A Rare Case of Biopsy-Proven Sacral Mass Metastatic From Follicular Thyroid Cancer With a Literature Review.

Thyroid cancer with metastatic disease to the pelvis is extremely rare. The patient in our case, an 86-year-old male, presented after total thyroidectomy for follicular thyroid cancer (FTC) with symptoms of recurrent urinary tract infections and retentions, surprisingly leading to the discovery of a large sacral mass on the CT abdomen and pelvis. The biopsy showed metastatic carcinoma with morphology and immunohistochemistry to be consistent with FTC. In our case, due to symptomatology, prostate cancer was initially considered high in the differential for primary source rather than thyroid cancer. The mass was considered too large for surgery, and he was referred to a radiation oncologist for radiation therapy for the sacral mass.

Effects of Electroacupuncture for Opioid-Induced Constipation in Patients With Cancer in China: A Randomized Clinical Trial.

Importance: Opioid-induced constipation (OIC) is prevalent among patients treated with opioids for cancer pain. Safe and effective therapies for OIC in patients with cancer remain an unmet need. Objective: To determine the efficacy of electroacupuncture (EA) for OIC in patients with cancer. Design, Setting, and Participants: This randomized clinical trial was conducted at 6 tertiary hospitals in China among 100 adult patients with cancer who were screened for OIC and enrolled between May 1, 2019, and December 11, 2021. Interventions: Patients were randomized to receive 24 sessions of EA or sham electroacupuncture (SA) over 8 weeks and then were followed up for 8 weeks after treatment. Main Outcomes and Measures: The primary outcome was the proportion of overall responders, defined as patients who had at least 3 spontaneous bowel movements (SBMs) per week and an increase of at least 1 SBM from baseline in the same week for at least 6 of the 8 weeks of the treatment period. All statistical analyses were based on the intention-to-treat principle. Results: A total of 100 patients (mean [SD] age, 64.4 [10.5] years; 56 men [56.0%]) underwent randomization; 50 were randomly assigned to each group. Among them, 44 of 50 patients (88.0%) in the EA group and 42 of 50 patients (84.0%) in the SA group received at least 20 (≥83.3%) sessions of treatment. The proportion of overall responders at week 8 was 40.1% (95% CI, 26.1%-54.1%) in the EA group and 9.0% (95% CI, 0.5%-17.4%) in the SA group (difference between groups, 31.1 percentage points [95% CI, 14.8-47.6 percentage points]; P < .001). Compared with SA, EA provided greater relief for most OIC symptoms and improved quality of life among patients with OIC. Electroacupuncture had no effects on cancer pain and its opioid treatment dosage. Electroacupuncture-related adverse events were rare, and, if any, all were mild and transient. Conclusions and Relevance: This randomized clinical trial found that 8-week EA treatment could increase weekly SBMs with a good safety profile and improve quality of life for the treatment of OIC. Electroacupuncture thus provided an alternative option for OIC in adult patients with cancer. Trial Registration: ClinicalTrials.gov Identifier: NCT03797586.

Sequencing Systemic Therapy Pathways for Advanced Hepatocellular Carcinoma: A Cost Effectiveness Analysis.

INTRODUCTION: Hepatocellular carcinoma (HCC) is the most common form of liver cancer worldwide and carries a poor prognosis. Historically, sorafenib was the only available systemic treatment for advanced HCC. However, in recent years, 6 new treatments have been approved by the US Food and Drug Administration (FDA): regorafenib, lenvatinib, cabozantinib, pembrolizumab, ramucirumab, and nivolumab. Data are lacking regarding the most appropriate sequencing pathway for these agents. Our objective was to conduct a comprehensive cost effectiveness analysis (CEA) of different 1st- and 2nd-line treatment pathways for HCC reflecting all new drug approvals, and then use our data to provide guidance for clinicians on which pathway is the most cost-effective. MATERIALS AND METHODS: Markov models were used to evaluate the cost effectiveness of 8 different 1st- and 2nd-line treatment sequences. The model allowed for 9 possible states. Cost effectiveness ratios (CER) and incremental CER (ICER) were calculated to compare costs between different pathways and against a willingness-to-pay (WTP) threshold. Efficacy and toxicity data were extracted from the landmark trials for each agent. All agents except ramucirumab were included. The cost of each agent was based on the wholesale acquisition cost (WAC) in USD as of June 2019. Monte-Carlo methods were used to simulate the experience of 1,000,000 patients per treatment sequence for a 12-month period. RESULTS: The pathway with the lowest CER was sorafenib, followed by pembrolizumab (USD 227,741.03/quality-adjusted life year [QALY]). ICER analysis supported implementing 2nd-line pembrolizumab-based pathways at a higher WTP threshold of 300,000/quality-adjusted life year. Sensitivity analysis did not substantially change these results. CONCLUSIONS: The most cost-effective strategy was 1st-line tyrosine kinase inhibitor therapy followed by 2nd-line immunotherapy. All pathways exceeded a commonly accepted WTP of USD 100-150,000/QALY. Our preliminary results warrant further studies to best inform real-world practices.

