Neoadjuvant chemotherapy improves survival rate in advanced urothelial carcinoma

Radical surgery (RS) with adjuvant chemotherapy (AC) or radiotherapy has been conventionally used for patients with advanced urothelial carcinoma (AUC). Recent research has indicated that systemic neoadjuvant chemotherapy (NC) with RS yields better outcomes than RS alone for patients with locally advanced bladder cancer. However, there are no reports indicating whether NC or AC would be beneficial for patients with AUC. The present study compared the survival rate for AUC patients receiving NC or AC. A retrospective analysis was conducted using data for 64 patients with AUC who underwent RS and systemic chemotherapy at our institution between March 2002 and March 2011. Of the 64 patients, 30 received NC before RS and 34 received RS followed by systemic AC. Pathologic stages (p = 0.002), grades (p = 0.018) and lymphovascular invasion (p = 0.047) were significantly lower in the patients who received NC first than in those who received RC first. Furthermore, analysis of the surgical specimens revealed that 26.7% of patients who received NC before RS had complete remission. There were no significant differences in demographic data, surgical complications, and chemotoxicity between the two patient groups. The progression-free survival (PFS) and overall survival (OS) of patients who received initial NC were significantly better than those of patients who received initial RC (p = 0.002 and 0.018, respectively). Our results indicate that NC administration before RS significantly improved the PFS and OS of AUC patients, without increasing surgical complications and chemotoxicity. Further prospectively controlled trials need to be conducted to confirm the effectiveness of NC for AUC patients.     

Caspase-dependent regulation of the ubiquitin–proteasome system through direct substrate targeting

Drosophila inhibitor of apoptosis (IAP) 1 (DIAP1) is an E3 ubiquitin ligase that regulates apoptosis in flies, in large part through direct inhibition and/or ubiquitinylation of caspases. IAP antagonists, such as Reaper, Hid, and Grim, are thought to induce cell death by displacing active caspases from baculovirus IAP repeat domains in DIAP1, but can themselves become targets of DIAP1-mediated ubiquitinylation. Herein, we demonstrate that Grim self-associates in cells and is ubiquitinylated by DIAP1 at Lys136 in an UbcD1-dependent manner, resulting in its rapid turnover. K48-linked ubiquitin chains are added almost exclusively to BIR2-bound Grim as a result of its structural proximity to DIAP1’s RING domain. However, active caspases can simultaneously cleave Grim at Asp132, removing the lysine necessary for ubiquitinylation as well as any existing ubiquitin conjugates. Cleavage therefore enhances the stability of Grim and initiates a feed-forward caspase amplification loop, resulting in greater cell death. In summary, Grim is a caspase substrate whose cleavage promotes apoptosis by limiting, in a target-specific fashion, its ubiquitinylation and turnover by the proteasome.Apoptosis, or programmed cell death, is broadly conserved throughout nature, from flies to humans (1). In most instances, the execution of apoptosis is carried out by cysteinyl aspartate-specific proteases (i.e., caspases) through proteolytic-based signal transduction pathways (2). Upstream initiator caspases, such as caspase-9 in humans and its paralogue Drosophila Nedd2-like caspase (DRONC) in flies, are first activated via their interactions with adapter proteins and in turn activate the downstream effector caspases, caspase-3 and Drosophila interleukin-1β–converting enzyme (DrICE), respectively (2, 3). Once activated, effector caspases are responsible for dismantling the cell through cleavage of literally hundreds of structural and regulatory proteins (4). Caspase cleavage can inactivate proteins or generate dominant-negative inhibitors, as in the case of gelsolin, RIP1, and eIF4E-BP1 (4). Moreover, caspase cleavage of numerous substrates, including IRF-3, ErbB2, cyclin E, claspin, SSRP1, and Twist, can enhance their turnover by the proteasome (5–10). Conversely, caspases can also constitutively activate proteins, particularly kinases such as PKC and Mst1 (11, 12), or change the function of a protein altogether, as seen in the conversion of antiapoptotic BCL-2 proteins into proapoptotic BAX-like proteins (13).Notably, even following the activation of caspases, inhibitor of apoptosis (IAP) proteins, such as X-linked IAP (XIAP) in mammals and DIAP1 in flies, can suppress apoptosis through inhibition of caspases (14–19). All IAPs contain baculovirus IAP repeat (BIR) domains and many possess RING and UBA domains, imparting them with E3 ubiquitin and NEDD8 ligase activity and the ability to bind polyubiquitin chains (20, 21). Thus, XIAP and DIAP1 directly bind and inhibit, ubiquitinylate, and/or neddylate initiator and effector caspases through distinct BIR domains (15, 16, 19, 22–24). In some circumstances, ubiquitinylation marks these enzymes for proteasomal degradation, whereas, in other cases, K63-based ubiquitinylation or neddylation fail to increase protein turnover but nevertheless inhibit protease activity through as yet ill-defined mechanisms (22, 25–27).Finally, a further level of regulation exists in the form of endogenous inhibitors of IAPs. These so-called “IAP antagonists” possess an IAP binding motif (IBM) through which they bind to IAPs and disrupt their interactions with caspases (28). Reaper, Hid, and Grim were the first IAP antagonists to be discovered in flies and were shown to regulate cell death during development, at least in part, by binding to DIAP1, displacing caspases, and inducing autoubiquitinylation and turnover of DIAP1 (18, 19, 29–35). In the present study, we have discovered that DIAP1, in conjunction with the E2 ubiquitin-conjugating enzyme UbcD1, polyubiquitinylates Grim through K48- but not K63-based linkages, resulting in increased Grim turnover. Grim self-associates in cells and binds to both the BIR1 and BIR2 domains in DIAP1, but only the BIR2-bound Grim is significantly ubiquitinylated by DIAP1 in a RING-dependent manner. More surprisingly, Grim is also cleaved by caspases at its C terminus, removing the only lysine residue present in this IAP antagonist. Following caspase cleavage, Grim still binds to DIAP1 but is no longer ubiquitinylated and therefore persists in cells, propagating the death signal through increased activation of caspases.     

