Factors Considered Important by Healthcare Professionals for the Management of Using Complementary Therapy in Diabetes: A Text-Mining Analysis.

Text-mining algorithms can identify the most prevalent factors of risk-benefit assessment on the use of complementary and integrative health approaches that are found in healthcare professionals' written notes. The aims of this study were to discover the key factors of decision-making on patients' complementary and integrative health use by healthcare professionals and to build a consensus-derived decision algorithm on the benefit-risk assessment of complementary and integrative health use in diabetes. The retrospective study of an archival dataset used a text-mining method designed to extract and analyze unstructured textual data from healthcare professionals' responses. The techniques of classification, clustering, and extraction were performed with 1398 unstructured clinical notes made by healthcare professionals between 2019 and 2020. The most important factor for decision-making by healthcare professionals about complementary and integrative health use in patients with diabetes was the ingredients of the product. Other important factors were the patient's diabetes control, the undesirable effects from complementary and integrative health, evidence-based complementary and integrative health, medical laboratory data, and the product's affordability. This exploratory text-mining study provides insight into how healthcare professionals decide complementary and integrative health use for patients with diabetes after a risk-benefit assessment from clinical narrative notes.

Risk factors of first and recurrent genitourinary tract infection in patients with type 2 diabetes treated with SGLT2 inhibitors: A retrospective cohort study.

AIMS: This retrospective study investigated the risk factors of sodium-glucose cotransporter 2 inhibitors (SGLT2i) -related genitourinary tract infection (GUTI). METHODS: We used longitudinal claims data from May 2016 to December 2017 from the Chang Gung Research Database. Diabetic patients who used SGLT2i were included. The baseline characteristics risk factors between patients who had GUTI and no GUTI were analyzed. RESULTS: There were 428(3.43%) patients with the first occurrence of urinary tract infection (UTI) and 5(0.04%) patients with genital tract infection (GTI). Female patients aged ≥ 65 years with HbA1c ≥ 9%, eGFR < 60 ml/min/1.73 m2, urine albumin/creatinine ratio (UACR) level ≥30 mg/g, dyslipidemia, diabetic microvascular complications and mood disorder had a higher risk of having the first occurrence of UTI. There was no significant risk factor of GTI. 117 UTI and 3 GTI patients received SGLT2i rechallenging. The recurrent UTI rate was 28.2% and no recurrent GTI was diagnosed. The risk factors included CHD, eGRF < 45 ml/min/1.73 m2, and mood disorder (OR, 95% CI: 4.39, 1.15-16.74; 4.11, 1.51-11.19; 5.93, 1.39-25.34, respectively). CONCLUSIONS: In diabetic patients who had underlying disease of eGRF < 45 ml/min/1.73 m2, CHD, and mood disorder had higher risk of recurrent UTI after rechallenging SGLT2i.

A comprehensive investigation of nutritional status and psoas muscle mass in predicting five-year survival in patients with liver transplant.

BACKGROUND/PURPOSE: Although nutrition and sarcopenia have impacts on the surgery outcome of patients who have received living donor liver transplant (LDLT), the use of the prognostic nutritional index (PNI) or psoas muscle mass index (PMI) as an indicator for five-year survival in those patients is still unclear. METHODS: A total of 138 patients receiving LDLT were followed at a medical center in Taiwan. As well as analysis of clinical factors using Cox regression, time-varying PNI and PMI values as before surgery (0) and at 3-, 6-, and 12- months after LDLT were analyzed by time-dependent Cox analysis. For those 124 patients who survived after 3 months of LDLT, the values of PNI-3m, PMI-3m and their combination were further analyzed. RESULTS: PNI and PMI were noted to be highly associated with mortality at three months post-LDLT (PNI-3m hazard ratio [HR] = 0.89, 95% confidence interval [CI]: 0.85-0.94, p < 0.001; PMI-3m HR = 0.58, 95% CI: 0.41-0.82, p = 0.002). Per the Youden index, the cut-off point of PNI-3m was 42.35, and that of PMI-3m was 1.94. Compared to the subjects with higher levels of PNI-3m and PMI-3m (N-high/M-high), the HRs for subjects with N-high/M-low, N-low/M-high, and N-low/M-low were 5.27 (p = 0.004), 4.46 (p = 0.010) and 12.97 (p < 0.001) respectively. CONCLUSION: PNI and PMI at the third month post-LDLT serve as excellent predictors for 5-year survival. For patients with lower levels of PNI-3m or PMI-3m, combination use of these indexes is suggested to provide better prognostic information.

