Der Sheng Sun

A multicenter phase II study of belotecan, a new camptothecin analogue, as a second-line therapy in patients with small cell lung cancer.

Belotecan (Camtobell, CKD602) is a new camptothecin derivative antitumor agent that belongs to the topoisomerase inhibitors. The aim of this phase II study was to evaluate the efficacy and safety of single agent belotecan as a second-line therapy in patients with small cell lung cancer (SCLC). Patients who were previously treated for SCLC were entered into the study. Belotecan was given by daily intravenous infusion for five consecutive days, every three weeks. Twenty-five patients were enrolled in this study. On an intention-to-treat basis, belotecan induced an overall response rate of 24%, a median overall survival of 9.9 months, a median time to progression of 2.2 months, and a 1-year survival rate of 38.3%. Grade 3/4 neutropenia developed in 88.0% of patients and grade 3/4 thrombocytopenia in 40.0%. Nonhematologic toxicity of grade 3 or 4 was low. The results suggest that belotecan is relatively active and well tolerated as a second-line agent in patients with SCLC.

Prognostic Role of the MicroRNA-200 Family in Various Carcinomas: A Systematic Review and Meta-Analysis

Background/Aims. The miRNA-200 (miR-200) family may act as key inhibitors of epithelial-to-mesenchymal transition. However, the potential prognostic value of miR-200s in various human malignancies remains controversial. This meta-analysis analyzed the associations between miR-200 levels and survival outcomes in a variety of tumors. Methods. Eligible published studies were identified by searching the Embase, PubMed, CINAHL, and Google scholar databases. Patient clinical data were pooled, and pooled hazard ratios (HRs) with 95% confidence intervals (95% CI) were used to calculate the strength of this association. Results. The pooled HRs suggested that high tissue expression of miR-200 family members was associated with better survival (overall survival [OS]: HR = 0.70, 95% CI 0.54–0.91; progression-free survival [PFS]: HR = 0.63, 95% CI 0.52–0.76) in thirty-four eligible articles. In contrast, higher expression of circulating miR-200 members was significantly associated with poor clinical outcome (OS, HR = 1.68, 95% CI 1.15–2.46; PFS, HR = 2.62, 95% CI 1.68–4.07). Conclusion. The results from this meta-analysis suggest that miR-200 family members are potential prognostic biomarkers in patients with various carcinomas. To apply these findings in the clinic, large prospective studies are needed to validate the prognostic values of miR-200s in individual cancer types.

Stage-Stratified Analysis of Prognostic Significance of Bax-Interacting Factor-1 Expression in Resected Colorectal Cancer

Background/Aim. Bax-interacting factor-1 (Bif-1) plays a crucial role in apoptosis and autophagy. The aim of this study was to evaluate Bif-1 protein expression and its prognostic significance in colorectal cancer (CRC). Methods. We analyzed Bif-1 protein expression in 251 resected specimens from patients with CRC by immunohistochemistry using tissue microarray. Results. Low Bif-1 expression was observed in 131 patients (52.2%) and high Bif-1 expression in 120 patients (47.8%). No significant differences were observed in clinicopathological parameters between patients with high and low Bif-1 expression. Kaplan-Meier survival analysis showed no difference in survival between patients with high and low Bif-1 expression. Stratified analysis of Bif-1 according to TNM stage demonstrated that low Bif-1 expression was significantly associated with a poor outcome in patients with stages I and II (P = 0.034). Stratified multivariate analysis demonstrated that low Bif-1 expression was an independent indicator of poor prognosis (hazard ratio, 0.459; 95% confidence interval, 0.285–0.739; P = 0.001). Conclusion. Patients with low levels of Bif-1 expression have shortened survival rates in CRC of stages I and II. This suggests that Bif-1 protein expression may be a useful prognostic marker in early-stage CRC.