BRAF/MEK Pathway is Associated With Breast Cancer in ER-dependent Mode and Improves ER Status-based Cancer Recurrence Prediction.

BACKGROUND: Aberrant BRAF/MEK signaling was found in nearly 50% of human malignancies and proved to play a critical role in the tumorigenesis of multiple cancers. However, this pathway was relatively seldom studied in breast cancer, and the role of this pathway in the pathogenesis of breast cancer is still controversial. MATERIALS AND METHODS: Breast cancer gene expression data from The Cancer Genome Atlas (TCGA) and 43 Affymetrix microarray datasets were analyzed. The BRAF/MEK pathway activity was presented with phosphorylated ERK level (for the TCGA dataset) or computed by a gene signature-based algorithm (for Affymetrix datasets). Aberrant activation of BRAF/MEK pathway in breast cancer was assessed in matched normal/tumor tissues. The associations of the BRAF/MEK pathway with clinical outcome in patients with breast cancer were analyzed by logistic regression, Cox regression, and Kaplan-Meier methods. RESULTS: Down-regulation of the BRAF/MEK pathway was observed in atypical ductal hyperplasia, ductal carcinoma in situ, and invasive breast cancers, with the exception of human epidermal growth factor receptor 2-positive and triple-negative breast cancers. Higher BRAF/MEK pathway activities were associated with better survival in estrogen receptor (ER)-positive (overall hazard ratio [HR], 0.85; P = 5.47E-5; n = 3128) or progesterone receptor-positive (overall HR, 0.85; P = 4.19E-3; n = 1537) breast cancers, but with worse survival in ER-negative (overall HR, 1.13; P = .01; n = 1107) or progesterone receptor-negative (overall HR, 1.13; P = .01; n = 1219) breast cancers. Combination with BRAF/MEK pathway activities could improve ER status-based recurrence prediction for breast cancer. CONCLUSION: BRAF/MEK pathway was associated with the recurrence risk of breast cancer in an ER status-dependent mode. Combination with BRAF/MEK pathway activities could improve the ER status-based recurrence prediction in breast cancer.

Positive acute viral infection markers, autoimmune disease and type II mixed cryoglobulinemia: a rare concurrence.

Cryoglobulins are abnormal serum immunoglobulins that tend to precipitate in intravascular compartments at temperatures lower than 37°C causing blood flow restriction to vital organs. They are divided into type I, II and III based on the immunoglobulin subtypes of the cryoprecipitates. Type II cryoglobulinemia is most commonly associated with viral infections, autoimmune diseases and lymphoproliferative disorders. Here, we reported an 80-year-old man who presented with fatigue, acute kidney injury, palpable purpura, anaemia and altered mental status. He was diagnosed with type II cryoglobulinemia with concomitant positive autoimmune markers, varicella IgM antibody and IgM hepatitis B core antibody. The patient responded well to intravenous and oral steroid treatment.

Screening for Cardiovascular Disease Risk Factors in a Physical Therapist Wound Care Practice: A Retrospective, Observational Study.