Ankle-Brachial Index Is Independently Associated With Cardiovascular Outcomes and Foot Ulcers in Asian Patients With Type 2 Diabetes Mellitus.

Background and Aims: The ankle-brachial index (ABI) is an efficient tool for objectively documenting the presence of lower-extremity peripheral arterial disease (PAD). The predictive factors of cardiovascular events and diabetic foot ulcer were not clear from the ABI examination in Taiwanese patients with type 2 diabetes mellitus (DM). Methods: We enrolled 482 patients with type 2 DM who regularly visited the outpatient department of Chang Gung Memorial Hospital and received ABI as well as brachial-ankle pulse wave velocity (ba-PWV) examinations from 2010 to 2017. Age, gender, PAD symptoms, comorbidities, family history of chronic diseases, lifestyle (smoking, alcohol consumption, and exercise), height, weight, waist circumference, monofilament testing and foot ulcer status were studied. Results: There were 104 (22%) patients (mean age, 67.8 years) with the ABI <1.0. These patients with low ABI (ABI<1.0) had a significantly older age (p=0.001), higher delta PWV (p<0.001), higher rates of stroke (p=0.007), myocardial infarction (p=0.016), and foot ulcer (p=0.039). In a multivariable analysis model, the adjusted odds ratio (aOR) for myocardial infarction, stroke, and foot ulcers associated with low ABI were 1.219 (0.397-3.743, p=0.729), 1.204 (0.556-2.610, p=0.638), and 2.712 (1.199-6.133, p=0.017), respectively. The patients with low PWV (PWV<1400 cm/s) were significantly younger (p<0.001) and had a lower rate of hypertension (p<0.001), and higher percentages of stroke (p=0.027) and dialysis (p=0.041) family history. Conclusions: Low ABI was associated with cardiovascular events and diabetic foot ulcer independently in patients with type 2 DM.

Effect of a Novel Macrophage-Regulating Drug on Wound Healing in Patients With Diabetic Foot Ulcers: A Randomized Clinical Trial.

Importance: Delayed healing of diabetic foot ulcers (DFUs) is known to be caused by dysregulated M1/M2-type macrophages, and restoring the balance between these macrophage types plays a critical role in healing. However, drugs used to regulate M1/M2 macrophages have not yet been studied in large randomized clinical trials. Objective: To compare the topical application of ON101 cream with use of an absorbent dressing (Hydrofiber; ConvaTec Ltd) when treating DFUs. Design, Setting, and Participants: This multicenter, evaluator-blinded, phase 3 randomized clinical trial was performed in 21 clinical and medical centers across the US, China, and Taiwan from November 23, 2012, to May 11, 2020. Eligible patients with debrided DFUs of 1 to 25 cm2 present for at least 4 weeks and with Wagner grade 1 or 2 were randomized 1:1 to receive ON101 or control absorbent dressings. Interventions: Twice-daily applications of ON101 or a absorbent dressing changed once daily or 2 to 3 times a week for 16 weeks, with a 12-week follow-up. Main Outcomes and Measures: The primary outcome was the incidence of complete healing, defined as complete re-epithelialization at 2 consecutive visits during the treatment period assessed on the full-analysis set (FAS) of all participants with postrandomization data collected. Safety outcomes included assessment of the incidences of adverse events, clinical laboratory values, and vital signs. Results: In the FAS, 236 eligible patients (175 men [74.2%]; mean [SD] age, 57.0 [10.9] years; mean [SD] glycated hemoglobin level, 8.1% [1.6%]) with DFUs classified as Wagner grade 1 or 2 (mean [SD] ulcer area, 4.8 [4.4] cm2) were randomized to receive either the ON101 cream (n = 122) or the absorbent dressing (n = 114) for as long as 16 weeks. The incidence of complete healing in the FAS included 74 patients (60.7%) in the ON101 group and 40 (35.1%) in the comparator group during the 16-week treatment period (difference, 25.6 percentage points; odds ratio, 2.84; 95% CI, 1.66-4.84; P < .001). A total of 7 (5.7%) treatment-emergent adverse events occurred in the ON101 group vs 5 (4.4%) in the comparator group. No treatment-related serious adverse events occurred in the ON101 group vs 1 (0.9%) in the comparator group. Conclusions and Relevance: In this multicenter randomized clinical trial, ON101 exhibited better healing efficacy than absorbent dressing alone in the treatment of DFUs and showed consistent efficacy among all patients, including those with DFU-related risk factors (glycated hemoglobin level, ≥9%; ulcer area, >5 cm2; and DFU duration, ≥6 months). Trial Registration: ClinicalTrials.gov Identifier: NCT01898923.