Adverse Outcomes After Noncardiac Surgery in Patients With Diabetes: A nationwide population-based retrospective cohort study

OBJECTIVE

To investigate whether diabetes affects perioperative complications or mortality and to gauge its impact on medical expenditures for noncardiac surgeries.

RESEARCH DESIGN AND METHODS

With the use of reimbursement claims from the Taiwan National Health Insurance system, we performed a population-based cohort study of patients with and without diabetes undergoing noncardiac surgeries. Outcomes of postoperative complications, mortality, hospital stay, and medical expenditures were compared between patients with and without diabetes.

RESULTS

Diabetes increased 30-day postoperative mortality (odds ratio 1.84 [95% CI 1.46–2.32]), particularly among patients with type 1 diabetes or uncontrolled diabetes and patients with preoperative diabetes-related comorbidities, such as eye involvement, peripheral circulatory disorders, ketoacidosis, renal manifestations, and coma. Compared with nondiabetic control patients, coexisting medical conditions, such as renal dialysis (5.17 [3.68–7.28]), liver cirrhosis (3.59 [2.19–5.88]), stroke (2.87 [1.95–4.22]), mental disorders (2.35 [1.71–3.24]), ischemic heart disease (2.08 [1.45–2.99]), chronic obstructive pulmonary disease (1.96 [1.29–2.97]), and hyperlipidemia (1.94 [1.01–3.76]) were associated with mortality for patients with diabetes undergoing noncardiac surgery. Patients with diabetes faced a higher risk of postoperative acute renal failure (3.59 [2.88–4.48]) and acute myocardial infarction (3.65 [2.43–5.49]). Furthermore, diabetes was associated with prolonged hospital stay (2.30 [2.16–2.44]) and increased medical expenditures (1.32 [1.25–1.40]).

