Gastrectomy in Advanced Gastric Cancer Effectively Palliates Symptoms and May Improve Survival in Select Patients

Background

The role of gastrectomy in the face of incurable gastric cancer is evolving. We sought to evaluate our experience with incomplete (i.e., R2) gastrectomy in advanced gastric cancer.

Methods

We reviewed 210 locally advanced or metastatic gastric cancers (1992–2008). Patient characteristics and outcomes were compared between three groups: gastrectomy (N?=?99), exploration without resection (N?=?66), and no surgery (N?=?45).

Results

Clinicopathologic characteristics were similar between groups. Symptoms successfully resolved after gastrectomy in 48 % with a complication rate of 32 % and mortality of 6 %. Overall median survival for all patients was 6.2 months: 10.0 months after gastrectomy, 4.1 months after exploration without resection, and 5.3 months for no surgery (p?<?0.001). Perioperative complications were the only predictor of symptom resolution following resection (OR?=?0.175). Resolution of symptoms (p?<?0.001, Hazards Ratio (HR)?=?0.09) and preoperative nausea/vomiting (p?=?0.017, HR?=?0.55) improved survival, while linitis plastica (p?=?0.035, HR?=?4.05) and spindle cell morphology (p?=?0.011, HR?=?1.98) were predictors of poor survival in patients undergoing resection.

Conclusions

Gastrectomy in the setting of advanced gastric cancer may be useful in up to half of patients with an acceptable perioperative mortality rate. Symptom resolution offers a potential survival advantage but is dependent upon a complication-free course, so should only be considered selectively.     

Biomechanical analysis of the upper thoracic spine after decompressive procedures

Background contextDecompressive procedures such as laminectomy, facetectomy, and costotransversectomy are routinely performed for various pathologies in the thoracic spine. The thoracic spine is unique, in part, because of the sternocostovertebral articulations that provide additional strength to the region relative to the cervical and lumbar spines. During decompressive surgeries, stability is compromised at a presently unknown point.PurposeTo evaluate thoracic spinal stability after common surgical decompressive procedures in thoracic spines with intact sternocostovertebral articulations.Study designBiomechanical cadaveric study.MethodsFresh-frozen human cadaveric spine specimens with intact rib cages, C7–L1 (n=9), were used. An industrial robot tested all spines in axial rotation (AR), lateral bending (LB), and flexion-extension (FE) by applying pure moments (±5 Nm). The specimens were first tested in their intact state and then tested after each of the following sequential surgical decompressive procedures at T4–T5 consisting of laminectomy; unilateral facetectomy; unilateral costotransversectomy, and subsequently instrumented fusion from T3–T7.ResultsWe found that in all three planes of motion, the sequential decompressive procedures caused no statistically significant change in motion between T3–T7 or T1–T12 when compared with intact. In comparing between intact and instrumented specimens, our study found that instrumentation reduced global range of motion (ROM) between T1–T12 by 16.3% (p=.001), 12% (p=.002), and 18.4% (p=.0004) for AR, FE, and LB, respectively. Age showed a negative correlation with motion in FE (r=?0.78, p=.01) and AR (r=?0.7, p=.04).ConclusionsThoracic spine stability was not significantly affected by sequential decompressive procedures in thoracic segments at the level of the true ribs in all three planes of motion in intact thoracic specimens. Age appeared to negatively correlate with ROM of the specimen. Our study suggests that thoracic spinal stability is maintained immediately after unilateral decompression at the level of the true ribs. These preliminary observations, however, do not depict the long-term sequelae of such procedures and warrant further investigation.     

A Clinical Pathway for Total Shoulder Arthroplasty—A Pilot Study

Background

Appropriate pain management after total shoulder arthroplasty (TSA) facilitates rehabilitation and may improve clinical outcomes.

Questions/purposes

This prospective, observational study evaluated a multimodal analgesia clinical pathway for TSA.

