Oncofetal Chondroitin Sulfate Is a Highly Expressed Therapeutic Target in Non-Small Cell Lung Cancer.

Broad-spectrum therapeutics in non-small cell lung cancer (NSCLC) are in demand. Most human solid tumors express proteoglycans modified with distinct oncofetal chondroitin sulfate (CS) chains that can be detected and targeted with recombinant VAR2CSA (rVAR2) proteins and rVAR2-derived therapeutics. Here, we investigated expression and targetability of oncofetal CS expression in human NSCLC. High oncofetal CS expression is associated with shorter disease-free survival and poor overall survival of clinically annotated stage I and II NSCLC patients (n = 493). Oncofetal CS qualifies as an independent prognosticator of NSCLC in males and smokers, and high oncofetal CS levels are more prevalent in EGFR/KRAS wild-type cases, as compared to mutation cases. NSCLC cell lines express oncofetal CS-modified proteoglycans that can be specifically detected and targeted by rVAR2 proteins in a CSA-dependent manner. Importantly, a novel VAR2-drug conjugate (VDC-MMAE) efficiently eliminates NSCLC cells in vitro and in vivo. In summary, oncofetal CS is a prognostic biomarker and an actionable glycosaminoglycan target in NSCLC.

In Vivo Delivery of a DNA-Encoded Monoclonal Antibody Protects Non-human Primates against Zika Virus.

Zika virus (ZIKV) infection is endemic to several world regions, and many others are at high risk for seasonal outbreaks. Synthetic DNA-encoded monoclonal antibody (DMAb) is an approach that enables in vivo delivery of highly potent mAbs to control infections. We engineered DMAb-ZK190, encoding the mAb ZK190 neutralizing antibody, which targets the ZIKV E protein DIII domain. In vivo-delivered DMAb-ZK190 achieved expression levels persisting >10 weeks in mice and >3 weeks in non-human primate (NHPs), which is protective against ZIKV infectious challenge. This study is the first demonstration of infectious disease control in NHPs following in vivo delivery of a nucleic acid-encoded antibody, supporting the importance of this new platform.

Adapting the Ideas of Translational Science for Translational Family Science.

Family science has been doing translational science since before it came into vogue. Nevertheless, the field has been subjected to the same forces in the broader academy that have created a widening chasm between discovery and practice. Thus, the primary objective of this article is to translate the principles, concepts, and models of translational science to solidify an identity for family science and help the field move forward in broader academic, care delivery, and policy arenas. Alternative models of translational science, primarily from biomedicine but also from other disciplines, are reviewed and critically analyzed, and core concepts and principles are isolated, elaborated, and applied to family science. Family science's long-standing commitment to the doctrine of evidence-based practice, and its ongoing endorsement of the principles of scientific duality and multidisciplinary utility, places it in a preeminent position for using the zeitgeist of translational science to move forward. Nonetheless, the field has important epistemological, practical, professional, and curricular steps to complete to better position itself as a distinct and valued body of scientists. Ultimately, we argue that embracing the principles, concepts, and models of translational science should be leveraged by family science to help brand itself as a unique and essential social science field for enhancing the human condition.

Relevance of platinum-sensitivity status in relapsed/refractory extensive-stage small-cell lung cancer in the modern era: a patient-level analysis of southwest oncology group trials.

BACKGROUND: Extensive-stage small-cell lung cancer (SCLC) patients who progress after platinum-based chemotherapy are traditionally categorized as platinum sensitive (progression ≥ 90 days from last platinum dose) or refractory (progression < 90 days), a practice arising from seminal observations of worse survival in refractory patients. Subsequent trials accounted for platinum sensitivity, resulting in higher sample sizes and increased resource use. METHODS: To assess whether platinum-sensitivity status remains associated with outcomes, patient-level data from recent Southwest Oncology Group trials in second- and/or third-line extensive-stage SCLC were pooled. Hazard ratios (HRs) for progression-free survival (PFS) and overall survival (OS) accounting for platinum sensitivity were calculated using unadjusted and adjusted Cox Proportional Hazard models. Recursive partitioning was performed to define prognostic risk groups. RESULTS: Of 329 patients, 151 were platinum sensitive and 178 refractory. HRs from unadjusted Cox PFS and OS models for refractory versus sensitive disease were 1.0 (95% confidence interval, 0.81-1.25; p = 0.98) and 1.24 (0.99-1.57; p = 0.06), respectively. Adjusted Cox models showed that only elevated serum lactate dehydrogenase (HR, 2.04; p < 0.001), males (HR, 1.36; p = 0.04), performance status of 1 (HR, 1.25; p = 0.02), and weight loss greater than or equal to 5% (1.53, p = 0.01) were independently associated with OS. Platinum-sensitivity status was not associated with PFS (HR, 1.11; p = 0.49) or OS (HR, 1.25; p = 0.14), except in a model that excluded 36 patients who received more than one prior chemotherapy regimen (HR, 1.34; p = 0.049). Prognostic groups with differential OS outcomes (high, intermediate, and poor risk) were identified. CONCLUSIONS: Platinum-sensitivity status may no longer be strongly associated with PFS or OS in at least one multivariate model. Validation of prognostic risk groups identified here is warranted. These data have critical implications in the design of future SCLC trials.