CONCLUSIONS

Diabetes increases postoperative 30-day mortality, complications, and medical expenditures in patients undergoing in-hospital noncardiac surgeries.Diabetes is a common chronic disease that causes widespread disability and death, with a global prevalence of 2.8% in 2000 and an estimated prevalence of 4.4% in 2030 (1). In the U.S., the national burden of diabetes was estimated to be $245 billion in 2012 (2). The epidemiology, pathogenesis, prevention, and treatment of diabetes have been well established over the past 2 centuries (3).Diabetes is an independent determinant of increased risk of perioperative complications and mortality in cardiovascular surgeries (4,5), yet how extensively diabetes affects postoperative mortality and complications in noncardiac surgeries has not been determined. Some studies indicated that survival outcomes and perioperative complications in noncardiac surgeries do not differ between patients with and without diabetes (6,7), whereas other research showed conflicting data about whether diabetes increased perioperative complications, mortality, hospital stay, and health care expenditures (8–16).Previous studies were limited by several factors, including a focus on a single type of noncardiac surgery (6,8,10,12,14), small sample size (6,7,9,13), inappropriate selection of nondiabetes control subjects (6–16), inadequate adjustment for potential confounders (7,9–12,15), and reporting of a single outcome after surgery (10,16). It remains unclear whether coexisting medical conditions, types of diabetes, glycemic control, and diabetes-related comorbidities affect postoperative outcomes in patients with diabetes.This study used Taiwan National Health Insurance Program reimbursement claims to investigate postoperative complications, 30-day mortality, length of hospital stay, and medical expenditures after adjustment by propensity score-matched pair method in patients with diabetes undergoing noncardiac surgeries. We also investigated the impact of coexisting medical conditions and diabetes-related comorbidities on postoperative 30-day mortality among patients with diabetes.     

Insulin Resistance,Incident Cardiovascular Diseases,and Decreased Kidney Function Among Nondiabetic American Indians: The Strong Heart Study

OBJECTIVE

Prevalence of insulin resistance is high in the American Indian population, likely as a result of the high prevalence of obesity. This condition may be influential for clinical outcomes such as cardiovascular disease (CVD) and decreased kidney function.

RESEARCH DESIGN AND METHODS

Normal glucose tolerant (NGT) participants free of hypertension and CVD at the baseline examination (1989–1992) (N = 964) of the Strong Heart Study were selected to explore the cross-sectional association between insulin resistance quantified by homeostasis model assessment (HOMA-IR) and demographic, behavioral, and cardiometabolic variables. The longitudinal association between baseline HOMA-IR and the development of CVD was also explored. The longitudinal association between baseline HOMA-IR and the development of high urinary albumin-to-creatinine ratio was explored among nondiabetic participants (N = 1,401).

RESULTS

Cross-sectionally, HOMA-IR was associated with sex, residence location, smoking, and high-risk cardiometabolic profile. Prospectively, insulin resistance is associated with the development of CVD and decreased kidney function in this population.

CONCLUSIONS

Insulin resistance may have an important role in the pathogenesis of CVD and chronic kidney disease. Since obesity contributes to the development of insulin resistance, intervention focusing on modifiable factors such as physical activity and weight control may reduce the development of these diseases.Insulin resistance plays a major role in the development of type 2 diabetes (1,2). It has been reported as an independent predictor of cardiovascular diseases (CVDs), hypertension, and dyslipidemia (3,4). It is also involved in the development of polycystic ovary syndrome (5), nonalcoholic fatty liver disease (6), and certain types of cancer (7,8). The list of clinical conditions associated with insulin resistance/compensatory hyperinsulinemia is expanding. With the increasing prevalence of insulin resistance in the American population (9), increased future burdens of associated clinical conditions are predicted.The American Indian population has high prevalence of insulin resistance, especially among the younger age-groups compared with the general U.S. population (10) (at ages 45–49 years metabolic syndrome 44 and 57% among Strong Heart Study [SHS] men and women, respectively, vs. 20 and 23% among all men and women in the Third National Health and Nutrition Examination Survey [NHANES III]). Understanding the clinical outcomes of insulin resistance in this unique population may assist in reducing the burden of insulin resistance and related diseases in all Americans.To the best of the authors’ knowledge, there are few reports about the prospective association of insulin resistance and the development of kidney dysfunction. Also, the role of insulin resistance per se in the development of CVD is less clear. Specifically, this analysis will study 1) prospective associations between insulin resistance quantified by homeostasis model assessment (HOMA-IR) and incident CVD events and 2) prospective association between insulin resistance and decreased kidney function measured by increased urinary albumin-to-creatinine ratio (UACR).     