The Effects of Bariatric Surgery on Renal, Neurological, and Ophthalmic Complications in Patients with Type 2 Diabetes: the Taiwan Diabesity Study.

BACKGROUND: Bariatric surgery has been shown to improve glycemic control in patients with type 2 diabetes. However, less is known whether it can also reduce diabetic renal, neurological, and ophthalmic complications. METHODS: This prospective multicenter cohort study compared renal, ophthalmic, and neurological complications between 49 patients with obesity/overweight receiving bariatric surgery and 338 patients receiving standard medical treatment after follow-up for 2 years. Patients received neurological examinations including toe tuning fork vibration test, ankle tendon reflex test, 10-g monofilament test, and ophthalmic examinations including visual acuity measurement and fundus examinations. Multiple regressions, propensity score weighting, and matching were employed to adjust for baseline differences. RESULTS: After 2 years of follow-up, patients with type 2 diabetes receiving bariatric surgery had greater reduction in BMI, HbA1c, and urine albumin-creatinine ratio, greater improvement in estimated glomerular filtration rate, and greater increase in tuning fork test score of right and left toes compared with the medical group. However, there is no improvement in 10 g-monofilament test, visual acuity, diabetic non-proliferative retinopathy, and proliferative retinopathy. Similar results were obtained using multiple regression adjustment, propensity-score weighting, or comparing age-, sex-, and BMI-matched subjects. CONCLUSIONS: After 2-year follow-up, patients with obesity/overweight and type 2 diabetes receiving bariatric surgery have increased glomerular filtration rate, reduced albuminuria, and improved tuning folk vibration sensation.

Study design and recruitment for a prospective controlled study of diabesity: Taiwan Diabesity Study.

BACKGROUND: Strong evidence has shown that metabolic surgery is more effective than medical treatment in the treatment of type 2 diabetic patients. However, no study demonstrated a survival benefit and reduction of diabetes-related end-organ damage. Here, we describe the study design of a large prospective cohort study, the Taiwan Diabesity Study (TDS) which would compare the long-term survival rate and end-organ damage between overweight/obese type 2 diabetic patients receiving metabolic surgery and medical treatment. METHODS: Eligibility criteria include type 2 diabetic patients with duration > 6 months, body mass index (BMI) over 25 kg/m2 and age between 20 and 67 years. Exclusion criteria are serum creatinine over 2.0 mg/dL, C-peptide below 1.0 ng/ml, recent history of cancer, and major diabetic complications. Eligible participants were recruited from six medical centers in Taiwan. The survival rate and diabetes-related end organ damage will be compared between the metabolic surgery group and medical group after follow-up for 10 years. RESULTS: In 3 years, 1016 participants were identified from 38,751 patients. The average BMI of patients was 30.6 (±2.6) kg/m2 and the average hemoglobin A1c was 8.2% (±1.5%) with 18% of them receiving insulin treatment. Among them, 126 patients received metabolic surgery and 890 patients received conventional medical treatment. The metabolic surgery group are younger, have a higher proportion of females, higher BMI and blood lipids as compared to the medical group. CONCLUSION: The TDS recruited 1016 overweight/obese type 2 diabetic patients including 126 patients receiving metabolic surgery and 890 patients receiving medical treatment.

Survival and associated risk factors in patients with diabetes and amputations caused by infectious foot gangrene.