Methods

Ten TSA patients received an interscalene nerve block (25 cm³ 0.375% ropivacaine) with intraoperative general anesthesia. Postoperative analgesia included regularly scheduled non-opioid analgesics (meloxicam, acetaminophen, and pregabalin) and opioids on demand (oral oxycodone and intravenous patient-controlled hydromorphone). Patients were evaluated twice daily to assess pain, anterior deltoid strength, handgrip strength, and sensory function.

Results

The nerve block lasted an average of 18 h. Patients had minimal pain after surgery; 0 (median score on a 0–10 scale) in the Post-Anesthesia Care Unit (PACU) but increased on postoperative day (POD) 1 to 2.3 (0.0, 3.8; median (25%, 75%)) at rest and 3.8 (2.1, 6.1) with movement. Half of the patients activated the patient-controlled analgesia four or fewer times in the first 24 h after surgery. Operative anterior deltoid strength was 0 in the PACU but returned to 68% by POD 1. Operative hand strength was 0 (median) in the PACU, but the third quartile (75%) had normalized strength 49% of preoperative value.

Conclusions

Patients did well with this multimodal analgesic protocol. Pain scores were low, half of the patients used little or no intravenous opiate, and some patients had good handgrip strength. Future research can focus on increasing duration of analgesia from the nerve block, minimizing motor block, lowering pain scores, and avoiding intravenous opioids.     

Evidence for safe tourniquet use in 500 consecutive upper extremity procedures

Background

Although pneumatic tourniquets are widely used in upper extremity surgery, further evidence is needed to support their safe use. Excessive pressure and prolonged ischemic time can cause soft-tissue injury. The purpose of this study was to determine the safety of tourniquet use in a yearlong, consecutive series of patients.

Methods

A retrospective review of all patients who underwent upper extremity surgery by two board-certified hand surgeons over a 1-year period was performed. Demographic variables, comorbidities, and complications were noted along with tourniquet parameters, including application site, ischemic pressure, and time.

Results

A total 505 patients were included in the study because a tourniquet was used during their operation. Patients ranged in age from 3 months to 90 years old (mean 40.1 years). More than half of the population was overweight (mean body mass index (BMI) 27.1), and 77.1 % of adults had at least one cardiac risk factor. No immediate or delayed tourniquet-related injuries were identified. The average operative time was 35.9 min, with an average tourniquet time of 33.1 min. Tourniquet inflation pressure of 250 or 225 mmHg was utilized in 78 and 21 % of adult patients, respectively; no patients had a pressure setting exceeding 275 mmHg.

Conclusion

In this series of more than 500 operations, there were no immediate or delayed tourniquet-related events using parameters determined perioperatively by the attending surgeon. Tourniquet pressures of 250 mmHg or less in adult patients with less than 2 h of ischemic time appear to be safe, even in the elderly and patients with multiple medical comorbidities.     

Liver biomarker and in vitro assessment confirm the hepatic origin of aminotransferase elevations lacking histopathological correlate in beagle dogs treated with GABAA receptor antagonist NP260

NP260 was designed as a first-in-class selective antagonist of α4-subtype GABA_A receptors that had promising efficacy in animal models of pain, epilepsy, psychosis, and anxiety. However, development of NP260 was complicated following a 28-day safety study in dogs in which pronounced elevations of serum aminotransferase levels were observed, although there was no accompanying histopathological indication of hepatocellular injury. To further investigate the liver effects of NP260, we assayed stored serum samples from the 28-day dog study for liver specific miRNA (miR-122) as well as enzymatic biomarkers glutamate dehydrogenase and sorbitol dehydrogenase, which indicate liver necrosis. Cytotoxicity assessments were conducted in hepatocytes derived from dog, rat, and human liver samples to address the species specificity of the liver response to NP260. All biomarkers, except ALT, returned toward baseline by Day 29 despite continued drug treatment, suggesting adaptation to the initial injury. In vitro analysis of the toxicity potential of NP260 to primary hepatocytes indicated a relative sensitivity of dog > human > rat, which may explain, in part, why the liver effects were not evident in the rodent safety studies. Taken together, the data indicate that a diagnostic biomarker approach, coupled with sensitive in vitro screening strategies, may facilitate interpretation of toxicity potential when an adaptive event masks the underlying toxicity.     