Quantitative 99Tcm-HMPAO white blood cells and 67Ga scanning in rheumatoid arthritis

This investigation assessed 99Tcm-HMPAO white blood cell (Tc-WBC) and 67Ga knee uptake indices before and after 90Y treatment in patients with intractable rheumatoid arthritis (RA) and correlated the uptake indices with the clinical score. Sixteen knee joints with RA were treated with intra-articular injection of 185 MBq of 90Y-silicate colloid (Amersham) flushed with 50 mg of hydrocortisone. Clinical score, quantitative 67Ga and Tc-WBC knee uptake indices were obtained before and three weeks after treatment. Our results showed that 9/16 (56%) had a good response and 7/16 (44%) had a poor response to 90Y injection. There was poor correlation between clinical improvement and changes in 67Ga and Tc-WBC knee uptake indices (r = 0.46 and 0.14, respectively). The correlation coefficient between changes in 67Ga and Tc-WBC knee uptake indices was 0.29.     

Lymphoscintigraphic studies of lymphatic drainage from the testes

Two colloidal radiopharmaceuticals, Au-198 and Tc-99m antimony, were used to evaluate the lymphatic drainage of the testis in experimental animals and humans. One to 24 hours after direct intratesticular injection of Au-198 colloid in dogs and 4-6 hours after injection of Tc-99m antimony colloid in men, distribution within retroperitoneal lymph nodes was demonstrated. Uptake within the para-aortic lymph nodes primarily draining the testis was decreased following proximal ligation of the spermatic vessels in dogs. Testicular lymphoscintigraphy successfully demonstrated an intact spermatic cord lymphatic communication to the para-aortic nodes in five of six patients with chronic lower-extremity lymphedema. When the intact testicle and spermatic cord were transposed to the thigh in a patient with chronic lymphedema of the lower extremity, percutaneous pedal lymphoscintigraphy successfully demonstrated uptake within the para-aortic lymph nodes draining the ipsilateral testis.     

Detection of anaerobic odontogenic infections by fluorine-18 fluoromisonidazole

Odontogenic infections are a potential risk for patients who receive cervicofacial radiotherapy and should be treated before irradiation. Anaerobic microbial infections are the most common causes. This study assessed the value of the hypoxic imaging agent fluorine-18 fluoromisonidazole (FMISO) in detecting anaerobic odontogenic infections. Positron emission tomography (PET) imaging was performed at 2 h after injection of 370 MBq (10 mCi) of FMISO in 26 nasopharyngeal carcinoma patients and six controls with healthy teeth. Tomograms were interpreted visually to identify hypoxic foci in the jaw. All patients received thorough dental examinations as a pre-radiotherapy work-up. Fifty-one sites of periodontitis, 15 periodontal abscesses, 14 sites of dental caries with root canal infection, 23 sites of dental caries without root canal infection, and seven necrotic pulps were found by dental examination. Anaerobic pathogens were isolated from 12 patients. Increased uptake of FMISO was found at 45 out of 51 sites of periodontitis, all 15 sites of periodontal abscess, all 14 sites of dental caries with root canal infection, all seven sites of necrotic pulp and 15 sites of dental caries without obvious evidence of active root canal infection. No abnormal uptake was seen in the healthy teeth of patients or in the six controls. The diagnostic sensitivity, specificity, positive and negative predictive values, and accuracy of FMISO PET scan in detecting odontogenic infections were 93%, 97%, 84%, 99% and 96%, respectively.¹⁸F-fluoride ion bone scan done in three patients showed that¹⁸F-fluoride ion plays no role in the demonstration of anaerobic odontogenic infection. FMISO PET scan is a sensitive method for the detection of anaerobic odontogenic infections, and may play a complementary role in the evaluation of the dental condition of patients with head and neck tumours prior to radiation therapy.     

Autopilot design using mixed H2 and H∞ optimal control

An autopilot for a transport aircraft is designed using mixed H₂ and H∞ optimal control. The control law design technique allows real parameter uncertainty to be accounted for in the design process. The autopilot consists of an inner loop that controls aircraft heading in response to external commands and an outer loop that tracks a localizer beam so that the aircraft is properly aligned with the runway for landing. The problem formulation and the robust control law design technique allow a wide range of performance and robustness requirements to be met. Analysis of the closed-loop system shows the controller performance and robustness for a number of flight conditions through two separate approach profiles.