Triple-negative breast cancer that progressed as estrogen receptor-positive skin metastases

To the Editor, Breast cancer is not a single disease entity but rather a heterogeneous disease with various biological behaviors. Breast cancer subtypes can be identified by gene or protein expression profiling using immunohistochemistry (IHC). The expression patterns of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) as detected by IHC are important factors in determining treatment modalities such as hormone therapy, HER2-targeted therapy, and cytotoxic chemotherapy. In recent years, discordance in ER, PR, and HER2 statuses between primary and recurrent breast cancer has been reported, but the discordance rate varies highly. Generally, a change from positive to negative status for ER and PR is more common than a gain of receptor expression, and more patients gain rather than lose HER2 expression [1,2]. Here, we report the unusual case of a patient who was diagnosed initially with triple-negative breast cancer (TNBC) but whose cancer progressed as ER-positive diffuse skin metastases after a short time. A 38-year-old female visited our hospital with a palpable right breast mass in July of 2011. Breast magnetic resonance imaging (MRI) showed a nodular mass with a diameter of 4.0 cm in the upper outer quadrant of the right breast and multiple enlarged lymph nodes in the right axillary region. A core needle biopsy of the breast mass was performed. Pathological examination revealed a poorly differentiated invasive ductal carcinoma, which was negative for ER, PR, and HER2. F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET)-computed tomography (CT) also showed a nodular mass and multiple lymph nodes with high FDG uptake (maximum standardized uptake value [SUVmax] 4.7) in the right breast and axillary region. There was no evidence of any other distant metastases. On the basis of these results, the patient was diagnosed with TNBC (cT2N3M0) and received three cycles of neoadjuvant chemotherapy with docetaxel and epirubicin. After the three cycles of chemotherapy, a partial response was confirmed by a breast CT scan, and the patient underwent a modified radical mastectomy in November of 2011. Histopathological examination revealed an invasive ductal carcinoma with necrosis and 11 metastatic lymph nodes among the 11 dissected axillary lymph nodes. We found lymphovascular invasion and tumor emboli in dermal lymphatic vessels combined with skin invasion. Immunohistochemical analyses showed negative staining for ER, PR, and HER2. The patient received an additional three cycles of adjuvant chemotherapy with docetaxel and epirubicin, and adjuvant radiotherapy of the right chest wall and regional lymphatics. In September of 2012, a surveillance PET-CT scan showed multiple enlarged lymph nodes with high FDG uptake (SUVmax 6.0) in the left supraclavicular, cervical, and internal mammary lymph nodes, and small nodular lesions with focal FDG uptake (SUVmax 1.9) in the right upper lung and left lower lung fields. A chest CT scan also showed a few tiny peripheral nodules in the right upper lung and left lower lung fields. On physical examination, there were several palpable masses in the left neck. An ultrasound-guided core needle biopsy of the cervical lymph node was performed, and pathological examination revealed an invasive ductal carcinoma. The expression of ER, PR, and HER2 was concordant with the prior right breast cancer, which was negative for ER, PR, and HER2. Subsequently, the patient received six cycles of palliative chemotherapy with docetaxel and cisplatin until January 2013. A follow-up PET-CT scan and chest CT scan showed a near-complete radiological response in the previous multiple metastatic lymph nodes and tiny lung lesions, and there was no evidence of active lesions with abnormal FDG uptake. Therefore, we planned to stop the chemotherapy and to follow up with the patient regularly. Two months later, the patient complained of multiple reddish nodules on her right chest wall, shoulder, and upper arm (Fig. 1A). Breast MRI showed skin enhancement of the right chest wall with an even thickness, and postoperative or postradiation skin changes were suspected (Fig. 1B). A skin biopsy was performed, and the slides were independently reviewed by two pathologists. ER and PR expression was scored using the semiquantitative Allred system, which takes into account the proportion of positive cells (graded from 0 to 5) and the staining intensity (graded from 0 to 3). Pathological examination showed an invasive ductal carcinoma with diffuse lymphatic invasion (Fig. 2A) that was positive for ER (intensity score, 3; proportion score, 3) and negative for PR and HER2 (Fig. 2B). A PET-CT scan showed heterogeneous hypermetabolic activity of the skin throughout the right chest wall and small hypermetabolic nodular lesions in the parasternal area, but there were no other visceral metastases. The patient, who was premenopausal, was administered hormone therapy comprised of a gonadotropin-releasing hormone agonist and tamoxifen (20 mg daily). After three cycles of hormone therapy, follow-up breast MRI showed stable disease for the skin enhancement of the right chest wall. Figure 1 (A) Skin metastases. Ulcerated nodules were noted with erythematous infiltration in the operation bed. (B) Breast magnetic resonance imaging revealed diffuse skin enhancement of the right chest wall with an even thickness. Figure 2 (A) Metastatic carcinoma cells with diffuse lymphatic invasion (asterisks) in the dermis were observed (H&E, ×200). (B) Positive immunohistochemical staining for the estrogen receptor was detected ( ×400). TNBC is defined as a tumor that does not express ER, PR, or HER2; it accounts for 15% to 20% of all breast cancers. TNBC is clearly a distinct clinical subtype but a heterogeneous subgroup with diversity in both tumor biology and prognosis [3]. Over the last decade, the following characteristics of TNBC have been identified: younger patient age, BRCA1-associated cancer, higher incidence of brain metastasis, platinum sensitivity, and poor prognosis [3]. Although the metastatic potential of TNBC is similar to that of other breast cancer subtypes, TNBC is more likely to cause early visceral metastases and is associated with a shorter median time to relapse and death [3]. Our patient experienced relapse with multiple metastases in the cervical lymph nodes and lung within 14 months after diagnosis. She achieved a near-complete radiological response to docetaxel and cisplatin chemotherapy but experienced progression as skin metastases only 2 months after the termination of chemotherapy. Skin metastases from visceral malignancies are uncommon; the reported incidence ranges from 0.7% to 9% [4]. Breast cancer is the most common cancer to metastasize to the skin, followed by lung, melanoma, colon, kidney, and ovarian malignancies. Few studies have investigated the patterns or characteristics of skin metastases in patients with TNBC. Kong et al. [5] evaluated whether the patterns of skin metastases differ according to breast cancer subtype. A retrospective analysis of 125 patients with skin metastases from breast cancer showed that such metastases were more common in hormone receptor-positive breast cancer than in TNBC (42.4% vs. 23.2%, respectively), and that erythematous infiltrations were more frequent in TNBC patients. Our patient presented with ulcerative nodular skin lesions combined with erythematous infiltration in the operation bed, and a change in subtype from TNBC to ER-positive breast cancer was found. Growing evidence of discordance in ER, PR, and HER2 expression between primary and recurrent breast cancer has been reported. The discordance rate varies between studies and can be as high as 40%. The switch to a different tumor phenotype leads to a change in treatment for approximately 20% of cases [1]. According to previous studies, a change from a positive to negative (receptor loss) status is more common than a change from a negative to positive (receptor gain) status. A loss of PR expression is the most frequent change, and changes in ER, PR, and HER2 expression in primary TNBC are relatively rare. Heitz et al. [1] reported that 44 (80.0%) of 55 patients with primary TNBC experienced recurrence of the same triple-negative phenotype, and that only two patients (3.6%) became positive for ER and negative for HER2. The mechanisms responsible for changes in biomarker expression between primary and recurrent breast cancer are not clearly understood, but several possibilities have been proposed, including methodological and technical errors, intratumoral heterogeneity, clonal selection caused by previous treatment, and a switch in tumor biology during progression [1,2]. In our case, we initially confirmed the negativity of the tumor for ER, PR, and HER2 and skin invasion combined with tumor emboli within dermal lymphatic channels in the primary breast cancer obtained from a surgical specimen. Considering that skin metastases occurred in the operation bed and that dermal lymphatic invasion was observed in both primary and recurrent tumor tissues, it is likely that the remaining tumor cells in the lymphatic system had progressed and spread out along the skin. This suggests a change in tumor biology during disease progression or intratumoral heterogeneity in ER expression in the primary breast tumor. Subpopulations of cancer cells in the same patient may exist across different geographical regions of a tumor or evolve over time, which is known as intratumoral heterogeneity. Another lesson from our case is that these biomarkers can change even with a short time to progression. Further study is needed to identify the mechanisms responsible for receptor gain in TNBC, the prognostic impact of a change in tumor phenotype, and the optimal therapeutic strategies.