Southwest Oncology Group S0802: a randomized, phase II trial of weekly topotecan with and without ziv-aflibercept in patients with platinum-treated small-cell lung cancer.

PURPOSE: Development of new therapies for previously treated small-cell lung cancer (SCLC) is a major unmet need. Here, we describe a randomized, phase II trial of weekly topotecan with or without ziv-aflibercept (VEGF-trap) in this clinical setting. PATIENTS AND METHODS: Patients with previously treated SCLC (one line of platinum-based chemotherapy), performance status of 0 to 1, adequate organ function, treated brain metastases, and no recent vascular events or bleeding diatheses were eligible. Eligible patients were stratified as platinum-sensitive or platinum-refractory and randomly assigned to receive weekly topotecan 4 mg/m(2) intravenously (IV) with or without ziv-aflibercept 6 mg/kg IV every 21 days. Progression-free survival (PFS) at 3 months was the primary end point. RESULTS: In 189 randomly assigned patients, treatment arms were well balanced with regard to clinical characteristics. The 3-month PFS was significantly improved with the addition of ziv-aflibercept in patients who had platinum-refractory disease (27% v 10%; P = .02) but not in patients with platinum-sensitive disease (24% v 15%; P = .22). Although response rate was low, disease control rate was higher with combination therapy than with topotecan alone in patients who had platinum-sensitive disease (37% v 18%; P = .05) and in those who had platinum-refractory disease (25% v 15%; P = .14). Overall survival (OS) was not significantly improved in either strata. Grades 3 to 5 toxicities were more common with the addition of ziv-aflibercept. CONCLUSION: Ziv-aflibercept improved the 3-month PFS in patients who had platinum-refractory SCLC, but its addition increased toxicity. OS was similar with combined ziv-aflibercept and topotecan compared with topotecan in both strata.

FN14 expression correlates with MET in NSCLC and promotes MET-driven cell invasion.

The five-year survival rate in advanced non-small cell lung cancer (NSCLC) remains below ten percent. The invasive and metastatic nature of NSCLC tumor cells contributes to the high mortality rate, and as such the mechanisms that govern NSCLC metastasis is an active area of investigation. Two surface receptors that influence NSCLC invasion and metastasis are the hepatocyte growth factor receptor (HGFR/MET) and fibroblast growth factor-inducible 14 (FN14). MET protein is over-expressed in NSCLC tumors and associated with poor clinical outcome and metastasis. FN14 protein is also elevated in NSCLC tumors and positively correlates with tumor cell migration and invasion. In this report, we show that MET and FN14 protein expressions are significantly correlated in human primary NSCLC tumors, and the protein levels of MET and FN14 are elevated in metastatic lesions relative to patient-matched primary tumors. In vitro, HGF/MET activation significantly enhances FN14 mRNA and protein expression. Importantly, depletion of FN14 is sufficient to inhibit MET-driven NSCLC tumor cell migration and invasion in vitro. This work suggests that MET and FN14 protein expressions are associated with the invasive and metastatic potential of NSCLC. Receptor-targeted therapeutics for both MET and FN14 are in clinical development, the use of which may mitigate the metastatic potential of NSCLC.

Objective review of mediastinal lymph node examination in a lung cancer resection cohort.

