Gold Nanoparticle-Carrying T Cells for the Combined Immuno-Photothermal Therapy.

Cancer immunotherapy is a promising therapy to treat cancer patients with minimal toxicity, but only a small fraction of patients responded to it as a monotherapy. In this study, a strategy to boost therapeutic efficacy by combining an immunotherapy based on ex vivo expanded tumor-reactive T cells is devised, or adoptive cell therapy (ACT), with photothermal therapy (PTT). Smart gold nanoparticles (sAuNPs), which aggregates to form gold nanoclusters in the cells, are loaded into T cells, and their photothermal effects within T cells are confirmed. When transferred into tumor-bearing mice, large number of sAuNP-carrying T cells successfully infiltrate into tumor tissues and exert anti-tumor activity to suspend tumor growth, but over time tumor cells evade and regrow. Of note, ≈20% of injected doses of sAuNPs are deposited in tumor tissues, suggesting T cells are an efficient nanoparticle tumor delivery vehicle. When T cells no longer control tumor growth, PTT is performed to further eliminate tumors. In this manner, ACT and PTT are temporally coupled, and the combined immuno-photothermal treatment demonstrated significantly greater therapeutic efficacy than the monotherapy.

Clinical characteristics and long-term outcomes of 97 Korean patients with mycosis fungoides.

BACKGROUND: Mycosis fungoides (MF) shows racial and regional differences in terms of clinical features. The availability of therapeutic options as well as drugs differs from one country to another. There are only limited data on the clinical characteristics and treatment experience of MF from South Korea. METHODS: Medical records of 97 patients with MF were retrospectively analyzed to investigate clinical features, survivals, and prognostic factors. Assessment of prognostic variables was done using univariate Cox proportional hazard models. RESULTS: Median age at time of diagnosis was 45 years. The median time from onset of skin lesion to diagnosis of MF was 36 months with a median follow-up period of 96 months. A number of clinical variants of MF were observed. Treatment mainly consisted of narrow-band UVB, systemic retinoids, methotrexate, chemotherapy, and regional radiotherapy. Complete remission was observed in 78% of patients with records on their clinical course. About 12% experienced disease progression. No clinical prognostic factor apart from TNM staging was identified. CONCLUSION: Despite delay in diagnosis, most cases of MF in Korea were diagnosed in early stages. Prognosis of our patients was more favorable than those of other geographic regions as reported in previous studies. Good response to treatment, consisting mainly of phototherapy and radiation therapy, and relatively indolent clinical behavior of disease were observed in this homogeneous cohort of Korean patients with MF.

Malignant potential of small pancreatic neuroendocrine neoplasm and its risk factors: A multicenter nationwide study.

BACKGROUND: Pancreatic neuroendocrine neoplasms (PNENs) show heterogeneous biological behavior, and most small PNENs show indolent features. Consequently, selected cases can be considered for observation only, according to the National Comprehensive Cancer Network guideline, however, supporting clinical evidence is lacking. We investigated the clinical course of small PNENs and their risk factors for malignant potential. METHODS: A total of 158 patients with small pathologically confirmed PNENs ≤2 cm in initial imaging were retrospectively enrolled from 14 institutions. The primary outcome was any metastasis or recurrence event during follow-up. RESULTS: The median age was 57 years (range, 22-82 years), and 86 patients (54%) were female. The median tumor size at initial diagnosis was 13 mm (range, 7-20 mm). PNENs were pathologically confirmed by surgery in 137 patients and by EUS-guided fine needle aspiration biopsy (EUS-FNAB) in 21 patients. Eight patients underwent EUS-FNAB followed by surgical resection. The results of WHO grade were available in 150 patients, and revealed 123 grade 1, 25 grade 2, and 2 neuroendocrine carcinomas. A total of 145 patients (92%) underwent surgical resection, and three patients had regional lymph node metastasis. During the entire follow-up of median 45.6 months, 11 metastases or recurrences (7%) occurred. WHO grade 2 (HR 13.97, 95% CI 2.60-75.03, p = 0.002) was the only predictive factor for malignant potential in multivariable analysis. CONCLUSIONS: WHO grade is responsible for the malignant potential of small PNENs ≤2 cm. Thus, EUS-FNAB could be recommended in order to provide early treatment strategies of small PNENs.