Factors associated with treatment interruption in elderly patients with cancer

Background/Aims This study was conducted to identify risk factors that predict vulnerability to cancer therapy on the basis of the clinical, geriatric, and quality of life assessment before starting treatment in elderly patients. Methods Seventy-five patients aged 65 years and over with newly diagnosed stage IV solid cancer receiving chemotherapy were analyzed. Clinical and laboratory data were collected. The geriatric assessment was performed using the Korean versions of the Modified Barthel Index, Instrumental Activities of Daily Living, Mini-Mental State Examination, and Geriatric Depression Scale. The European Organisation for Research and Treatment of Cancer Quality-of-Life Core Questionnaire (EORTC-QLQ-C30) was also performed. Results Forty-one patients stopped cancer treatment during or after the end of first-line therapy and were classified as the treatment interruption group. By univariate analysis, treatment interruption was associated with metastases to ≥ 2 distant sites, lower albumin level, lower EORTC-QLQ-C30 physical and role functioning scores, and higher EORTC-QLQ-C30 fatigue and appetite loss symptom scores. By multivariate analysis, treatment interruption was significantly associated with low score for the EORTC-QLQ-C30 physical functioning scale (odds ratio [OR], 1.020; 95% confidence interval [CI], 1.002 to 1.039; p = 0.030), and ≥ 2 sites of distant metastases (OR, 2.965; 95% CI, 1.012 to 8.681; p = 0.047). Conclusions The EORTC-QLQ-C30 physical functioning score and metastases to ≥ 2 organs, which indicate a poor physical functional status and metastatic high tumor burden, were significantly associated with interruption of first-line treatment in elderly patients with cancer.