BACKGROUND: Accurate staging of resected lung cancer requires mediastinal lymph node (MLN) examination. MLN dissection (MLND) and systematic sampling (SS) are acceptable procedures; random sampling (RS) and no sampling (NS) are not. Forty percent of US lung cancer resections have NS. We closely examined the pattern of MLN examination in a lung resection cohort. METHODS: This is a retrospective review of all lung cancer resections in Memphis, TN, from 2004 to 2007. We compared operating surgeons' claims to the pathology report and an audit of the operation narrative by an independent surgeon. RESULTS: Forty-five percent of resections were reported by surgeons as MLND, 8% RS, and 48% NS. None met pathology criteria for MLND, 9% were SS, 50% were RS, and 42% were NS. The concordance rate between the operating surgeon and pathology report was 39%. The surgeon audit suggested 29% of resections had MLND, 26% RS, and 45% NS. Concordance between operating and auditing surgeons was 71%. Sublobar resection, T1 stage, and age were associated with NS. CONCLUSIONS: Most resections had suboptimal MLN examination. Concordance was poor between surgeon claims, objective review of pathology reports, and an independent surgeon audit. The higher concordance between operating and auditing surgeons may suggest incomplete pathology examination of MLN material. The terms used by operating surgeons to describe MLN retrieval were often inaccurate.

Pathologic lymph node staging practice and stage-predicted survival after resection of lung cancer.

BACKGROUND: Lymph node status is the most important prognostic factor in resectable nonsmall-cell lung cancer (NSCLC). We examined the relationship between the pattern of lymph node examination (including the number and anatomic location of resected lymph nodes), pathologic nodal stage, and survival after NSCLC resection. METHODS: Retrospective review of all NSCLC resections in the Memphis Metropolitan Area from January 1, 2004, to December 31, 2007. RESULTS: In 656 resections, the number of lymph nodes examined differed significantly between patients grouped by pathologic nodal stage (p<0.0001) and extent of resection (p<0.001). Thirty-seven percent of "mediastinal node-negative" patients had no mediastinal lymph nodes examined. Patients with pN1 and no mediastinal lymph node examination had better [corrected] survival than patients with mediastinal lymph node examination (p < 0.02) . Approximately 10% of patients with pN0 and pN2 disease had no hilar/intrapulmonary lymph nodes examined. CONCLUSIONS: Suboptimal lymph node staging was prevalent in this cohort. Large proportions of pN1 and pN0 patients were probably understaged. In patients with pathologic positive pulmonary/hilar lymph nodes, mediastinal lymph node examination was associated with poorer survival [corrected]. Interventions are needed to improve lymph node staging of NSCLC.

Quality of surgical resection for nonsmall cell lung cancer in a US metropolitan area.

BACKGROUND: Curative treatment of early stage nonsmall cell lung cancer (NSCLC) requires good quality surgical resection (GQR). The degree of compliance with national recommendations for GQR is poorly defined. We sought to quantitatively define the degree of compliance in a consecutive series of NSCLC resections. METHODS: Medical records of patients who underwent curative-intent resection for NSCLC in the Memphis, TN metropolitan area from January 1, 2004 to December 31, 2007 were retrospectively reviewed (N = 746 patients). GQR criteria were obtained from the National Comprehensive Cancer Network (NCCN), the RADIANT adjuvant study of erlotinib, and the American College of Surgeons Oncology Group (ACOSOG) Z0030 study. Factors associated with or without achievement of GQR were evaluated. Categorical variables were compared using chi-square or Fisher exact test, and survival curves by the log-rank test. RESULTS: Twenty-three and one-half percent of patients met GQR criteria as established by RADIANT, 8.2% by NCCN, and 0.9% by ACOSOG. The most common limiting factor in achieving GQR was inadequate lymph node sampling. The only patient factor associated with GQR was race (African-Americans were more likely than Caucasians to have GQR per RADIANT and NCCN criteria [P = .022 and P = .0489, respectively]). There was no significant survival difference between GQR and non-GQR patients. CONCLUSIONS: The vast majority of curative-intent resections did not achieve GQR standards. The greatest deficit is in surgical sampling of mediastinal (Level 2) lymph nodes, but evaluation of Level 1 lymph nodes is also suboptimal. Interventions are needed to improve current surgical practices and achieve minimum standards for accurate staging, prognostication, and eligibility for clinical trials.