BACKGROUND: Infectious gangrene of the foot is a serious complication of diabetes that usually leads to a certain level of lower-extremity amputation (LEA). Nevertheless, the long-term survival and factors associated with mortality in such patients have yet to be elucidated. METHODS: A total of 157 patients with type 2 diabetes who received treatment for infectious foot gangrene at a major diabetic foot center in Taiwan from 2002 to 2009 were enrolled, of whom 90 had major LEAs (above the ankle) and 67 had minor LEAs (below the ankle). Clinical data during treatment were used for the analysis of survival and LEA, and survival was tracked after treatment until December 2012. RESULTS: Of the 157 patients, 109 died, with a median survival time of 3.12 years and 5-year survival rate of 40%. Age [hazard ratio 1.04 (95% confidence interval 1.01-1.06)], and major LEA [1.80 (1.05-3.09)] were independent factors associated with mortality. Patients with minor LEAs had a better median survival than those with major LEAs (5.5 and 1.9 years, respectively, P < 0.01). An abnormal ankle-brachial index was an independent risk factor [odds ratio 3.12 (95% CI 1.18-8.24)] for a poor outcome (major LEA) after adjusting for age, smoking status, hypertension, major adverse cardiac events, and renal function. CONCLUSIONS: Efforts to limit amputations below the ankle resulted in better survival of patients with infectious foot gangrene. An abnormal ankle-brachial index may guide physicians to make appropriate decisions with regards to the amputation level.

Glucose Variability and ß- Cell Response by GLP-1 Analogue added-on CSII for Patients with Poorly Controlled Type 2 Diabetes.

The effects of twice-daily GLP-1 analogue injections added on continuous subcutaneous insulin infusion (CSII) in patients with poorly controlled type 2 diabetes (T2DM) were unknown. After optimization of blood glucose in the first 3 days by CSII during hospitalization, patients with poorly controlled T2DM were randomized to receive CSII combined with injections of exenatide or placebo for another 3 days. A total of 51 patients (30 in exenatide and 21 in placebo groups) with mean A1C 11% were studied. There was no difference in mean glucose but a significant higher standard deviation of plasma glucose (SDPG) was found in the exenatide group (50.51 ± 2.43 vs. 41.49 ± 3.00 mg/dl, p = 0.027). The improvement of incremental area under the curve (AUC) of glucose and insulinogenic index (Insulin 0-peak/ Glucose 0-peak) in 75 g oral glucose tolerance test was prominent in the exenatide group (p < 0.01). The adiponectin level was significantly increased with exenatide added on (0.39 ± 0.32 vs. -1.62 ± 0.97 µg/mL, in exenatide and placebo groups, respectively, p = 0.045). In conclusion, the add-on of GLP-1 analogue to CSII increased glucose variability and the ß - cell response in patients with poorly controlled T2DM.

Risk factors for in-hospital mortality in patients with type 2 diabetes complicated by community-acquired Klebsiella pneumoniae bacteremia.

BACKGROUND/PURPOSE: Patients with diabetes are at a high risk of infection-related morbidity and mortality. Klebsiella pneumoniae bacilli are prevalent among diabetic patients, especially in Asian populations. The present study aimed to identify risk factors for in-hospital mortality among diabetic patients complicated by community-acquired K. pneumoniae bacteremia. METHODS: We evaluated the clinical characteristics of 341 Taiwanese type 2 diabetic patients who were treated for community-acquired K. pneumoniae bacteremia. We then analyzed outcome predictors, and in particular comorbidities and the site of infection. RESULTS: The overall in-hospital mortality rate was 14.1%. Comorbid cancer was the leading factor, accounting for 32.1% of all cases of mortality. Pulmonary infection, primary bacteremia, afebrile or shock presentation and low serum albumin level were risk factors for in-hospital mortality. Regardless of comorbidities, pulmonary infection [odds ratio (OR) 10.74, 95% confidence interval (CI) 2.02-57.09] and albumin level (OR 0.15, 95% CI 0.03-0.76) were the main risk predictors. The receiver operating characteristic curve indicated that a serum albumin level lower than 2.4 g/dL (71.1% sensitivity and 77.4% specificity) suggested a poor prognosis in the diabetic patients with K. pneumoniae bacteremia. In patients with pulmonary infection, the capsular serotypes of K. pneumoniae were not related to poor outcomes, and an initial presentation of blunted fever or shock were independent factors for mortality. CONCLUSION: Cancer, pulmonary infection, and low serum albumin levels were independent indicators of in-hospital mortality in the diabetic patients complicated by K. pneumoniae bacteremia. The sites of infection and host characteristics should always elicit medical attention when treating these patients.