Circulating Microparticles and Coagulation Profiles in Patients with Advanced Stage Solid Tumors

Dear Editor, Cancer patients with venous thromboembolism (VTE) have poor survival rates [1, 2]. In addition to well-known coagulation biomarkers, microparticles (MPs) in patients with cancer have recently been studied [3]. MPs are typically defined as membrane vesicles 0.1–1.0 μm in diameter, formed by exocytic budding from cells during cell activation or apoptosis. We postulated that the initial levels of hemostatic biomarkers at cancer diagnosis would be useful in predicting and managing the clinical course of cancer in these patients. We analyzed coagulation profiles and circulating MPs in patients at the initial diagnosis of cancer and determined the clinical course and survival of these patients over two years. This study was approved by the Institutional Review Board of the Catholic Medical Center (UC14SISI0100), Korea. Between May and December 2014, we included 67 consecutive patients diagnosed as having solid tumors in this prospective study and received their informed consent. Cancer sites included the stomach (N=13), colorectum (N=13), lung (N=9), head and neck (N=9), biliary tract (N=8), esophagus (N=4), breast (N=4), bladder (N=3), pancreas (N=2), and cervix (N=2). Survival and the occurrence of VTE were monitored at diagnosis and after two years. Coagulation biomarkers were analyzed at the initial cancer diagnosis. MPs were quantified by flow cytometry as previously described [4]. Particles that stained with annexin V (BD Biosciences, San Jose, CA, USA) and CD41 (BD Biosciences) were called platelet-derived microparticles (PMPs), whereas those that stained with annexin V and CD31 (BD Biosciences) were called endothelial cell-derived microparticles (EMPs). MPs in the MP gate (<1 μM, determined using 1-μM beads) were counted [5]. Prothrombin time (PT), activated partial thromboplastin time (aPTT), Clauss fibrinogen, D-dimer, and fibrinogen degradation product (FDP) levels were determined using a CS5100 analyzer (Sysmex Corporation, Kobe, Japan). Protein C and protein S activity were measured using a STA R Max analyzer (Diagnostica Stago, Parsippany, NJ, USA). The program G*Power indicated a requirement of 67 samples for a power of 80% [6]. Student’s independent sample t-, Mann-Whitney U, chi-square, and Fisher’s exact tests were performed as appropriate. Receiver operating characteristic (ROC) curves were analyzed to define cutoffs to differentiate the nonsurvival group. Mean survival time (MST) based on the biomarkers was estimated by Kaplan-Meier analysis. All statistical analyses were performed by using the MedCalc program (MedCalc Software bvba, Mariakerke, Belgium). The survival rate was 52.2% (35/67). Levels of D-dimers, fi-

Definitive radiotherapy for cutaneous epithelioid hemangioendothelioma: a case report and literature review

Epithelioid hemangioendothelioma (EHE) is a rare tumor of the vascular endothelium and the most common involved sites are liver, lung and bone. Approximately one-third are also known to occur in other sites, such as the skin or large vessels. Although a number of treatment modalities have been tried, treatment responses after definitive radiotherapy (RT) have not been well described. Here, we report the case of multiple cutaneous EHE on both feet in an 81-year-old woman successfully treated by definitive RT. She underwent definitive RT of 60 Gy using a volumetric modulated arc therapy and all involved lesions were completely resolved with a small residual discoloration. At 20 months of follow-up after completion of RT, no progressive or recurrent lesions on either foot were observed.