Understanding the prevalence of cardiovascular risk factors among individuals seeking physical therapist services in a wound care center is important, especially if aerobic exercise or other physical activity is recommended. PURPOSE: This study assessed the prevalence of cardiovascular risk factors in individuals seeking physical therapist services for an integumentary disorder in an outpatient wound care center. METHODS: Using a retrospective, observational study design, records from patients who were screened upon initial evaluation by a physical therapist for cardiovascular risk according to the American College of Sports Medicine (ACSM) guidelines were abstracted. The screening process entailed assessment of current signs and symptoms of cardiovascular, pulmonary, or metabolic disease; an individual or family history of cardiovascular disease; whether the patient was considered obese; and whether the patient was a current smoker, had a sedentary lifestyle, dyslipidemia, elevated glucose, or blood pressure ⟩140/90 mm Hg. Patient demographics and wound history also were summarized and described, including wound type and duration and pain associated with the wound. Wounds then were classified by the physical therapist as either venous leg ulcers or nonvenous leg ulcers based upon the referring physician's diagnosis. Descriptive statistics and frequency distributions were calculated to assess the prevalence of individual cardiovascular risk factors, total number of cardiovascular risk factors, cardiovascular risk stratification, and patient disposition. Frequencies of individual cardiovascular risk factors, total number of cardiovascular risk factors, and cardiovascular risk stratification also were assessed between patients with venous leg ulcers and nonvenous leg ulcers using chi-square tests for categorical data and t tests for continuous data. The alpha level was set at P <.05. RESULTS: Among the 70 study participants (41 male, 29 female; mean age 63.5 ± 15.1 years), 38 were treated for venous leg ulcers and 32 were treated for nonvenous leg ulcers. Overall, 38 patients (54%) had a history of cardiovascular disease and 29 (41%) had current signs and symptoms of cardiovascular disease. Patients with nonvenous leg ulcers had a significantly higher frequency of having a family history of cardiovascular disease than patients with venous leg ulcers (28% vs. 8%; P = .03). According to the ACSM guidelines, 5 patients (7%) were considered low risk, 22 (31%) were moderate risk, and 43 (62%) were at high risk for experiencing a future cardiovascular event. Cardiovascular risk did not vary significantly according to wound type. CONCLUSION: The patient risk-stratification profile in this study strongly suggested physical therapists should screen for cardiovascular risk factors before prescribing aerobic exercise or other physical activity for all patients being seen for an integumentary disorder in an outpatient wound care practice.

Exophytic primary gastric squamous cell carcinoma and H. pylori gastritis.

Primary gastric squamous cell carcinoma (SCC) is rare, and the simultaneous Helicobacter pylori infection has not been reported in the literature. Here, we presented a patient with concurrent H. pylori gastritis and primary gastric SCC. A 54-year-old Hispanic man presented with diarrhoea, chills, night sweats and weight loss of 16 lbs for the previous 6 weeks. Abdominal CT revealed large exophytic mass from the stomach infiltrating multiple organs. Biopsy was performed and histology showed squamoid features. Immunohistochemistry stain was positive for p40, CK5/6, CK7 and Helicobacter type organisms. Patient was diagnosed with primary gastric SCC and has been receiving chemotherapy. We also reviewed the diagnosis, prognosis and treatment of primary gastric SCC.

Outcomes and Quality of Life of Systemic Therapy in Advanced Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is one of the most commonly diagnosed cancers worldwide; most patients are diagnosed with advanced disease for which there is no known cure. Tremendous progress has been made over the past decade in the development of new agents for HCC, including small-molecule kinase inhibitors such as sorafenib, lenvatinib, cabozantinib, regorafenib, and monoclonal antibodies like ramucirumab, nivolumab, and pembrolizumab. Ideal use of these agents in clinics has improved the long-term outcome of patients with advanced HCC as well as introduced unique toxicities that can affect quality of life. These toxicities usually are thought to be partially related to cirrhosis, a major risk factor for the development of HCC and a pathophysiological barrier complicating the optimal delivery of antineoplastic therapy. Additionally, side effects of medications together with advanced HCC symptoms not only decrease quality of life, but also cause treatment interruptions and dose reductions that can potentially decrease efficacy. Physicians caring for patients with advanced HCC are called to optimally manage HCC along with cirrhosis in order to prolong life while at the same time preserve the quality of life. In this review, we aimed to summarize outcomes and quality of life with the use of modern systemic treatments in advanced HCC and provide a physician reference for treatment toxicity and cirrhosis management.

Clinical outcomes and associated factors of radioiodine-131 treatment in differentiated thyroid cancer with cervical lymph node metastasis.

