Treatment trends in oropharyngeal carcinoma: Surgical technology meets the epidemic.

OBJECTIVE: To characterize temporal trends in treatment patterns for oropharyngeal carcinoma, and to evaluate the emerging role of surgical therapy in the era of transoral robotic surgery (TORS). METHODS: Patients with oropharynx cancer between 2004 and 2016 identified using the National Cancer Database. Demographics and primary treatment modalities were obtained. Treatment was classified as surgery alone, surgery with radiation/chemotherapy, or primary radiation/chemotherapy. Annual distribution of cases treated by the various modalities was tabulated by site and early (I/II) versus late (III/IV) stage disease (AJCC 7th edition). The "TORS era" was defined as beginning in 2010. RESULTS: 149,534 patients were identified. The majority (56.8%) were treated with radiation ± chemotherapy. 53,069 patients had surgery as part of treatment, 72.6% (N = 38,533) of which received adjuvant therapy. 5293 TORS procedures were performed between 2010 and 2016 with trends away from open and other endoscopic procedures. Despite a 31.0% increase in the number of cases treated surgically from before TORS (2009) to 2016, the percentage of cases treated surgically decreased from 35.0% to 32.7%, with a 44.2% increase in non-surgical therapy. Increases in the percentage of patients treated surgically were observed for base of tongue tumors (24.3-25.2%) and early stage disease (59.9-62.2%). CONCLUSION: Despite the increase in the overall number of patients with oropharynx cancer, the percentages of patients treated surgically remains relatively stable. Notable increases were observed for base of tongue tumors and early stage disease.

Travel distance: Impact on stage of presentation and treatment choices in head and neck cancer.

OBJECTIVES: The objective was to examine the impact of travel distance on stage of presentation and treatment choices in head and neck squamous cell carcinoma in the rural setting. METHODS: 6029 cases diagnosed from 2002 to 2011 were obtained from the state cancer registry. Travel time was calculated to the nearest academic medical centers, otolaryngologist, and radiation treatment facilities. Multivariate logistic regression was used to examine the association of travel time with stage of presentation as well as the likelihood of appropriate therapy after adjustment for other demographic variables. RESULTS: Patients in the highest quartile for travel distance to academic centers were 33% more likely to present with early stage disease (p = 0.02), and 42% more likely to receive appropriate surgical therapy for oral cavity cancer. Patients were 70% more likely to receive appropriate surgery if they were farthest from the nearest radiation center (p = 0.03). Proximity to otolaryngology care was not significant. CONCLUSION: Increased travel distance to academic medical centers is associated with increased likelihood of proper therapy for surgically treated tumors of the head and neck. Impact on these findings on improvements in access to care is discussed.

Transoral robotic resection of a combined laryngocele.

This case report describes the use of trans-oral robotic surgery (TORS) for the excision of a combined laryngocele. Mixed or combined laryngoceles extend from the supraglottic larynx through the thyrohyoid membrane into the neck. Surgical excision for these benign lesions often requires combined external (transcervical) and internal (transoral endoscopic) approaches which carry significant morbidity. We present the case of a 37-year-old male who was diagnosed with a large laryngopyocele and was subsequently managed with a transoral excision using the da Vinci Si surgical robot system. The procedure was without complications and the patient was discharged on the second post-operative day on a full liquid diet supplemented with a naso-gastric feeding tube. Postoperative stroboscopy performed 1 month later demonstrated a well-healed hemilarynx and a normal voice. The patient is on a regular diet and now over three years removed from surgery with no evidence of recurrence. We conclude that TORS is an effective tool in the management of benign laryngeal pathology including combined laryngoceles, resulting in reduced morbidity.

Pharmaco-economics of levosimendan in cardiology: a European perspective.

INTRODUCTION: Heart failure places a significant economic burden on health care. Acute heart failure requires hospitalization and often frequent re-hospitalization in expensive wards where vasoactive rescue therapy is often added on top of standard medications. In these lean times, there is a growing need for cost-effective therapeutic options that supply superior support and in addition shorten the length of stay in hospital and reduce re-hospitalization rates. The inodilator levosimendan represents the latest addition to the vasoactive treatments of acute heart failure patients, and it appears to meet these expectations. Our aim was to answer the question whether the treatment efficacy of levosimendan - when selected as therapy for patients hospitalized for acute heart failure - brings savings to hospitals in various European countries representing different economies. METHODS AND RESULTS: We took a conservative approach and selected some a fortiori arguments to simplify the calculations. We selected seven European countries to represent different economies: Italy, Spain, Greece, Germany, Sweden, Finland and Israel. Data on the costs of medications and on the cost per day were collected and fed in a simple algorithm to detect savings. These saving varied from country to country, from a minimum of €0.50 in Germany to a maximum of €354.64 in Sweden. CONCLUSIONS: The use of levosimendan as a therapy for patients hospitalized for acute heart failure provides a net saving to hospitals driven by a reduction in the length of hospital stay. This finding is true in each of the countries considered in this study.