Effect of desalted Salicornia europaea L. ethanol extract (PM-EE) on the subjects complaining memory dysfunction without dementia: a 12 week, randomized, double-blind, placebo-controlled clinical trial.

Desalted Salicornia europaea L. (SE) inhibits acetylcholine esterase, attenuates oxidative stress and inflammatory cytokines, and activates neurotrophic pathway. We performed 12-week, randomized, double-blind, placebo-controlled study to evaluate the efficacy of PhytoMeal(a desalted SE)-ethanol extract (PM-EE), in improving the cognitive performance in patients with subjective memory impairment. 63 participants complaining memory dysfunction without dementia (Korean Mini-Mental State Examination [K-MMSE] score ≥ 23) were assigned to PM-EE 600 mg/day or placebo. The cognitive domain of the Alzheimer's disease assessment scale-Korean version (ADAS-K) was set as the primary outcome. After 12 weeks, there was no differences in the changes in the primary outcome or the frequency of adverse events between the groups. In the subgroup analysis for the 30 subjects with mild cognitive impairment (MCI, baseline K-MMSE scores ≤ 28), PM-EE significantly improved the color-reading score of the Korean color-word stroop test (8.2 ± 25.0 vs. - 4.7 ± 13.2, P = 0.018). Our findings suggest that PM-EE is safe but might not be effective in this setting of this study. However, PM-EE may improve the frontal executive function in the patients with MCI. Further large-sized studies with longer follow-up period is warranted (trial registration number KCT0003418).

Mycosis fungoides development after combined immune checkpoint blockade therapy in a patient with malignant melanoma: a case report.

Immune checkpoint blockade therapy can induce immune-related toxicity, but cutaneous lymphoma development has not been reported. A 56-year-old woman presented with two well-demarcated erythematous macules on the right sole and vitiligo on her extremities. Her facial melanoma had been treated with combination therapy (ipilimumab and pembrolizumab), followed by pembrolizumab monotherapy, a year prior. Microscopy revealed small-to-medium-sized lymphocytes permeating along with the basal epidermal layer. These were immuno-positive for CD2, CD3, and CD5, and showed complete CD7 loss; CD30, TCR-beta F1, and PD-1 were also detected. They exclusively expressed CD8, not CD4, and had a Ki-67 labeling index of 30-40%. Epstein-Barr virus in-situ hybridization was negative. Clonal T-cell receptor beta and gamma chain gene rearrangements were detected. Hence, the lesions were diagnosed as mycosis fungoides. This is the first report of mycosis fungoides development after anti-melanoma immunotherapy. The patient is currently on steroid ointments and phototherapy.

Reversibly pH-responsive gold nanoparticles and their applications for photothermal cancer therapy.

Microenvironment responsive nanomaterials are attractive for therapeutic applications with regional specificity. Here we report pH responsive gold nanoparticles which are designed to aggregate in acidic condition similar to cancer environment and returned to its original disassembled states in a physiological pH. The pH responsive behavior of the particles is derived by change of electrostatic interaction among the particles where attraction and repulsion play a major role in low and high pH of the environment, respectively. Since different electrostatic interaction behavior of the particles in varied pH is induced not by irreversible chemical change but by simple protonation differences, the pH responsive process of assembly and disassembly is totally reversible. The low pH specific aggregation of gold nanoparticles resulted in red shift of plasmonic absorption peak and showed higher photothermal efficacy in acidic pH than in normal physiological pH. The low pH specific photothermal effect with long wave laser irradiation was directly applied to cancer specific photothermal therapy and resulted higher therapeutic effect for melanoma cancer cells than non-pH responsive gold nanoparticles.

A case of recurrent pigmented macules in Laugier-Hunziker syndrome treated using a Q-switched Nd-YAG laser.