Cervical lymph node metastasis (CLNM) is common in differentiated thyroid cancer (DTC). Radioiodine-131 (131I) treatment is recommended for the removal of residual thyroid tissue following thyroidectomy. To date, the effect of 131I therapy on the outcomes of patients with DTC with CLNM is unclear. The aim of the present study was to evaluate the final outcome of patients with DTC with CLNM according to 131I administration, and to analyze the factors that may affect clinical outcomes. A total of 357 patients with DTC with CLNM were recruited and divided into three groups: Those who received 2, 3 or 4 doses of 131I therapy, respectively. Successful ablation was defined as levels of stimulated serum thyroglobulin <2 ng/ml in the absence of CLNM. The rates of successful ablation were 80.35 (229/285), 76.36 (42/55) and 70.59% (12/17) for patients who received 2, 3 and 4 doses, respectively. The patients with DTC with CLNM who were <45 years old, with tumor sizes <2 cm, solitary nodules and TNM stage I-II disease exhibited significantly higher rates of successful ablation compared with the patients who were ≥45 years old, with tumor size ≥2 cm, multiple nodules and stage III-IV disease. Multivariate analyses revealed that tumor size, number of nodules and TNM stage were independent risk factors associated with successful ablation in patients with DTC with CLNM who received 2 doses of 131I therapy. 131I administration is a useful therapy to eradicate cervical lymph node metastasis in patients with DTC, and may be preferentially indicated in patients with DTC with CLNM who are aged <45 years, with tumor sizes <2 cm, solitary nodules and lower TNM stages, in order to control and prevent recurrence and/or metastases.

POEMS syndrome presentation with progressive weakness in upper and lower limbs: A case report.

Polyneuropathy, organomegaly, endocrinopathy, M proteins, and skin changes (POEMS) syndrome is a rare variant of plasma cell disorders with multiple systemic manifestations. A 50-year-old female patient presented with progressive weakness in her upper and lower limbs; tingling, numbness and burning in her feet; polyneuropathy (demyelinating in the majority of cases of POEMS syndrome); monoclonal plasma cell disorder (typicallyλ-restricted in cases of POEMS syndrome); sclerotic lesions on the spine and pelvis; organomegaly, including hepatomegaly, splenomegaly and lymphadenopathy; edema; pleural effusion; adrenal, thyroidal, pituitary, gonadal and pancreatic endocrinopathy; skin changes, including hyperpigmentation, dry skin and hypertrichosis; thrombocytosis; pulmonary hypertension; low vitamin B12 and weight loss. Following the diagnosis of POEMS syndrome, the patient was treated only with pain-alleviating corticosteroids. Respiratory failure-induced mortality occurred 24 months after the patient first experienced difficulty walking and numbness in her lower extremities. The present study suggests that abnormal symptoms in cases of POEMS syndrome should be further evaluated during the diagnosis and treatment.

Opioid tapering in patients with prescription opioid use disorder: A retrospective study.

BACKGROUND AND AIMS: Opioid use disorder (OUD) refers to a maladaptive pattern of opioid use leading to clinically significant impairment or distress. OUD causes, and vice versa, misuses and abuse of opioid medications. Clinicians face daily challenges to treat patients with prescription opioid use disorder. An evidence-based management for people who are already addicted to opioids has been identified as the national priority in the US; however, options are limited in clinical practices. In this study, we aimed to explore the success rate and important adjuvant medications in the medication assisted treatment with temporary use of methadone for opioid discontinuation in patients with prescription OUD. METHODS: This is a retrospective chart review performed at a private physician office for physical medicine and rehabilitation. We reviewed all medical records dated between December 1st, 2011 and August 30th, 2016. The initial evaluation of the included patients (N=140) was completed between December 1st, 2011 and December 31st, 2014. They all have concumittant prescription OUD and chronic non-cancer pain. The patients (87 female and 53 male) were 46.7±12.7 years old, and had a history of opioid use of 7.7±6.1 years. All patients received the comprehensive opioid taper treatments (including interventional pain management techniques, psychotherapy, acupuncture, physical modalities and exercises, and adjuvant medications) on top of the medication assisted treatment using methadone (transient use). Opioid tapering was considered successful when no opioid medication was used in the last patient visit. RESULTS: The 140 patients had pain of 9.6±8.4 years with 8/10 intensity before treatment which decreased after treatment in all comparisons (p<0.001 for all). Opioids were successfully tapered off in 39 (27.9%) patients after 6.6±6.7 visits over 8.8±7.2 months; these patients maintained opioid abstinence over 14.3±13.0 months with regular office visits. Among the 101 patients with unsuccessful opioid tapering, 13 patients only visited the outpatient clinic once. Significant differences were found between patients with and without successful opioid tapering in treatment duration, number of clinic visits, the use of mirtazepine, bupropion, topiramate, and trigger point injections with the univariate analyses. The use of mirtazepine (OR, 3.75; 95% CI, 1.48-9.49), topiramate (OR, 5.61; 95% CI, 1.91-16.48), or bupropion (OR, 2.5; 95% CI, 1.08-5.81) was significantly associated with successful opioid tapering. The associations remain significant for mirtazepine and topiramate (not bupropion) in different adjusted models. CONCLUSIONS: With comprehensive treatments, 27.9% of patients had successful opioid tapering with opioid abstinence for over a year. The use of mirtazepine, topiramate, or likely bupropion was associated with successful opioid tapering in the medication assisted treatment with temporary use of methadone. Opioid tapering may be a practical option and should be considered for managing prescription OUD. IMPLICATIONS: For patients with OUD, indefinite opioid maintenance treatment may not be necessary. Considering the ethical values of autonomy, nonmaleficence, and beneficence, clinicians should provide patients with OUD the option of opioid tapering.