Utility of a histone deacetylase inhibitor (PXD101) for thyroid cancer treatment.

BACKGROUND: We evaluated the therapeutic effects of the histone deacetylase inhibitor PXD101 alone and in combination with conventional chemotherapy in treating thyroid cancer. METHODOLOGY/PRINCIPAL FINDINGS: We studied eight cell lines from four types of thyroid cancer (papillary, follicular, anaplastic and medullary). The cytotoxicity of PXD101 alone and in combination with three conventional chemotherapeutic agents (doxorubicin, paclitaxel and docetaxel) was measured using LDH assay. Western blot assessed expression of acetylation of histone H3, histone H4 and tubulin, proteins associated with apoptosis, RAS/RAF/ERK and PI3K/AKT/mTOR signaling pathways, DNA damage and repair. Apoptosis and intracellular reactive oxygen species (ROS) were measured by flow cytometry. Mice bearing flank anaplastic thyroid cancers (ATC) were daily treated with intraperitoneal injection of PXD101 for 5 days per week. PXD101 effectively inhibited thyroid cancer cell proliferation in a dose-dependent manner. PXD101 induced ROS accumulation and inhibited RAS/RAF/ERK and PI3K/mTOR pathways in sensitive cells. Double-stranded DNA damage and apoptosis were induced by PXD101 in both sensitive and resistant cell lines. PXD101 retarded growth of 8505C ATC xenograft tumors with promising safety. Combination therapy of PXD101with doxorubicin and paclitaxel demonstrated synergistic effects against four ATC lines in vitro. CONCLUSIONS: PXD101 represses thyroid cancer proliferation and has synergistic effects in combination with doxorubicin and paclitaxel in treating ATC. These findings support clinical trials using PXD101 for patients with this dismal disease.

Utility of a PI3K/mTOR inhibitor (NVP-BEZ235) for thyroid cancer therapy.

BACKGROUND: We assessed the utility of the dual PI3K/mTOR inhibitor NVP-BEZ235 (BEZ235) as single agent therapy and in combination with conventional chemotherapy for thyroid cancer. METHODOLOGY/PRINCIPAL FINDINGS: Eight cell lines from four types of thyroid cancer (papillary, follicular, anaplastic, medullary) were studied. The cytotoxicity of BEZ235 and five conventional chemotherapeutic agents alone and in combination was measured using LDH assay. Quantitative western blot assessed expression of proteins associated with cell cycle, apoptosis and signaling pathways. Cell cycle distribution and apoptosis were measured by flow cytometry. Murine flank anaplastic thyroid cancers (ATC) were treated with oral BEZ235 daily. We found that BEZ235 effectively inhibited cell proliferation of all cancer lines, with ATC exhibiting the greatest sensitivity. BEZ235 consistently inactivated signaling downstream of mTORC1. BEZ235 generally induced cell cycle arrest at G0/G1 phase, and also caused apoptosis in the most sensitive cell lines. Baseline levels of p-S6 ribosomal protein (Ser235/236) and p27 correlated with BEZ235 sensitivity. Growth of 8505C ATC xenograft tumors was inhibited with BEZ235, without any observed toxicity. Combination therapy of BEZ235 and paclitaxel consistently demonstrated synergistic effects against ATC in vitro. CONCLUSIONS: BEZ235 as a single therapeutic agent inhibits thyroid cancer proliferation and has synergistic effects in combination with paclitaxel in treating ATC. These findings encourage future clinical trials using BEZ235 for patients with this fatal disease.

Down-regulation of matrix metalloproteinase-7 inhibits metastasis of human anaplastic thyroid cancer cell line.