Epidermal growth factor receptor polymorphisms and risk for toxicity in paediatric patients treated with gefitinib.

PURPOSE: To investigate associations between germline genetic variations in the epidermal growth factor receptor (EGFR) and toxicity in paediatric patients treated with gefitinib. PATIENTS AND METHODS: Gefitinib treatment and toxicity data from five paediatric clinical trials were combined. EGFR genotypes evaluated included -191C>A, -216G>T, Arg497Lys and intron 1 CA sequence repeat number. The genetic variations were evaluated for associations with grade one or greater rash or diarrhoea during the first course of treatment. RESULTS: The analysis included 110 patients, 60 (55%) with grade one or greater rash and 47 (43%) with grade one or greater diarrhoea. Among patients with the -216 GG (n=51), GT (n=41) and TT (n=16) genotypes, grade one or greater rash occurred in 52.9%, 46.3% and 87.5% of patients (p=0.003, recessive model), respectively. Diarrhoea occurred in 27.5%, 58.5% and 43.8% of patients with respective GG, GT and TT genotypes (p=0.004, dominant model). The -191C>A, intron 1 CA repeat number and Arg497Lys genotypes were not significantly associated with either rash or diarrhoea. EGFR -216 and -191 polymorphisms were in linkage disequilibrium (D'=0.66, p=0.01). The haplotype (-191C, -216T) was associated with increased risk for rash (p=0.049), but was not more predictive of rash than the single -216 polymorphism. CONCLUSION: These findings indicate that EGFR -216G>T genotype is a predictive marker for the development of skin rash and diarrhoea in paediatric patients treated with gefitinib. Continued investigation of relationships between germline EGFR polymorphisms and the efficacy of EGFR inhibitors in paediatric patients is warranted.

Outcome of surgical resection for pathologic N0 and Nx non-small cell lung cancer.

PURPOSE: Metastasis to lymph nodes (LNs) connotes poor prognosis in non-small cell lung cancer (NSCLC). Sufficient LNs must be examined to accurately determine LN negativity. Patients with no LNs examined (pNx) have an indeterminate stage, may have undetected disease and erroneous assignment to a low-risk group. To evaluate this possibility, we compared the survival of patients with node-negative disease and at least one LN examined (pN0) to those with pNx. METHODS: Retrospective analysis of all resections for NSCLC from January 1, 2004 to December 31, 2007 at hospitals in the Memphis Metropolitan Area. RESULTS: Of 746 resections, 90 (12.1%) were Nx; 506 (67.8%) N0. Demographic and histologic characteristics were similar. A total of 54.4% Nx patients had sublobar resection, compared with 5.5% N0 (p < 0.0001). In the N0 cohort, the median (range) number of LNs was 5 (1-45); N1 LNs, 3 (0-38); N2 LNs, 1 (0-29); 35.4% had no mediastinal LNs examined; 9.1% had only mediastinal LNs. Eighty- five percent of N0 patients had less than 10 LNs. The 3-year survival estimate for the T1NxM0 versus T1N0M0 patients was 70% versus 79% (p = 0.17); for T2NxM0 versus T2N0M0, it was 25% versus 65% (p < 0.01). CONCLUSIONS: A high percentage of patients undergoing surgical resection for NSCLC have no LNs examined, most of these patients have had sublobar resection. Majority with node-negative disease have fewer than 10 LNs, a large proportion have no mediastinal LNs, raising the possibility of understaging. Patients with pT2Nx do significantly worse than those with pT2N0.

Complications of bariatric surgery: implications for the covering physician.

Bariatric surgery is the only effective option for sustained weight loss for morbidly obese patients. The increasing prevalence of obesity in America and the application of a laparoscopic approach to bariatric surgery have combined to dramatically increase the number of patients undergoing these types of operations. The number of bariatric surgeons and centers devoted to surgery of the morbidly obese is also rising. These facts lead to the assumption that there will be more patients with complications specific to bariatric surgery that must be cared for by general surgeons in the immediate future. Covering surgeons and those without expertise in bariatric surgery need to know how to diagnose and manage these potential complications in emergent and outpatient settings. This paper reviews some of the more common bariatric operations, complications, and conservative treatment options.

An assessment of the antinociceptive efficacy of intrathecal and epidural contulakin-G in rats and dogs.