Laugier-hunziker syndrome (LHS) is a sporadic and acquired melanotic pigmentation of lips and oral mucosa which is not associated with gastrointestinal hamartomas in contrast to Peutz-Jeghers syndrome. Treatment using Q-switched neodymium: yttrium-aluminum-garnet (QS-ND:YAG) laser, Q-switched alexandrite laser and, cryotherapy have been reported. However, to the best of our knowledge, there is no report regarding long-term follow-up for recurrence. Herein we report the clinical features and the treatment of recurrent pigmented lesions in LHS patients. A patient diagnosed with LHS seven years ago presented with recurrent labial macules. She had undergone QS-ND:YAG laser 7 years ago and the labial macules have been gone several years. A physical examination revealed the macules were mainly on new locations and the spots on the site where the laser was previously done rarely recur. The untreated pigmented macules on gum were maintained in the same shape for seven years. Recurrent lesions of the lips and previously untreated macules on the gums were successfully treated again with the QS-ND:YAG laser as done in 7 years ago. Our case shows a long-term clinical course of laser-treated labial macules in LHS and treatment response of recurred lesions.

Comprehensive Cancer Panel Sequencing Defines Genetic Diversity and Changes in the Mutational Characteristics of Pancreatic Cancer Patients Receiving Neoadjuvant Treatment.

Background/Aims: Pancreatic ductal adenocarcinoma (PDA) is associated with an extremely poor prognosis. This study assessed the genetic diversity among patients with PDA and compared their mutational profiles before and after treatment. Methods: Tumors and matched blood samples were obtained from 22 PDA patients treated with neoadjuvant chemoradiation therapy. The somatic mutations were analyzed with comprehensive cancer gene panel (CCP). In addition, the biopsy samples obtained at diagnosis and the surgically resected samples after treatment were compared for seven patients. The CCP provided formalin-fixed paraffin-embedded sample-compatible multiplexed target selection for 409 genes implicated in cancer. Results: Assessments of the MLH1, MLH3, MSH2, and PMS2 genes showed that the four patients with the highest relative burdens of mutations harbored somatic mutations in at least three of these genes. Genes in the histone-lysine N-methyltransferase 2 (KMT2) family, such as KMT2D, KMT2A, and KMT2C, were frequently mutated in tumor samples. Survival was worse in patients with ARID1A gene mutations than those without ARID1A gene mutations. Mutation patterns were compared between tissue samples before and after neoadjuvant treatment in seven patients who underwent surgical resection. The allelic fraction of mutations in KRAS codon 12 was lower in the surgically resected samples than in the endoscopic ultrasonography-guided fine needle aspiration biopsy samples of six patients. The number of mutant alleles of the histone lysine methyltransferase gene WHSC1 also decreased after treatment. Conclusions: These results indicate that tumor tissue from PDA patients is genetically diverse and suggest that ARID1A mutations may be a potential prognostic marker for PDA.

Does Risk-Adapted Proton Beam Therapy Have a Role as a Complementary or Alternative Therapeutic Option for Hepatocellular Carcinoma?

To evaluate the role of risk-adapted proton beam therapy (PBT) in hepatocellular carcinoma (HCC) patients, a total of 243 HCC patients receiving risk-adapted PBT with three dose-fractionation regimens (regimen A [n = 40], B [n = 60], and C [n = 143]) according to the proximity of their gastrointestinal organs (<1 cm, 1⁻1.9 cm, and ≥2 cm, respectively) were reviewed: The prescribed doses to planning target volume 1 (PTV1) were 50 gray equivalents (GyE) (EQD2 [equivalent dose in 2 Gy fractions], 62.5 GyE10), 60 GyE (EQD2, 80 GyE10), and 66 GyE (EQD2, 91.3 GyE10) in 10 fractions, respectively, and those of PTV2 were 30 GyE (EQD2, 32.5 GyE10) in 10 fractions. In all patients, the five-year local recurrence-free survival (LRFS) and overall survival (OS) rates were 87.5% and 48.1%, respectively, with grade ≥3 toxicity of 0.4%. In regimens A, B, and C, the five-year LRFS and OS rates were 54.6%, 94.7%, and 92.4% (p < 0.001), and 16.7%, 39.2%, and 67.9% (p < 0.001), respectively. The five-year OS rates of the patients with the Modified Union for International Cancer Control (mUICC) stages I, II, III, and IVA and Barcelona Clinic Liver Cancer (BCLC) stages A, B, and C were 69.2%, 65.4%, 43.8%, and 26.6% (p < 0.001), respectively, and 65.1%, 40%, and 32.2% (p < 0.001), respectively. PBT could achieve promising long-term tumor control and have a potential role as a complementary or alternative therapeutic option across all stages of HCC.