Management of patients with pain and severe side effects while on intrathecal morphine therapy: A case study.

BACKGROUND AND AIMS: The use of intrathecal morphine therapy has been increasing. Intrathecal morphine therapy is deemed the last resort for patients with intractable chronic non-cancer pain (CNCP) who failed other treatments including surgery and pharmaceutical interventions. However, effective treatments for patients with CNCP who "failed" this last resort because of severe side effects and lack of optimal pain control remain unclear. METHODS AND RESULTS: Here we report two successfully managed patients (Ms. S and Mr. T) who had intractable pain and significant complications years after the start of intrathecal morphine therapy. The two patients had intrathecal morphine pump implantation due to chronic consistent pain and multiple failed surgical operations in the spine. Years after morphine pump implantation, both patients had significant chronic pain and compromised function for activities of daily living. Additionally, Ms. S also had four episodes of small bowel obstruction while Mr. T was diagnosed with end stage severe "dementia". The successful management of these two patients included the simultaneous multidisciplinary approach for pain management, opioids tapering and discontinuation. CONCLUSION: The case study indicates that for patients who fail to respond to intrathecal morphine pump therapy due to side effects and lack of optimal pain control, the simultaneous multidisciplinary pain management approach and opioids tapering seem appropriate.

Publication Trends in Acupuncture Research: A 20-Year Bibliometric Analysis Based on PubMed.

OBJECTIVE: Acupuncture has become popular and widely practiced in many countries around the world. Despite the large amount of acupuncture-related literature that has been published, broader trends in the prevalence and scope of acupuncture research remain underexplored. The current study quantitatively analyzes trends in acupuncture research publications in the past 20 years. METHODS: A bibliometric approach was used to search PubMed for all acupuncture-related research articles including clinical and animal studies. Inclusion criteria were articles published between 1995 and 2014 with sufficient information for bibliometric analyses. Rates and patterns of acupuncture publication within the 20 year observational period were estimated, and compared with broader publication rates in biomedicine. Identified eligible publications were further analyzed with respect to study type/design, clinical condition addressed, country of origin, and journal impact factor. RESULTS: A total of 13,320 acupuncture-related publications were identified using our search strategy and eligibility criteria. Regression analyses indicated an exponential growth in publications over the past two decades, with a mean annual growth rate of 10.7%. This compares to a mean annual growth rate of 4.5% in biomedicine. A striking trend was an observed increase in the proportion of randomized clinical trials (RCTs), from 7.4% in 1995 to 20.3% in 2014, exceeding the 4.5% proportional growth of RCTs in biomedicine. Over the 20 year period, pain was consistently the most common focus of acupuncture research (37.9% of publications). Other top rankings with respect to medical focus were arthritis, neoplasms/cancer, pregnancy or labor, mood disorders, stroke, nausea/vomiting, sleep, and paralysis/palsy. Acupuncture research was conducted in 60 countries, with the top 3 contributors being China (47.4%), United States (17.5%), and United Kingdom (8.2%). Retrieved articles were published mostly in complementary and alternative medicine (CAM) journals with impact factors ranging between 0.7 and 2.8 in the top 20 journals, followed by journals specializing in neuroscience, pain, anesthesia/analgesia, internal medicine and comprehensive fields. CONCLUSION: Acupuncture research has grown markedly in the past two decades, with a 2-fold higher growth rate than for biomedical research overall. Both the increases in the proportion of RCTs and the impact factor of journals support that the quality of published research has improved. While pain was a consistently dominant research focus, other topics gained more attention during this time period. These findings provide a context for analyzing strengths and gaps in the current state of acupuncture research, and for informing a comprehensive strategy for further advancing the field.