Contulakin-G is a novel conopeptide with an incompletely defined mechanism of action. To assess nociceptive activity we delivered Contulakin-G as a bolus intrathecally (0.03, 0.1, 0.3, 3 nmol) or epidurally (10, 30, 89 nmol) in rats. Intrathecal Contulakin G significantly decreased Phase II and, to a lesser degree, Phase I paw flinching produced by intradermal formalin. Intrathecal and epidural doses of ED50s were 0.07 nmol and 45 nmol, respectively, giving an epidural/intrathecal ED50 ratio = 647). In dogs, intrathecal Contulakin-G (50-500 nmoL) produced a dose-dependent increase in the thermally evoked skin twitch latency by 30 min after administration, as did morphine (150 and 450 nmol). Epidural morphine (750 and 7500 nmol), but not epidural 1000 nmol Contulakin-G, also significantly decreased skin twitch in dogs. No changes in motor function were seen in any rats or dogs receiving these doses of Contulakin-G. In dogs, no physiologically significant dose-dependent changes in motor function, heart rate, arterial blood pressure, or body temperature were found. Contulakin-G is a potent antinociceptive drug when delivered intrathecally with no observable negative side effects in rats or dogs and may provide an alternative to opioid spinal analgesics.

Time course and role of morphine dose and concentration in intrathecal granuloma formation in dogs: a combined magnetic resonance imaging and histopathology investigation.

BACKGROUND: Intrathecal morphine infusion leads to intrathecal granulomas. In dogs, the authors examined time course of granuloma formation and the role of concentration in granuloma development. METHODS: Dogs were prepared with lumbar intrathecal catheters and vest-mounted pumps. To define the time course of granuloma formation, serial magnetic resonance imaging was performed in animals receiving 10 or 31 days of morphine infusion (12.5 mg/ml at 40 microl/h). At these times, morphine was removed from the infusate, and further magnetic resonance images were acquired over 14-35 additional days. To assess dose versus concentration, dogs received 28-day infusions of vehicle, 12 mg morphine/day as 12.5 mg/ml at 40 microl/h, or 1.5 mg/ml at 334 microl/h (12 mg/day) for 28 days. Additional dogs received 3 mg/day as 12.5 mg/ml at 10 mul/h. RESULTS: Serial magnetic resonance images in dogs receiving morphine (12.5 mg/ml at 40 microl/h) revealed pericatheter-enhancing tissues as early as 3 days with a prominent signal by 10 days. Removal of morphine reduced the mass volume within 7 days. At a fixed infusion rate, the incidence of granuloma formation with the continuous intrathecal infusion of morphine ranged from 0 in vehicle-treated dogs to 100% in dogs treated with 12.5 mg/ml at 40 microl/h (12 mg/day). Infusion of 12 mg/day at 1.5 mg/ml (334 microl/h) resulted in granuloma in one of four animals. The authors found that infusion of morphine in different concentrations at a fixed rate resulted in a dose-dependent increase in concentration, with the granuloma-producing, dose-yielding lumbar cerebrospinal fluid morphine concentrations around 40 microg/ml. CONCLUSIONS: Serial magnetic resonance imaging showed a rapid formation and regression of the masses initiated by intrathecal morphine infusion. These masses are dependent on local concentration.

Opiate pharmacology of intrathecal granulomas.