Case report of cutaneous nodule caused by Gordonia bronchialis in an immunocompetent patient after receiving acupuncture.

Gordonia species were recently found to cause human infection. Most Gordonia bronchialis infections are associated with sternal wounds and foreign bodies. Here, we present a case of a firm cutaneous nodule caused by G. bronchialis on an immunocompetent patient's lower extremity after receiving acupuncture. Our present case indicates that spontaneous cutaneous infection of G. bronchialis can develop even in a healthy patient. With the popularity of complementary and alternative medicine, physicians should be aware that G. bronchialis infection can be associated with Oriental medicine similar to mycobacterial infection. Recognizing the diverse clinical features of newly emerging Gordonia species will facilitate appropriate diagnosis and management of future patients.

Effect of Early Management on Pain and Depression in Patients with Pancreatobiliary Cancer: A Randomized Clinical Trial.

Background: The present study assessed whether early palliative care (EPC) targeting pain and depression and automated symptom monitoring could improve symptoms in patients with advanced pancreatobiliary cancer. Methods: Patients diagnosed with pathologically confirmed locally advanced or metastatic pancreatic or biliary tract cancer who had cancer-related pain (brief pain inventory (BPI) worst pain score >3) and/or depression (Center for Epidemiological Studies-Depression Scale (CES-D) >16) were randomized within 8 weeks after diagnosis to receive EPC or on-demand palliative care (n = 144 each). EPC included (1) nursing assessment of pain and depression, (2) pain control based on National Comprehensive Cancer Network guidelines, (3) depression control by psychoeducation and/or consultation with a psychiatric specialist, and (4) patient education. The primary end points were ≥50% reductions from baseline to week 4 in pain and depression scores. Results: The proportion of patients in the EPC and usual care groups with ≥50% reductions in pain (29.5% vs. 25.2%; p = 0.4194) and depression (30.8% vs. 36.8%; p = 0.5732) scores from baseline to week 4 did not differ significantly. The proportion of patients with BPI worst pain score ≤3 was significantly higher (51.1% vs. 38.9%, p = 0.0404) and the reduction in pain intensity score significantly greater (1.5 vs. 1.0 points, p = 0.0318) in the EPC than in the usual care group. At 4 weeks, patients in the EPC group reported significant increases in global health status, role of functioning, nausea and vomiting, and pain scores on the European Organization for Research and Treatment of Cancer Core Quality of Life questionnaire (EORTC QLQ-C30) general questionnaire. Conclusions: Although the primary outcome was not met, this trial indicates that EPC may improve early pain relief in patients with advanced pancreatobiliary cancers.

A Systematic Review on Sasang Constitutional Type-Associated Susceptibility to Disorders in Korea.

BACKGROUND/OBJECTIVE: Sasang constitutional medicine is a component of traditional Korean medicine that classifies individuals into four Sasang constitutional types (SCTs) by their physical and psychological traits. Each SCT is known to show different susceptibilities to disorders. This systematic review investigated the effect of SCT as a risk factor for various disorders. METHODS: A systematic literature survey was conducted by searching seven databases for all articles on the prevalence rates of disorders according to SCT and sex. RESULTS: From 14,272 relevant articles, 15 studies (13 disorders) were ultimately identified to verify different prevalence rates by SCT. Of the 13 disorders, 6 (prehypertension, general obesity, abdominal obesity, metabolic syndrome, diabetes mellitus, and irritable bowel syndrome [IBS]) had a significantly different prevalence by SCT. Metabolic syndrome and its associated disorders showed the highest prevalence in Taeumin-type individuals, whereas IBS was most prevalent in Soeumin-type individuals. In general, these findings were consistent with the results obtained in an analysis of male and female participants. CONCLUSIONS: This study revealed that susceptibility to disorders was affected by SCT to some extent. Further studies are needed to determine the concrete features of SCT-related susceptibility, which may be helpful in preventive medicine with Sasang constitutional practice.