The impact of sarcopenia on health-related quality of life in elderly people: Korean NationalHealth and Nutrition Examination Survey

Background/Aims The purpose of the study is to investigate the associations between sarcopenia and health-related quality of life in elderly men and women in Korea. Methods In a cross-sectional study using data from 2008 to 2011 Korean National Health and Nutrition Examination Survey, 4,937 adults aged 60 years and older who underwent a dual-energy X-ray absorptiometry scan were included in the study. Sarcopenia is defined as an appendicular skeletal muscle index of two standard deviations or more below the mean for young, healthy reference populations. The health-related quality of life was measured using the EuroQol-5 dimension questionnaire. Results The overall prevalence of sarcopenia was 6.6% in these Korean people over the age of 60 years: 11.1% for men and 3.2% for women. Sarcopenic men tended to have lower income, lower physical activity, lower body mass index, and smaller waist circumference compared with nonsarcopenic men. Sarcopenic women tended to have higher body mass index and larger waist circumference compared with nonsarcopenic women. Sarcopenic men showed higher impairments in mobility, self-care, usual activities, and pain/discomfort compared with nonsarcopenic men. Women with sarcopenia also showed higher impairments in mobility, self-care, usual activities, and anxiety/depression compared with nonsarcopenic women. Sarcopenia showed an association with impairments in selfcare for men, and with impairments in self-care, usual activities, and anxiety/depression for women, after adjusting for other confounding factors. Conclusions There is a significant association between sarcopenia and impaired health-related quality of life in this elderly Korean population, and these results differ between men and women.

Gastroenteropancreatic—origin neuroendocrine carcinomas: Three case reports with favorable responses following localized radiotherapy and a review of literature

Rationale: The radiotherapy (RT) responses of gastroenteropancreatic (GEP)-origin neuroendocrine tumors remain unclear. We report cases of favorable response after localized RT of GEP-origin neuroendocrine carcinomas (GEP-NECs). Patient concerns: 1. An 82-year-old male presented with a lower esophageal mass. Positron emission tomography computed tomography (PET-CT) scan showed a lower esophageal mass and gastrohepatic lymph nodes. 2. A 52-year-old female presented with abdominal discomfort. CT scan showed a 9.8 cm-sized enhancing mass in the lesser sac abutting the stomach, pancreas and liver. 3. A 54-year-old male patient presented with anal pain and bleeding. CT scan showed a remnant mass in the perirectal area after trans-anal excision. Diagnoses: The diagnoses of GEP-NECs were pathologically confirmed by biopsy or excision, and immunohistochemical stainings of Ki-67, CD56, synaptophysin and chromogranin-A. Interventions: 1. The patient was treated with definitive RT. 2. The patient was treated with RT after two cycles of etoposide-cisplatin chemotherapy. 3. The patient was treated with adjuvant RT. Outcomes: 1. Complete remission was achieved based on CT scan four months after RT. 2. CT scan showed partial regression of the mass with a 5 cm-diameter at six months after RT. Adjuvant chemotherapy was administered after RT. 3. The residual mass was almost completely regressed at CT scan four months after RT. Lessons: In cases of GEP-NECs, RT can be a useful treatment modality with favorable tumor response for patients with inoperable conditions or those suffering from bulky tumor masses.

Prognostic Value of Metastatic Tumoral Caveolin-1 Expression in Patients with Resected Gastric Cancer

Objective Caveolin-1 (Cav-1), as the main component of caveolae, has complex roles in tumourigenesis in human malignancies. We investigated Cav-1 in primary and metastatic tumor cells of gastric cancer (GC) and its association with clinical outcomes. Methods We retrieved 145 cases of GC who had undergone curative gastrectomy. The expression levels of Cav-1 was evaluated by immunohistochemistry, and its association with clinicopathological parameters and patient survival was analyzed. Results High expression of Cav-1 protein of the GC in the stomach and metastatic lymph node was 12.4% (18/145) and 16.5% (15/91). In the multivariate analysis, tumoral Cav-1 protein in metastatic lymph node showed prognostic significance for relapse-free survival (RFS, HR, 3.934; 95% CI, 1.882–8.224; P = 0.001) and cancer-specific survival outcome (CSS, HR, 2.681; 95% CI, 1.613–8.623; P = 0.002). Among the GCs with metastatic lymph node, it remained as a strong indicator of poor prognosis for RFS (HR, 3.136; 95% CI, 1.444–6.810; P = 0.004) and CSS (HR, 2.509; 95% CI, 1.078–5.837; P = 0.032). Conclusion High expression of tumoral Cav-1 protein in metastatic lymph node is associated with unfavorable prognosis of curative resected GC, indicating the potential of novel prognostic markers.