Acupuncture is Effective for Chronic Knee Pain: A Reanalysis of the Australian Acupuncture Trial.

Context • In the October 2014 issue of the Journal of the American Medical Association (JAMA), Hinman et al published the results of an Australian clinical trial on acupuncture in a paper entitled "Acupuncture for Chronic Knee Pain: A Randomized Clinical Trial" (JAMA report), in which they concluded that neither acupuncture nor laser acupuncture had any greater effects than sham laser acupuncture for pain or function for patients aged 50 y and older with moderate-to-severe knee pain. That study has been criticized extensively by international scholars for its validity because serious methodological flaws existed throughout the study's design, implementation, and conclusions. Objective • The current study intended to re-examine the prior study's conclusions about the efficacy of acupuncture for chronic knee pain. Design • The current research team performed a reanalysis of relevant data from the JAMA report. Intervention • The original study included 4 groups: (1) an acupuncture group, which received needle acupuncture, inferred by the current authors to have been set up to be a positive control in the original study; (2) a laser acupuncture group, which received laser acupuncture; (3) a sham laser acupuncture group, which received sham laser acupuncture and acted as the negative controls for the laser acupuncture intervention; and (4) a control group, which received conventional care but no acupuncture or laser treatments. The study lasted 12 wk. Outcome Measures • The measures included evaluations in the following areas: (1) poststudy modifications-an evaluation of the consistency of the JAMA report with the study's intentions as identified for a grant that was originally approved and funded by the Australian National Health and Medical Research Council (NHMRC) in 2009, as indicated in the study's trial registration, and as compared with the published protocols and to the study's originally stated objectives; (2) high heterogeneity-an assessment of the heterogeneity among the 4 groups for the overall outcome related to pain; (3) ineffectiveness of laser acupuncture-an analysis of laser acupuncture's efficacy for chronic knee pain as stated in the JAMA report, using effect size (ES); (4) effectiveness of acupuncture-a reanalysis of acupuncture's efficacy for chronic knee pain in comparison with the original analysis in the JAMA report, using ES; and (5) acupuncture after data adjustment-a new analysis of acupuncture's efficacy for chronic knee pain using data from the original study that was discussed in the JAMA report, using ES, with an estimation after data adjustment and elimination of the dilution effect of the Zelen design. Results • Contrary to a general impression that acupuncture was the focus, laser acupuncture was the primary intervention tested in the actual study, "Laser Acupuncture in Patients With Chronic Knee Pain: A Randomized, Placebo Controlled Trial." The study discussed in the JAMA report was neither a truly randomized, controlled trial (RCT) for acupuncture nor was it an appropriately designed, randomized study in general. High heterogeneity was found among its groups in the evaluation of overall pain in patients. Both the ES of 0.60 that had been set by Hinman et al for the minimal clinically important difference (MCID) and the resulting interpretation of results in the JAMA report were not appropriate. Using the original study's criteria of efficacy, the reanalysis has confirmed that the laser acupuncture was not effective, whereas the acupuncture was found to be moderately effective for chronic knee pain (P < .05) for both overall pain and function at 12 wk, with an ES of 0.58, or after the adjustment of the data, with an ES of 0.67. Conclusions • The JAMA study was neither a conventional RCT nor an appropriately randomized trial, and its results are probably invalid. The ES of 0.60 for the MCID that was used in the JAMA study and the resulting explanation were not appropriate. Even with an ES of 0.60 for the MCID, acupuncture remained effective after data adjustment. Consequently, compared with conventional care, acupuncture treatment was found to be moderately effective for chronic knee pain in patients aged 50 y and older.

Chronic and non-healing wounds: The story of vascular endothelial growth factor.