Systematic review on herb-induced liver injury in Korea.

Herbal drugs are generally regarded as safe due to their extensive clinical use especially in East Asian countries. However, the potential toxicity of herbal drugs has become an important medical issue recently, resulting in numerous reports of drug-induced liver injury (DILI). Here, we performed a systematic review of herbal medicines with the potential to cause hepatotoxicity in Korea. A literature search of six databases, including PubMed and five Korean electronic databases, was performed to identify cases of herb-induced liver injury (HILI) in Korea, yielding 31 unique reports, including 21 single herb and 10 multi-herb preparations. From these reports, we identified 97 cases of HILI (47 males, 49 females, and 1 unknown sex) consisting of 74.7% hepatocellular-type injury, 10.8% cholestatic-type injury, and 14.5% mixed-type injury. Causative agents included 21 unique herbal preparations, including 11 single species and 10 multispecies, with Polygoni Multiflori (39.2%) and Dictamnus dasycarpus (37.1%) as the most frequent agents. These analyses presented a feature of HILI, and produced a comprehensive list of herbs with a higher risk of hepatotoxicity in Korea. Further studies will be necessary to ascertain the mechanisms by which these herbs induce HILI and to determine whether these effects are specific to the Korean population.

Complete mitochondrial genome of the jellyfish, Chrysaora quinquecirrha (Cnidaria, Scyphozoa).

We sequenced 16,775 bp of the linear mitochondrial DNA of the jellyfish Chrysaora quinquecirrha and characterized them. C. quinquecirrha has 13 protein-coding genes (PCGs), 16S rRNA and 12S rRNA with 3 tRNAs (tRNA-Leu, tRNA-Ser(TGA), tRNA-Met) as shown in Aurelia sp. nov. Both have another two PCGs such as helicase and orf363 with telomeres at both ends. The PCGs of C. quinquecirrha shows anti-G bias on 2nd and 3rd positions of PCGs as well as anti-C bias on 1st and 3rd positions of PCGs.

Worse outcome of sorafenib therapy associated with ascites and Child-Pugh score in advanced hepatocellular carcinoma.

BACKGROUND AND AIM: The outcomes of sorafenib therapy in patients with advanced hepatocellular carcinoma (HCC) and impaired liver function remain unresolved. Although Child-Pugh (CP) classification is widely used for patient categorization, heterogeneity within a given CP class makes outcomes less predictable. The aim was to investigate the prognostic significance of CP score elements on the outcome of sorafenib in patients with advanced HCC and impaired liver function. METHODS: Of 1385 consecutive patients with advanced HCC in our center between January 2007 and December 2010, we reviewed the medical records of 325 patients who received sorafenib monotherapy. RESULTS: Median duration of sorafenib was 2.0 months (range 0.4-24.2) and median follow-up was 4.9 months (range 0.5-43.4). Disease control rates were significantly higher in CP class A (CPA) than in CP class B (CPB) patients. Median overall survival (OS) was 5.8 months. Subgroups with different CP scores showed significantly different OS (months): CPA5, 8.4; CPA6, 5.1; CPB7, 3.5; CPB8-9, 2.6 (P < 0.001). The presence of ascites was a significant prognostic factor in CPB7 patients (hazard ratio 2.262; P = 0.016). OS of CPB7 patients without ascites was similar to that of CPA6 patients (4.6 months) and was significantly longer than that of CPB7 patients with ascites (2.5 months; P = 0.027). OS of CPB7 patients with ascites was similar to that of CPB8-9 patients. CONCLUSIONS: CP score was more important than CP class in predicting the outcome of sorafenib therapy in patients with advanced HCC. Among the CP score components, presence of ascites was a significant prognostic factor, especially in CPB7 patients.

