Eun Joo Kang

The relationship between preeclampsia, pregnancy-induced hypertension and maternal risk of breast cancer: A meta-analysis

Abstract Background. It has long been recognized that some human breast cancers are hormone dependent. Preeclampsia is a syndrome of pregnancy defined by the onset of hypertension and proteinuria and characterized by dysfunction of the maternal endothelium. Many hormonal changes occur with preeclampsia, and we hypothesize that these changes may influence the risk of maternal breast cancer. We also analyzed the relation between pregnancy-induced hypertension (PIH) and maternal risk of breast cancer. Methods. Among 13 relevant publications about preeclampsia and six relevant publications about PIH, some studies find preeclampsia associated with a lower risk of breast cancer, but others did not. Therefore, these results are inconclusive. We conducted meta-analysis to evaluate more precisely the relationship between preeclampsia, PIH and maternal risk of breast cancer. Results. The pooled estimate of the hazard ratio (HR) associated with preeclampsia was 0.86 (95% CI 0.73–1.01), and that associated with PIH was 0.83 (0.66–1.06), both based on the random effects model. Conclusion. Some suggestive but not entirely consistent nor conclusive evidence was found on the association between the history of preeclampsia or PIH with the subsequent risk of breast cancer.

Pregnancy-Associated Risk Factors of Postpartum Breast Cancer in Korea: A Nationwide Health Insurance Database Study

Patients with postpartum breast cancer have been reported to have a poor prognosis. The present study aimed to evaluate the pregnancy-related risk factors of postpartum breast cancer in Korea. We collected patient data from the Korea National Health Insurance (KNHI) Claims Database of the Health Insurance Review and Assessment Service (HIRA) for the 2009–2013 period. We evaluated the pregnancy-related risk factors for postpartum breast cancer in two population groups. For Group 1 (women who had given birth during the 2010–2012 period), data on those who were diagnosed with breast cancer from childbirth to 1-year postpartum were extracted. For Group 2, we extracted the data of women who gave birth in 2010 and traced them until December 31, 2013. In Group 1, 1,384,551 deliveries and 317 postpartum breast cancer patients were recorded in Korea between January 1, 2010, and December 31, 2012. Women aged ≥35 years (Odds Ratio [OR], 2.003; 95% Confidence Interval [CI], 1.567–2.560) and those who gave birth via cesarean delivery (OR, 1.237; 95% CI, 0.986–1.553) were considered to be at a higher risk for breast cancer. Lower risk was noted in primiparous women (OR, 0.737; 95% CI, 0.585–0.928). In Group 2, the data of 457,924 women who gave birth in 2010 were traced until December 31, 2013. Among them, 655 patients were diagnosed with breast cancer, and age ≥35 years and cesarean delivery were associated with an higher risk of breast cancer, whereas primiparous status was associated with a lower risk of breast cancer. In conclusion, older age (≥35 years) and cesarean delivery are significant risk factors for postpartum breast cancer, and primiparous women have a lower risk of developing postpartum breast cancer.

Prognostic Factors and Skeletal-Related Events in Patients with Small Cell Lung Cancer with Bone Metastases at the Time of Diagnosis

Background/Objective: The aim of this study was to evaluate the characteristics and prognostic factors of small cell lung cancer (SCLC) with bone metastases. We also investigated the characteristics and predictive factors of skeletal-related events (SREs) in these patients. Materials and Methods: Sixty-one patients who were first diagnosed with SCLC with bone metastases at our institution were included in this retrospective analysis. Results: The overall survival (OS) of patients with bone metastases was shorter than that of patients without bone metastases (4.13 vs. 6.17 months, p = 0.015). Poor Eastern Cooperative Oncology Group (ECOG) performance status (PS; ≥2) and higher serum alkaline phosphatase (ALP; above upper normal limit × 2) were independent poor prognostic factors (p = 0.027 for ECOG PS, p = 0.002 for ALP). More than 1 SRE occurred in 21 patients (34.4%). Cervical spine metastasis, thoracic spine metastasis, pelvic bone metastasis, more than 5 bone metastatic regions and higher serum lactate dehydrogenase were correlated with the occurrence of SREs. Thoracic spinal metastasis was a strong predictive factor for the occurrence of SREs (odds ratio = 5.475; 95% CI: 1.080-27.755). Conclusion: Our study demonstrates the poor prognosis of SCLC patients with bone metastases. Physicians should treat SCLC patients with bone metastases with caution.

Comparison of the Efficacy between Pemetrexed plus Platinum and Non-Pemetrexed plus Platinum as First-Line Treatment in Patients with Wild-Type Epidermal Growth Factor Receptor Nonsquamous Non-Small Cell Lung Cancer: A Retrospective Analysis.