Epigenetic drugs such as histone deacetylase inhibitors (HDACIs) possess anticancer properties due to its ability to regulate genes associated with tumor growth, differentiation, apoptosis and metastasis. In addition to its apoptotic effect, phenylbutyrate (PB), a carboxylic acid HDACI, inhibited an anaplastic (ATC) thyroid cancer cell line ARO from penetrating a matrigel coated transwell with concomitant suppression of a metastasis-associated gene, matrix metalloproteinase-7 (MMP-7) and stimulation of a transformation suppressor protein, reversion-inducing- cysteine-rich protein with Kazal motifs without affecting MMP-2 expression levels. Direct evidence suggesting MMP-7 down-regulated cancer metastasis came from the observation of a decreased pulmonary metastasis in SCID mice xeno-transplanted with MMP-7-knocked-down ARO cells. In addition, H-89, a protein kinase A inhibitor, remarkably restored the down-regulaed MMP-7 level treated by PB. Thus, the suppressive effect of PB on MMP-7 was partially carried out through H3 phosphoacetylation. To conclude, our findings suggest PB inhibits MMP-7 expression epigenetically through phosphoacetylation of histone proteins, and thereby, reduced invasive ability of an ATC thyroid cancer cell line.

Characteristics of Klebsiella pneumoniae bacteremia in community-acquired and nosocomial infections in diabetic patients.

BACKGROUND: Although diabetes mellitus is known as a major risk factor for Klebsiella pneumoniae infection, the differences in clinical characteristics between community-acquired and nosocomial K. pneumoniae bacteremia in diabetic patients have been rarely reported. METHODS: This retrospective analysis enrolled 193 adult diabetic patients with K. pneumoniae bacteremia hospitalized between January 2005 and December 2006. The chi-squared test, analysis of variance (ANOVA), Student's t test, Fisher exact test, and Cox regression model were used for statistical analysis. RESULTS: Of the enrolled patients, 147 had community-acquired infections and 46 had nosocomial infections. Compared with the community group, the nosocomial group had higher rates of in-hospital mortality (41.3% vs. 18.4%, p=0.001), malignancy (50.0% vs. 19.0%, p<0.001), and leukopenia (21.7% vs. 5.4%, p=0.001) but had lower levels of serum C-reactive protein (124.3 mg/L vs. 188.7 mg/L, p=0.018) and HbA1c (8.1% vs. 9.5%, p=0.025). The rate of infection with the extended-spectrum ß-lactamase-producing strain (ESBL infection) in the nosocomial group was 11 times higher than that in the community group (45.7% vs. 4.1%, p<0.001). ESBL infection accounted for 53% of mortality in the nosocomial group. Pneumonia was more common in the nosocomial group, while local abscess was more common in the community group. The risk factors for mortality were pneumonia, leukopenia, cirrhosis, and a high serum creatinine ratio (creatinine level at admission/baseline). CONCLUSIONS: The nosocomial group had more ESBL infections which might account for the higher mortality. The HbA1c level during the course of infection did not affect the outcome. Pneumonia, leukopenia, cirrhosis, and a high serum creatinine ratio at admission were the risk factors for poor outcome.

Synergy of a herpes oncolytic virus and paclitaxel for anaplastic thyroid cancer.

PURPOSE: Novel therapeutic regimens are needed to improve the dismal outcomes of patients with anaplastic thyroid cancer (ATC). Oncolytic herpes simplex virus have shown promising activity against human ATC. We studied the application of oncolytic herpes simplex virus (G207 and NV1023) in combination with currently used chemotherapeutic drugs (paclitaxel and doxorubicin) for the treatment of ATC. EXPERIMENTAL DESIGN AND RESULTS: All four agents showed dose-response cytotoxicity in vitro for the human ATC cell lines KAT4 and DRO90-1. G207, combined with paclitaxel, showed synergistic cytotoxicity. Chou-Talalay combination indices ranged from 0.56 to 0.66 for KAT4, and 0.68 to 0.74 for DRO90-1 at higher affected fractions. Paclitaxel did not enhance G207 viral entry and early gene expression or G207 viral replication. Paclitaxel combined with G207 compared with single-agent treatment or controls showed significantly increased microtubule acetylation, mitotic arrest, aberrant chromatid separation, inhibition of metaphase to anaphase progression, and apoptosis. A single i.t. injection of G207 combined with biweekly i.p. paclitaxel injections in athymic nude mice bearing KAT4 flank tumors showed significantly reduced mean tumor volume (74 +/- 38 mm(3)) compared with G207 alone (388 +/- 109 mm(3)), paclitaxel alone (439 +/- 137 mm(3)), and control (520 +/- 160 mm(3)) groups at 16 days. There was no morbidity in vivo attributable to therapy. CONCLUSIONS: Mechanisms of paclitaxel antitumoral activity, including microtubule acetylation, mitotic block, and apoptosis, were enhanced by G207, which also has direct oncolytic effects. Combination of G207 and paclitaxel therapy is synergistic in treating ATC and holds promise for patients with this fatal disease.