BACKGROUND: Chronic intrathecal morphine infusion produces intradural granulomas. The authors examined a variety of opioids infused intrathecal for analgesic activity and toxicity. METHODS: Two sets of experiments were undertaken in dogs with chronic intrathecal catheters: (1) Six-hour intrathecal infusions were used to determine the full analgesic dose and the maximum tolerated dose. (2) To establish toxicity, the maximum tolerated dose was given for up to 28 days by continuous intrathecal infusion. Drugs examined were morphine sulfate, hydromorphone, D/L-methadone, L-methadone, D-methadone, fentanyl, [d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO), naloxone, or saline. RESULTS ANALGESIA AND TOLERABILITY: Six-hour intrathecal infusion of agonists resulted in a time-dependent increase in thermal escape latency. At higher concentrations, dose-limiting motor dysfunction and sedation occurred, and hypersensitivity occurred. The concentrations, in mg/ml, for full analgesic dose/maximum tolerated dose were as follows: morphine, 0.9/12.0; hydromorphone, 1.0/3.0; D/L-methadone, 2.8/3; L-methadone, 1.0/> 1.0; fentanyl, 0.3/2.0; DAMGO, 0.1/> 2.0; D-methadone, > 1/> 1; naloxone, > 10/> 10. SPINAL PATHOLOGY: Chronic intrathecal infusion of the maximum tolerated dose revealed 100% intradural granuloma formation after morphine, hydromorphone, L-methadone, and naloxone. DAMGO induced a mass in only a single animal (one of three). D/L- and D-methadone produced intradural granulomas but were also associated with parenchymal necrosis. Saline and fentanyl animals displayed no granulomas. CONCLUSIONS: Intrathecal opiate-induced granulomas are not strictly dependent on opioid receptor activation. Therefore, opiates at equianalgesic doses present different risks for granuloma formation. Importantly, D/L- and D-methadone also resulted in parenchymal necrosis, an affect associated with the N-methyl-D-aspartate antagonist action of the D-isomer.

Safety evaluation of intrathecal substance P-saporin, a targeted neurotoxin, in dogs.

Intrathecal (IT) substance P-Saporin (SP-SAP), a 33-kDa-targeted neurotoxin, produces selective destruction of superficial neurokinin 1 receptor (NK1r)-bearing cells in the spinal dorsal horn. In rats, SP-SAP prevents the formation of hyperalgesia and can reverse established neuropathic pain behavior in rodents. To determine the safety of this therapeutic modality in a large animal model, beagles received bolus IT lumbar injections of vehicle, SP-SAP (1.5, 15, 45, or 150 microg), or a nontargeted preparation of saporin (SAP, 150 microg) for immunohistological analysis of spinal cords. Doses of 15 microg SP-SAP and above produced a significant and equivalent loss of NK1r-bearing cells and dendrites in lumbar laminae II and I compared to vehicle- or SAP-treated animals. Cervical regions in all animals displayed no loss of NK1r immunoreactivity as compared to controls. Total numbers of neurons in the lumbar dorsal horn or alpha-motor neurons in the ventral horn demonstrated no significant changes. No increases in the astrocytic marker glial fibrillary acidic protein were noted following treatment with SP-SAP, suggesting a lack of generalized neurotoxicity. Additional dogs received doses of 1.5-150 microg SP-SAP or SAP and were sacrificed after 28 or 90 days to assess behavioral and physiological parameters. Although some acute motor signs were observed with both SP-SAP and SAP, no long-lasting significant events were noted in any of these animals. These data indicate no adverse toxicity at doses up to 10 times those necessary for producing loss of superficial NK1r-bearing neurons in a large animal model.

Further results of incorporating innovative procedures in a surgical residency.

The instruction in precipitously advancing surgical technologies remains a real challenge to every surgery program. Our institution's ongoing experience with an identified center for student and resident education and clinical investigation provides an option for addressing these needs in a general surgery residency. Over the past 8 years, we have developed and described previously the Center for Advanced Surgical Technologies (CAST) in a joint undertaking of the Department of Surgery and the Norton Hospital, an affiliated hospital on our medical school campus. The idea behind this program has been to focus and develop high-quality skills in the hospital in many areas of advanced technology. CAST has subsequently provided a vehicle for excellent clinical research as well as the development of specially focused advanced surgical technologies, fellowships, and a large number of publications that have often focused on new, advanced methods for imaging surgical disease and minimal access treatment. This program has had a very positive impact on the general surgery residency as a whole and has permitted a steadily advancing agenda of new technologies, while relegating recently emerged but perfected technologies into the central aspect of our accredited general surgery residency.

Assessment of acute thermal nociception in laboratory animals.

Models of acute nociception using a thermal stimulus are widely employed as screening methods for nociceptive properties of new drug compounds. In this chapter, detailed descriptions for conducting of two of the most commonly used models; the hot plate test and the "Hargreaves test," are described. These models are applicable to both rats and mice and have the advantage of allowing repeated and multiple testing using a single animal because the stimulus is transitory and produces no tissue damage. Additionally, a modification of these models using a skin-twitch reflex that is applicable to large laboratory animals such a dogs or sheep is described. Guidance concerning potential confounding variable are discussed, as are tips for reducing variably among testing sessions.