Background: Despite the development of molecular research and targeted therapy, patients with wild-type epidermal growth factor receptor (EGFR) non-small cell lung cancer (NSCLC) still receive platinum doublet chemotherapy as the standard first-line treatment. We investigated the efficacy of first-line regimens in patients with wild-type EGFR nonsquamous NSCLC. Methods: We retrospectively analyzed the efficacy of various platinum doublet regimens as first-line treatments. Between 2007 and 2013, a total of 165 patients with wild-type EGFR nonsquamous NSCLC were included in this study. Results: Seventy-one (43.0%) patients were treated with pemetrexed plus platinum (PP) and 94 (57.0%) with non-pemetrexed plus platinum (NPP). The overall response rate was not different between the PP- and NPP-treated groups (26.8 vs. 28.7%, respectively; p = 0.78). The median progression-free survival (PFS) and overall survival (OS) also showed no differences between the two treatment groups (p = 0.12 for PFS, p = 0.42 for OS). The median PFS and OS for the PP group were 4.6 months (95% CI, 3.8-5.4) and 18.7 months (95% CI, 11.7-25.8), respectively, and for the NPP group, they were 4.2 months (95% CI, 3.4-5.0) and 12.2 months (95% CI, 10.3-14.1), respectively. In the subgroup analysis, most subgroups showed no significant difference in PFS and OS between the two treatment groups. Conclusion: Our data showed that the efficacy of various platinum doublet regimens was similar in patients with wild-type EGFR nonsquamous NSCLC.

Prognostic factors for the selection of patients eligible for second-line chemotherapy in advanced biliary tract cancer

Background: The efficacy of second-line chemotherapy (CT2) after the failure of first-line chemotherapy (CT1) for advanced biliary tract cancer (BTC) has not been established. We investigated the favorable prognostic factors for CT2 to determine which patients could be expected to benefit from CT2. Methods: From a total of 168 patients who were treated with chemotherapy at our institution between January 2003 and December 2012, we retrospectively reviewed 50 patients who received CT2. Patients were treated with various chemotherapeutic combinations as CT1 and CT2. Results: The median overall survival (OS) of patients who received and CT2 was 10.2 and 5.5 months, respectively. Good performance status (PS), a serum albumin level >3.5 g/dl and metastasis to only 1 organ were independent prognostic factors that affected the OS of the patients who received CT2. Patients who had only 1 metastastic organ, a good PS and a serum albumin level >3.5 g/dl at the beginning of CT2 demonstrated prolonged survival compared to patients who did not exhibit these 3 factors (9.5 vs. 4.3 months, p < 0.005). Conclusions: CT2 should be considered for patients with advanced BTC, especially for those who have only 1 metastatic organ and remain in generally good medical condition after the failure of CT1.

Overexpression of PD-L2 is associated with shorter relapse-free survival in patients with malignant salivary gland tumors

Objectives PD-1/PD-L1 and CTLA-4 have been investigated and are thought to play an important role in tumor evasion. This study aimed to investigate expression patterns of immune-related molecules, and their clinical impacts in malignant salivary gland tumors. Patients and methods We performed immunohistochemical staining for PD-L1, PD-L2, CTLA-4, PD-1, and CD8+ tumor-infiltrating lymphocytes in 70 malignant salivary gland tumors. Protein expression was assessed by H-score by multiplying the staining intensity by the percentage of cells with positive staining. Results The tumors comprised mucoepidermoid carcinomas (38.6%), adenoid cystic carcinomas (21.4%), salivary duct carcinomas (15.7%), and others. In malignant salivary gland tumors, PD-L2 expression was high, while expression of PD-L1 was relatively low in terms of the percentage of positively stained cells and the staining intensity. In univariate analysis, PD-L2 expression (H-score <1 vs ≥1), PD-1 (H-score <1 vs ≥1), and CD8+ tumor-infiltrating lymphocytes (H-score <1 vs ≥1) were significant prognostic factors. In multivariate analysis, low PD-L2 expression (H-score <1) was independently associated with shorter relapse-free survival (hazard ratio =6.514; 95% confidence interval, 1.2–36.2; P=0.032). Conclusion In summary, PD-L2 is potentially an important biomarker in malignant salivary gland tumors, especially in regard to relapse.

Bladder and Liver Involvement of Visceral Larva Migrans May Mimic Malignancy

Visceral larva migrans (VLM) syndrome is a clinical manifestation of systemic organ involvement by Toxocara species. VLM with involvement of the bladder and liver is a rare finding. A 62-year-old woman presented with diffuse bladder wall thickening and multiple liver masses with peripheral eosinophilia and urinary symptoms. We considered malignancy or eosinophilic cystitis through clinical manifestations and imaging findings. However, no suspicious malignant lesions were observed on cystoscopy and liver mass biopsy revealed the presence of eosinophilic necrotizing granuloma without malignant cells. Anti-Toxocara antibodies were detected by western blotting and the patient was diagnosed with VLM syndrome. After taking prednisolone, urinary symptoms disappeared. On abdominal CT scan taken after three months, the size of multiple liver masses and bladder wall thickening had decreased. VLM syndrome should be suspected in patients with an atypical imaging pattern and peripheral eosinophilia.