Sensitivity of squamous cell carcinoma lymph node metastases to herpes oncolytic therapy.

PURPOSE: Cancer metastases may have phenotypic and genetic differences from their primary cancers of origin. Engineered, replication-competent, attenuated viruses based on herpes simplex virus-1 (HSV-1) have shown potent oncolytic effects in treating primary tumors in animal tumor models, but their efficacy in treating lymph node metastases is poorly understood. We compared the efficacy of an attenuated oncolytic HSV-1 (NV1023) in treating a series of murine squamous carcinoma cell lines derived from serial implantation and harvest from metastatic lymph nodes. EXPERIMENTAL DESIGN AND RESULTS: The auricles of C3H/HeJ mice were implanted with SCCVII. Cervical nodal metastases were isolated, expanded in vitro, and reimplanted into new mice. A series of cell lines (LN1-LN7) were generated through seven serial passages. Cells from higher LN passages showed consistent trends toward increased migratory and invasive ability, increased cell surface nectin-1 (an HSV-1 receptor) expression, and increased glycoprotein D binding. Exposure to NV1023 showed increased viral entry, replication, and cytotoxicity with higher LN passages. Intratumoral injection of NV1023 in a murine flank tumor model caused significantly greater tumor regression and increased viral infection of LN7 compared with SCCVII. CONCLUSIONS: These results show that lymph node metastases may undergo selection for characteristics, including increased nectin-1 expression, that make them more sensitive targets for herpes oncolytic therapy. These findings support the clinical application of these agents for the treatment of lymph node metastases.

Operative strategy for follicular thyroid cancer in risk groups stratified by pTNM staging.

This study determined cancer survival rates and follow-up status at different pTNM stages to stratify risk groups in follicular thyroid carcinoma. Two hundred and fourteen follicular thyroid cancer patients (167 females, 47 males) who underwent surgery and followed-up treatment at a single medical center were enrolled in this retrospective study. Tumors were staged by UICC-TNM criteria (6th edition). Low risk for follicular thyroid cancer was defined as pT1N0M0. (Moderate-risk group) was defined as all other patients in pTNM stage I, and high risk as patients in stages II-IV. After mean follow-up of 9.6+/-0.3 years, 1.6% (2/120), 21.9% (7/32), 5.6% (1/18) and 52.3% (23/44) of patients in pTNM stages I-IV, respectively, died of thyroid cancer. Of 214 follicular thyroid cancer patients, 35 (16.4%), 85 (39.7%) and 94 (43.9%) were defined as low-, moderate- and high-risk groups at the time of surgery. None of the low-risk patients died, and all achieved disease-free status. In the moderate- and high-risk groups, 2.4% (2/85) and 27.7% (26/94) died of thyroid cancer. The moderate- and high-risk groups underwent near-total thyroidectomy and (131)I therapies, and 15 of 107 (14.9%) died of thyroid cancer while 18 (16.8%) had persistent disease at the end of the study period. Multiple regression analysis demonstrated that tumor size, radioactive iodide therapy and post-operative thyroglobulin level significantly differ between the mortality and survival groups. In conclusion, the low-risk follicular thyroid cancer group as defined by pTNM staging had excellent prognosis. Total thyroidectomy and post-operative radioactive iodide therapy are mandatory in moderate- and high-risk groups. Over one-fourth of the follicular thyroid cancer patients in the high-risk group died of thyroid cancer despite aggressive treatment.

Nectin-1 is a marker of thyroid cancer sensitivity to herpes oncolytic therapy.