Nonclinical pharmacokinetics and metabolism of EPZ‐5676, a novel DOT1L histone methyltransferase inhibitor

(2R,3R,4S,5R)‐2‐(6‐Amino‐9H‐purin‐9‐yl)‐5‐((((1r,3S)‐3‐(2‐(5‐(tert‐butyl)‐1H‐benzo[d]imidazol‐2‐yl)ethyl)cyclobutyl)(isopropyl)amino)methyl)tetrahydrofuran‐3,4‐diol (EPZ‐5676) is a novel DOT1L histone methyltransferase inhibitor currently in clinical development for the treatment of MLL‐rearranged leukemias. This report describes the preclinical pharmacokinetics and metabolism of EPZ‐5676, an aminonucleoside analog with exquisite target potency and selectivity that has shown robust and durable tumor growth inhibition in preclinical models. The in vivo pharmacokinetics in mouse, rat and dog were characterized following i.v. and p.o. administration; EPZ‐5676 had moderate to high clearance, low oral bioavailability with a steady‐state volume of distribution 2–3 fold higher than total body water. EPZ‐5676 showed biexponential kinetics following i.v. administration, giving rise to a terminal elimination half‐life (t_1/2) of 1.1, 3.7 and 13.6 h in mouse, rat and dog, respectively. The corresponding in vitro ADME parameters were also studied and utilized for in vitro–in vivo extrapolation purposes. There was good agreement between the microsomal clearance and the in vivo clearance implicating hepatic oxidative metabolism as the predominant elimination route in preclinical species. Furthermore, low renal clearance was observed in mouse, approximating to f_u‐corrected glomerular filtration rate (GFR) and thus passive glomerular filtration. The metabolic pathways across species were studied in liver microsomes in which EPZ‐5676 was metabolized to three monohydroxylated metabolites (M1, M3 and M5), one N‐dealkylated product (M4) as well as an N‐oxide (M6). Copyright © 2014 John Wiley & Sons, Ltd.     

Project Kealahou: Improving Hawai‘i's System of Care for At-Risk Girls and Young Women through Gender-Responsive,Trauma-Informed Care

Project Kealahou (PK) is a six-year, federally-funded program aimed at improving services and outcomes for Hawai‘i''s female youth who are at risk for running away, truancy, abuse, suicide, arrest and incarceration. PK builds upon two decades of sustained cross-agency efforts among the state''s mental health, juvenile justice, education, and child welfare systems to promote system-of-care (SOC) principles of community-based, individualized, culturally and linguistically competent, family driven, youth-guided, and evidence-based services. In addition, PK emphasizes trauma-informed and gender-responsive care in serving its target population of females ages 11–18 years who have experienced psychological trauma.Results from the first four years of the implementation of PK in the Department of Health''s (DOH) Child and Adolescent Mental Health Division (CAMHD) highlight the serious familial, socioeconomic, functional, and interpersonal challenges faced by the young women who receive services in Hawai‘i''s SOC. Despite the challenges faced by PK youth and their families, preliminary results of the evaluation of PK show significant improvements across multiple clinical and functional domains of service recipients. A financial analysis indicates that these outcomes were obtained with a minimal overall increase in costs when compared to standard care alone. Overall, these results suggest that PK may offer a cost effective way to improve access, care, and outcomes for at-risk youth and their families in Hawai‘i.     