Investigating the Feasibility of Targeted Next-Generation Sequencing to Guide the Treatment of Head and Neck Squamous Cell Carcinoma

Purpose Head and neck squamous cell carcinoma (HNSCC) is a deadly disease in which precision medicine needs to be incorporated. We aimed to implement next-generation sequencing (NGS) in determining actionable targets to guide appropriate molecular targeted therapy in HNSCC patients. Materials and Methods Ninety-three tumors and matched blood samples underwent targeted sequencing of 244 genes using the Illumina HiSeq 2500 platform with an average depth of coverage of greater than 1,000×. Clinicopathological data from patients were obtained from 17 centers in Korea, and were analyzed in correlation with NGS data. Results Ninety-two of the 93 tumors were amenable to data analysis. TP53 was the most common mutation, occurring in 47 (51%) patients, followed by CDKN2A (n=23, 25%), CCND1 (n=22, 24%), and PIK3CA (n=19, 21%). The total mutational burden was similar between human papillomavirus (HPV)–negative vs. positive tumors, although TP53, CDKN2A and CCND1 gene alterations occurred more frequently in HPV-negative tumors. HPV-positive tumors were significantly associated with immune signature-related genes compared to HPV-negative tumors. Mutations of NOTCH1 (p=0.027), CDKN2A (p < 0.001), and TP53 (p=0.038) were significantly associated with poorer overall survival. FAT1 mutations were highly enriched in cisplatin responders, and potentially targetable alterations such as PIK3CA E545K and CDKN2A R58X were noted in 14 patients (15%). Conclusion We found several targetable genetic alterations, and our findings suggest that implementation of precision medicine in HNSCC is feasible. The predictive value of each targetable alteration should be assessed in a future umbrella trial using matched molecular targeted agents.

Quantification of circulating cell-free DNA to predict patient survival in non-small-cell lung cancer

We used computed tomography (CT) to explore the prognostic value of cell-free (cf) DNA quantification and its predictive efficacy over time after chemotherapy in non-small-cell lung cancer (NSCLC) patients. In total, 177 NSCLC patients were enrolled in a prospective biomarker trial. Consecutive paired blood collection was performed to determine cfDNA concentrations at baseline CT and throughout serial follow-ups. The best cfDNA cut-off value to predict progression-free and overall survival was determined using X-tile analysis. Among 112 chemo-naive patients with stage IV adenocarcinoma, 43 were available for follow-up analysis. Cox regression multivariate analysis indicated that a high cfDNA concentration was an independent negative prognostic factor for progression-free survival (hazard ratio: 2.60; 95% confidence interval: 1.65-4.10; p = 0.008) and overall survival (hazard ratio: 2.63; 95% confidence interval: 1.66-4.17; p < 0.001). However, cfDNA concentration changes during treatment did not correlate with radiological CT responses at first follow-up or best response. No pattern was noted in the percent change in the cfDNA concentration from baseline or subsequently measured level to progression. The serum cfDNA concentration is thus associated with NSCLC patient prognosis, but does not appear to be a clinically valid marker for tumor responses.

Detection of somatic variants and EGFR mutations in cell-free DNA from non-small cell lung cancer patients by ultra-deep sequencing using the ion ampliseq cancer hotspot panel and droplet digital polymerase chain reaction

Highly sensitive genotyping assays can detect mutations in cell-free DNA (cfDNA) from cancer patients, reflecting the biology of each patient’s cancer. Because circulating tumor DNA comprises a small, variable fraction of DNA circulating in the blood, sensitive parallel multiplexing tests are required to determine mutation profiles. We prospectively examined the clinical utility of ultra-deep sequencing analysis of cfDNA from 126 non-small cell lung cancer (NSCLC) patients using the Ion AmpliSeq Cancer Hotspot Panel v2 (ICP) and validated these findings with droplet digital polymerase chain reaction (ddPCR). ICP results were compared with tumor tissue genotyping (TTG) results and clinical outcomes. A total of 853 variants were detected, with a median of four variants per patient. Overall concordance of ICP and TTG analyses was 90% for EGFR exon 19 deletion and 88% for the L858R mutation. Of 34 patients with a well-defined EGFR activating mutation defined based on the results of ICP and TTG, 31 (81.6%) showed long-term disease control with EGFR TKI treatment. Of 56 patients treated with an EGFR tyrosine kinase inhibitor (TKI), the presence of the de novo T790M mutation was confirmed in 28 (50%). Presence of this de novo mutation did not have a negative effect on EGFR TKI treatment. Ultra-deep sequencing analysis of cfDNA using ICP combined with confirmatory ddPCR was effective at defining driver genetic changes in NSCLC patients. Comprehensive analysis of tumor DNA and cfDNA can increase the specificity of molecular diagnosis, which could translate into tailored treatment.