The pathophysiology of the chronicity and non-healing status of wounds remains unknown. This paper presents the following hypothesis: abnormal patterns of vascular endothelial growth factor receptors (VEGFRs) are the culprits of wound chronicity and non-healing. More specifically, for patients with poor circulation, the decreased VEGFR-2 level is the cause of poor wound healing; for patients with non-compromised circulation, for example, patients with concurrent chronic wounds and active autoimmune diseases, the increased VEGFR-1 level is related to the non-healing status of wounds. The hypothesis is supported by the following facts. VEGFR-1 is the main contributor for inflammation and VEGFR-2 facilitates angiogenesis; soluble VEGFR-1 (sVEGFR-1) inactivates both VEGFR-1 and VEGFR-2. Patients with auto-immune disease have abnormally increased VEGFR-1 and decreased sVEGFR. Wounds in patients with active autoimmune diseases have poor response to electric stimulation which facilitates chronic wound healing in patients without active autoimmune diseases via increasing vascular endothelial growth factor (VEGF) secretion. Patients with chronic wounds (including diabetic foot ulcers and venous leg ulcers) but no active autoimmune diseases have decreased VEGFR-2 levels. We thus believe that abnormal patterns of VEGFRs are the culprits of wound chronicity and non-healing. For wounds with compromised circulation, VEGFR-2 decrease contributes to its chronicity; whereas for wounds with non-compromised circulation, VEGFR-1 increase is the leading cause of the non-healing status of chronic wounds. Treatments and research in wound care should be tailored to target these changes based on circulation status of wounds. Complete elucidation of changes of VEGFRs in chronic and non-healing wounds will enhance our understandings in tissue healing and thus better our selection of appropriate treatments for chronic and non-healing wounds.

CCL21/CCR7 enhances the proliferation, migration, and invasion of human bladder cancer T24 cells.

OBJECTIVE: To investigate the effects of CCL21/CCR7 on the proliferation, migration, and invasion of T24 cells and the possible associated mechanisms: expression of MMP-2 and MMP-9, and regulation of BCL-2 and BAX proteins. METHODS: T24 cells received corresponding treatments including vehicle control, antibody (20 ng/mL CCR7 antibody and 50 ng/ml CCL21), and 50, 100, and 200 ng/ml CCL21. Proliferation was evaluated by MTT assay; cell migration and invasion were assayed using a transwell chamber. Cell apoptosis was induced by Adriamycin (ADM). The rate of cell apoptosis was examined by flow cytometry using annexin V-FITC/PI staining. Western-blot was used to analyze MMP-2 and MMP-9 and BCL-2 and BAX proteins. RESULTS: CCL21 promoted T24 cell proliferation in concentration-dependent manner with that 200 ng/mL induced the largest amount of proliferation. Significant differences of cell migration were found between CCL21treatment groups and the control group in both the migration and invasion studies (P < 0.001 for all). The expressions of MMP-2 and MMP-9 proteins were significantly increased after CCL21 treatment (p < 0.05 for all). Protein expression of Bcl-21 follows an ascending trend while the expression of Bax follows a descending trend as the concentration of CCL21 increases. No difference was found between the control group and antibody group for all assessments. CONCLUSION: CCL21/CCR7 promoted T24 cell proliferation and enhanced its migration and invasion via the increased expression of MMP-2 and MMP-9. CCL21/CCR7 had antiapoptotic activities on T24 cells via regulation of Bcl-2 and Bax proteins. CCL21/CCR7 may promote bladder cancer development and metastasis.

[A genetic and clinical study in a family with familial hypercholesterolemia].

OBJECTIVE: To investigate the low density lipoprotein receptor (LDLR) gene and apolipoprotein (Apo) B gene mutation in a Chinese family with familial hypercholesterolemia (FH) and give the kindreds clinical check-ups. METHODS: After physical examination, the kindreds underwent ECG and ultrasound checks. Blood samples were tested for lipid profiles. The promoter and all eighteen exons of LDLR gene were investigated by using PCR and agarose gel electrophoresis in combination with DNA sequence analysis. The results were compared with the normal sequences in GenBank and FH database (www.ucl.ac.uk/fh) to find mutations. In addition, the apolipoprotein B100 gene for known mutations (R3500Q, R3531C, R3501W and R3480W) that cause familial defective ApoB100 (FDB) was also tested using the same method. RESULTS: A novel homozygous G > A mutation at the 1581 bp of exon 10 was detected in the proband and his siblings. It caused a substitution of amino acid Glu to Gly at codon 496. A novel heterozygous G > A mutation at the 1581 bp of exon 10 was detected in his parents. No mutations of R3500Q, R3531C, R3501W and R3480W of ApoB100 were observed. ECGs were normal. Atherosclerosis were found in all family members by ultrasound checks. CONCLUSIONS: The homozygous G > A mutation at the 1581 bp of exon 10 was first determined in our country. The change of amino acid Glu to Gly is responsible for FH of the family. The type of the gene mutation was not found in the FH database (www. ucl.ac.uk/fh). It's a new type of LDLR mutation.