Formation of new melasma lesions in the periorbital area following high-fluence, 1064-nm, Q-switched Nd/YAG laser.

Although ultraviolet (UV) light or exogenous hormones have been associated with the development or exacerbation of melasma, the use of laser as a treatment modality has not been cited as a factor linked to the development of melasma lesions. It is unclear whether epidermal trauma caused by laser or other treatment can lead to the formation of a new melasma lesion. We report on the formation of new melasma lesions in a patient who was treated for acquired bilateral nevus of Ota-like macules (ABNOM) with a high-fluence 1064 nm Q-switched (QS) neodymium-doped yttrium aluminum garnet (Nd/YAG) laser.

CA 19-9 level as indicator of early distant metastasis and therapeutic selection in resected pancreatic cancer.

PURPOSE: In patients with pancreatic cancer treated with curative resection, we evaluated the effect of clinicopathologic parameters on early distant metastasis within 6 months (DM6m) to identify patients who might benefit from surgery. METHODS AND MATERIALS: The study involved 84 patients with pancreatic cancer who had undergone curative resection between August 2001 and April 2009. The parameters of gender, age, tumor size, histologic differentiation, T classification, N classification, pre- and postoperative carbohydrate antigen (CA) 19-9 level, resection margin, and adjuvant chemoradiotherapy were analyzed to identify the risk factors associated with DM6m. RESULTS: Of the 84 patients, locoregional recurrence developed in 35 (41.7%) and distant metastasis in 58 (69%). Of the 58 patients with distant metastasis, DM6m had developed in 27 (46.6%). Multivariate analysis showed that preoperative CA 19-9 level was significantly associated with DM6m (p<.05). Of all 84 patients, DM6m was observed in 9.1%, 50%, and 80% of those with a preoperative CA 19-9 level of ≤100 U/mL, 101-400 U/mL, and >400 U/mL, respectively (p<.001). CONCLUSIONS: The preoperative CA 19-9 level might be a useful predictor of DM6m and to identify those who would benefit from surgical resection.

Synthesis and biological properties of benzo-annulated rutaecarpines.

A series of benzo-annulated rutaecarpines were prepared from anthranilic acid and 3-aminonaphthalene-2-carboxylic acid by Fischer indole synthesis as key reaction. Cytotoxicity was somewhat increased by the introduction of benzo-annulation, which was not directly related to the inhibitory activity against topoisomerases (topo) I and II. Benzo-annulation on ring A led to significant increase of inhibitory activity against topo II while annulations on ring E increased inhibitory activity against topo I.

Adjuvant chemoradiation therapy in gallbladder cancer.

BACKGROUND AND OBJECTIVES: Gallbladder cancer is a relatively uncommon gastrointestinal malignancy. Indications for adjuvant chemoradiation therapy after surgical resection have not yet been determined. We aimed this study to elucidate the effectiveness of adjuvant chemoradiation therapy according to TNM stage for gallbladder cancer. METHODS: Between March 2001 and March 2009, 100 patients with gallbladder cancer underwent surgical resection. We divided the patients according to TNM stage, and subdivided further according to whether adjuvant chemoradiation therapy was added or not. The clinicopathologic factors, recurrence and survival were retrospectively analyzed. RESULTS: Patients with gallbladder cancer at T2N0M0, T2N1M0, T3N0M0, and T3N1M0 stages were enrolled in this study. Among the four stages, the two lymph node-negative stages (T2N0M0 and T3N0M0) did not show any gain in survival by adding adjuvant chemoradiation therapy. Conversely, the remaining lymph node-positive stages (T2N1M0 and T3N1M0) showed gain in disease-free survival, and the lymph node-positive T2 stage (T2N1M0) showed gain in disease-specific survival. In patients with lymph node-positive T2/T3 GB cancers, adjuvant chemoradiation therapy was an independent prognostic factor for survival. CONCLUSIONS: Adjuvant chemoradiation therapy is recommended for lymph node-positive T2/T3 gallbladder cancer following surgical resection.