CONTEXT: The prognosis for patients diagnosed with anaplastic thyroid cancer is dismal, with a median survival time of only 6 months. Novel therapies are needed for these and other thyroid cancers that are refractory to conventional therapy. OBJECTIVES: Our goals were to assess the ability of an attenuated, replication-competent, oncolytic herpes virus (NV1023) to enter and lyse human thyroid cancers and determine whether herpes simplex virus receptor expression is a determinant of NV1023 efficacy. DESIGN: A panel of 12 human thyroid cancer cell lines including anaplastic, medullary, follicular, and papillary cancers were exposed to NV1023 and assessed for susceptibility to viral entry and oncolysis. The expression of herpes simplex virus glycoprotein D receptors nectin-1 and herpes virus entry mediator was assessed by quantitative fluorescence-activated cell sorter and correlated with NV1023 entry and oncolysis. RESULTS: There was significant variation in the ability of NV1023 to enter thyroid cancer cells as measured by lacZ expression. Thyroid cancer nectin-1 expression correlated strongly with NV1023 entry. Nectin-1 transfections and antibody receptor blocking studies validated the importance of nectin-1 for NV1023 entry. Follicular cancers were least sensitive to NV1023 oncolysis. All anaplastic, medullary, and papillary cancers tested exhibited greater than 85% cytotoxicity 7 d after exposure to NV1023 at multiplicity of infection 1, although oncolysis was variable at multiplicity of infection 0.01. Significant correlations between nectin-1 expression and NV1023 oncolysis were identified using Pearson's coefficients. CONCLUSIONS: NV1023 causes significant cytotoxicity of anaplastic, medullary, and papillary thyroid cancers. Nectin-1 is a novel marker of thyroid cancer sensitivity to herpes oncolytic therapy that might guide patient selection for therapy.

Clinical application of self-expanding metallic stent in the management of acute left-sided colorectal malignant obstruction.

AIM: To summarize our experience with the application of self-expanding metallic stent (SEMS) in the management of acute left-sided colorectal malignant obstruction. METHODS: A retrospective chart review of all patients undergoing placement of SEMS between April 2000 and January 2004 was performed. RESULTS: Insertion of SEMS was attempted in 26 patients under fluoroscopic guidance with occasional endoscopic assistance. The sites of lesions were located in splenic flexure of two patients, left colon of seven patients, sigmoid colon of eight patients and rectum of nine patients. The intended uses of SEMS were for palliation in 7 patients and as a bridge to elective surgery in 19 patients. In the latter group, placement of SEMS allowed for preoperative systemic and bowel preparation and the following one-stage anastomosis. Successful stent placement was achieved in 22 (85%) of the 26 patients. The clinical bowel obstruction resolved 24 hours after successful stent placement in 21 (95%) patients. Three SEMS-related minor complications occurred, two stents migrated and one caused anal pain. CONCLUSION: SEMS represents an effective and safe tool in the management of acute malignant colorectal obstruction. As a bridge to surgery, SEMS can provide time for systematic support and bowel preparation and obviate the need for fecal diversion or on-table lavage. As a palliative measure, SEMS can eliminate the need for emergent colostomy.

Primary pituitary lymphoma presenting as hypophysitis.

A 47-year-old man had suffered from prolonged fever for two months without clinical evidence of infection. Blood biochemistry and endocrine dysfunction indicated that he had pituitary insufficiency. Thorough whole body imaging studies merely identified a 22 x 14 mm mass lesion in the sella turcica. Tumor pathology and special cell marker study revealed the infiltration of atypical T-lymphoid cells and concomitant presence of some B-lymphoid cells. The fever subsided gradually following subtotal tumor resection and steroid supplementation. However, the mass lesion had invaded the cavernous sinus and optic chiasma shortly after surgery. Six months after his initial visit, metastasis lesions in the liver, the left adrenal gland, and retroperitoneal lymph nodes were discovered. In contrast to cells in the pituitary, the pathological investigation of the liver mass confirmed it to be exclusively of T-cell origin. Therefore, it is plausible that the pituitary dysfunction was related to an inflammatory process, namely hypophysitis, as well as the T-cell lymphoma. This case exemplifies the rarely noted condition of primary pituitary lymphoma with concomitant hypophysitis. Clinical diagnosis is indiscernible until the occurrence of systemic tumor metastasis.