A probabilistic method to estimate the burden of maternal morbidity in resource-poor settings: preliminary development and evaluation

Background

Maternal morbidity is more common than maternal death, and population-based estimates of the burden of maternal morbidity could provide important indicators for monitoring trends, priority setting and evaluating the health impact of interventions. Methods based on lay reporting of obstetric events have been shown to lack specificity and there is a need for new approaches to measure the population burden of maternal morbidity. A computer-based probabilistic tool was developed to estimate the likelihood of maternal morbidity and its causes based on self-reported symptoms and pregnancy/delivery experiences. Development involved the use of training datasets of signs, symptoms and causes of morbidity from 1734 facility-based deliveries in Benin and Burkina Faso, as well as expert review. Preliminary evaluation of the method compared the burden of maternal morbidity and specific causes from the probabilistic tool with clinical classifications of 489 recently-delivered women from Benin, Bangladesh and India.

Results

Using training datasets, it was possible to create a probabilistic tool that handled uncertainty of women’s self reports of pregnancy and delivery experiences in a unique way to estimate population-level burdens of maternal morbidity and specific causes that compared well with clinical classifications of the same data. When applied to test datasets, the method overestimated the burden of morbidity compared with clinical review, although possible conceptual and methodological reasons for this were identified.

Conclusion

The probabilistic method shows promise and may offer opportunities for standardised measurement of maternal morbidity that allows for the uncertainty of women’s self-reported symptoms in retrospective interviews. However, important discrepancies with clinical classifications were observed and the method requires further development, refinement and evaluation in a range of settings.

     

Ingestion and sublethal effects of physically and chemically dispersed crude oil on marine planktonic copepods

Planktonic copepods play a key function in marine ecosystems, however, little is known about the effects of dispersants and chemically dispersed crude oil on these important planktonic organisms. We examined the potential for the copepods Acartia tonsa, Temora turbinata and Parvocalanus crassirostris to ingest crude oil droplets and determined the acute toxicity of the dispersant Corexit^® 9500A, and physically and chemically dispersed crude oil to these copepods. We detected ingestion of crude oil droplets by adults and nauplii of the three copepod species. Exposure to crude oil alone (1 µL L^?1, 48 h) caused a reduction of egg production rates (EPRs) by 26–39 %, fecal pellet production rates (PPRs) by 11–27 %, and egg hatching (EH) by 1–38 % compared to the controls, depending on the species. Dispersant alone (0.05 µL L^?1, 48 h) produced a reduction in EPR, PPR and EH by 20–35, 12–23 and 2–11 %, respectively. Dispersant-treated crude oil was the most toxic treatment, ~1.6 times more toxic than crude oil alone, causing a reduction in EPR, PPR and EH by 45–54, 28–41 and 11–31 %, respectively. Our results indicate that low concentrations of dispersant Corexit 9500A and chemically dispersed crude oil are toxic to marine zooplankton, and that the ingestion of crude oil droplets by copepods may be an important route by which crude oil pollution can enter marine food webs.     

Drug Carriers Based on Graphene Oxide and Hydrogel: Opportunities and Challenges in Infection Control Tested by Amoxicillin Release

Graphene oxide (GO) was proposed as an efficient carrier of antibiotics. The model drug, amoxicillin (AMOX), was attached to GO using a peptide linker (Leu-Leu-Gly). GO-AMOX was dispersed in a hydrogel to which the enzyme responsible for releasing AMOX from GO was also added. The drug molecules were released by enzymatic hydrolysis of the peptide bond in the linker. As the selected enzyme, bromelain, a plant enzyme, was used. The antibacterial nature of the carrier was determined by its ability to inhibit the growth of the Enterococcus faecalis strain, which is one of the bacterial species responsible for periodontal and root canal diseases. The prepared carrier contained only biocompatible substances, and the confirmation of its lack of cytotoxicity was verified based on the mouse fibrosarcoma cell line WEHI 164. The proposed type of preparation, as a universal carrier of many different antibiotic molecules, can be considered as a suitable solution in the treatment of inflammation in dentistry.