mean, and it can be traced back to chromosome and endocrine disorders. The authors executed this study to suggest guidelines for the study of the micropenis and standard information for penile length in Korean newborns. METHODS: The subjects of this study were 168 male infants between 37 and 42 weeks of gestational age, none of whom had any complications during pregnancy or birth; each had been born in Daegu Fatima Hospital between February and June 2007. Penile length was measured using conventional stretched penile length measurement (CPLM) and syringe methods. RESULTS: Penile length was 3.02+/-0.25 cm (F=36.467, R(2)=0.180, P<0.001) when measured with CPLM, and 3.29+/-0.26 cm (F=9.149, R(2)=0.052, P<0.001) with the syringe method. There was no statistically significant difference in the penile length of newborn infants as a result of taking measurements with the two methods, and both methods showed significance at 0.631 in terms of Pearson's correlation coefficient, at the level of P=0.01. CONCLUSION: In this study, penile length tended to be longer when gestational age was longer, and a micropenis can be assumed to be one less than 2.5 cm using CPLM and less than 2.8 cm using the syringe method. In the case of a concealed penis, the syringe method is helpful. When a micropenis is assumed, close observation by outpatient department personnel, and additional endocrine and chromosome studies should be undertaken after sufficiently consulting the parents.

Normative data of penile length in Korean newborns / 소아과

PURPOSE: As modern society has became more open, interest in healthy internal and external growth has increased, including that pertaining to penile length in children. A micropenis is defined as one where penile length is more than 2 SD (standard deviation) below the mean, and it can be traced back to chromosome and endocrine disorders. The authors executed this study to suggest guidelines for the study of the micropenis and standard information for penile length in Korean newborns. METHODS: The subjects of this study were 168 male infants between 37 and 42 weeks of gestational age, none of whom had any complications during pregnancy or birth; each had been born in Daegu Fatima Hospital between February and June 2007. Penile length was measured using conventional stretched penile length measurement (CPLM) and syringe methods. RESULTS: Penile length was 3.02+/-0.25 cm (F=36.467, R(2)=0.180, P<0.001) when measured with CPLM, and 3.29+/-0.26 cm (F=9.149, R(2)=0.052, P<0.001) with the syringe method. There was no statistically significant difference in the penile length of newborn infants as a result of taking measurements with the two methods, and both methods showed significance at 0.631 in terms of Pearson's correlation coefficient, at the level of P=0.01. CONCLUSION: In this study, penile length tended to be longer when gestational age was longer, and a micropenis can be assumed to be one less than 2.5 cm using CPLM and less than 2.8 cm using the syringe method. In the case of a concealed penis, the syringe method is helpful. When a micropenis is assumed, close observation by outpatient department personnel, and additional endocrine and chromosome studies should be undertaken after sufficiently consulting the parents.

Study of the risk factors for pulmonary interstitial emphysema related to mechanical ventilator care / 소아과

PURPOSE: Pulmonary interstitial emphysema (PIE) primarily occurs in preterm infants suffering from respiratory distress syndrome (RDS) and kept under mechanical ventilator care. Therefore, this study aimed to examine various risk factors for PIE, to identify conditions that can decrease the possibility of PIE development. METHODS: PIE classification was conducted for 183 patients diagnosed to have RDS and receiving mechanical ventilator care with pulmonary surfactant between March 2000 and February 2007. The characteristics of each patient were analyzed through retrospective examination of their medical histories. RESULTS: Among 183 patients, 17 had PIE; all factors, including birth weight, gestational age, RDS grade III or above, chorioamnionitis, and premature rupture of membranes, were statistically significant (P<0.05). The period of mechanical ventilator use was statistically significant, but the peak mean airway pressure and peak partial pressure of inspired oxygen were not. PIE mainly occurred on the right side or both sides rather than the left side and mostly developed within 72 h. The PIE group showed higher mortality rate than the control group, and the major cause of mortality was pneumothorax. CONCLUSION: Risk factors for PIE in infants suffering from RDS and kept under mechanical ventilator care include low gestational age, low birth weight, chorioamnionitis, and premature rupture of membranes. If any risk factors are noted, the infant must be observed closely for at least 72 h after birth.

A Case of Recurrent Bacterial Meningitis Associated with Lumbosacral Dermal Sinus during Early Infancy / 대한소아신경학회지

Acute bacterial meningitis is an uncommon, potentially life-threatening infection and recurrent episodes of bacterial meningitis are rarely seen. But when they occur, an exhaustive search for the mechanisms underlying the recurrent episodes must be pursued, especially some possible routes of migration of bacteria to the cerebrospinal fluid. Dermal sinus tracts are common skin manifestations seen with spinal dysraphism and may be associated with recurrent meningitis. Here, we present a case of a 2-month-old girl who had a small dimple on the lower lumbosacral area. She was attacked twice by purulent bacterial meningitis due to a dermal sinus tract and a tethered cord. She was treated with the excision of the tract, the removal of the dermoid and the detethering of the cord. Staphylococcus and Klebsiella were cultured separately and assumed to be causative agents. The lesion was suspected on the physical examination and demonstrated by lumbosacral magnetic resonance imaging.

A Case of Chronic Inflammatory Demyelinating Polyradiculoneuropathy Associated with Perianal Abscess by Klebsiella pneumoniae / 대한소아신경학회지

Chronic inflammatory demyelinating polyradiculoneuropathy(CIDP) is a rare acquired demyelinating disease of peripheral nervous system(PNS), characterized by relapsing or progressive proximal and distal muscle weakness with possible sensory loss. It is one of several chronic neuropathic syndromes that are believed to have an autoimmune etiology. We experienced a case of CIDP in a 3-month-old boy associated with perianal abscess by Klebsiella pneumoniae who had a precipitous onset of symptoms after anesthesia. He was treated with intravenous immunoglobuline with little improvement but showed a remarkable clinical and electrophysiologic improvement after methylprednisolone pulse therapy. We report this case with a brief review of related literature.

A Case of Prenatal Diagnosis of Congenital Fetal Goiter in Hyperthyroidism Mother / 대한주산의학회잡지

We report a case of prenatal diagnosis of fetal congenital goiter at 31weeks of gestation by ultrasonogram and fetal hypothyroidism confirmed at birth as thyroid function test by umbilical cord blood sampling. Maternal Graves' disease and the drugs used to treat hyperthyroidism in pregnant women can affect the fetus, causing hyperthyroidism or hypothyroidism and goiter. Fetal hypothyroidism may be caused by transplacental passage of either maternal thyrotropic-binding inhibitory immunoglobulin(TBII) antibodies or maternal treatment with propylthiouracil(PTU). Untreated fetal hypothyroidism may result in mental retardation, perceptual-motor, visual-spatial, and language developmental problems. In this article fetal thyroid function was not assessed by cordocentesis, but fetal congenital goiter was detected ultrasound. Ultrasound should be used to detect fetal goiter from 20 weeks onward. Fetal goiter should resolve when maternal PTU treatment is decreased. We have diagnosed fetal hypothyroidism in utero by ultrasonography. Significance of in utero management of fetal hypothyroidism is discussed.