Preoperative and perioperative use of levosimendan in cardiac surgery: European expert opinion.

In cardiac surgery, postoperative low cardiac output has been shown to correlate with increased rates of organ failure and mortality. Catecholamines have been the standard therapy for many years, although they carry substantial risk for adverse cardiac and systemic effects, and have been reported to be associated with increased mortality. On the other hand, the calcium sensitiser and potassium channel opener levosimendan has been shown to improve cardiac function with no imbalance in oxygen consumption, and to have protective effects in other organs. Numerous clinical trials have indicated favourable cardiac and non-cardiac effects of preoperative and perioperative administration of levosimendan. A panel of 27 experts from 18 countries has now reviewed the literature on the use of levosimendan in on-pump and off-pump coronary artery bypass grafting and in heart valve surgery. This panel discussed the published evidence in these various settings, and agreed to vote on a set of questions related to the cardioprotective effects of levosimendan when administered preoperatively, with the purpose of reaching a consensus on which patients could benefit from the preoperative use of levosimendan and in which kind of procedures, and at which doses and timing should levosimendan be administered. Here, we present a systematic review of the literature to report on the completed and ongoing studies on levosimendan, including the newly commenced LEVO-CTS phase III study (NCT02025621), and on the consensus reached on the recommendations proposed for the use of preoperative levosimendan.

Repetitive use of levosimendan for treatment of chronic advanced heart failure: clinical evidence, practical considerations, and perspectives: an expert panel consensus.

BACKGROUND: The intravenous inodilator levosimendan was developed for the treatment of patients with acutely decompensated heart failure. In the last decade scientific and clinical interest has arisen for its repetitive or intermittent use in patients with advanced chronic, but not necessarily acutely decompensated, heart failure. Recent studies have suggested long-lasting favourable effects of levosimendan when administered repetitively, in terms of haemodynamic parameters, neurohormonal and inflammatory markers, and clinical outcomes. The existing data, however, requires further exploration to allow for definitive conclusions on the safety and clinical efficacy of repetitive use of levosimendan. METHODS AND RESULTS: A panel of 30 experts from 15 countries convened to review and discuss the existing data, and agreed on the patient groups that can be considered to potentially benefit from intermittent treatment with levosimendan. The panel gave recommendations regarding patient dosing and monitoring, derived from the available evidence and from clinical experience. CONCLUSIONS: The current data suggest that in selected patients and support out-of-hospital care, intermittent/repetitive levosimendan can be used in advanced heart failure to maintain patient stability. Further studies are needed to focus on morbidity and mortality outcomes, dosing intervals, and patient monitoring. Recommendations for the design of further clinical studies are made.

Endoscopic CO2 laser management of chemoradiation-related cricopharyngeal stenosis.

OBJECTIVE: Treatment of head and neck cancer with chemoradiation (CRT) can result in strictures of the cervical esophagus, often at the level of the cricopharyngeus. The objective of this study is to assess the feasibility of endoscopic CO2 laser cricopharyngeal myotomy for stricture ablation in the setting of prior CRT. METHODS: A retrospective review of patients who underwent endoscopic CO2 laser cricopharyngeal myotomy for dysphagia after radiation for squamous cell carcinoma of the head and neck (SCCHN). Pre- and postoperative barium swallow and swallowing assessment were performed before and after surgery. Outcomes and complication rates were examined. RESULTS: Endoscopic CO2 laser cricopharyngeal myotomy was performed in 10 patients with dysphagia secondary to cricopharyngeal stenosis/stricture, which developed following treatment for SCCHN with chemoradiation. All patients demonstrated radiographic improvement in stricture, with complete resolution of stricture in 9 of 10 patients. All patients noted improvement in dysphagia with 9 of 10 patients demonstrating significant advancement of diet by modified barium swallow. No complications were observed. CONCLUSION: Endoscopic CO2 cricopharyngeal myotomy can be performed safely in the setting of prior CRT, with significant improvement in swallowing in select patients. Indications and technical considerations will be discussed.

Microvascular reconstruction after intra-arterial chemotherapy with concomitant radiation.

OBJECTIVE: While the success of microvascular reconstruction is well established, even in the setting of prior radiotherapy, the outcomes in the setting of prior chemoradiation are less well documented. We present our experience with microvascular reconstruction in a unique cohort of patients previously treated with concomitant hyperfractionated radiation and intra-arterial chemotherapy (HYPERRADPLAT). Despite the observation in prior studies of minimal vessel damage in this setting, the hypothesis of this study is that in the late setting of most salvage surgical therapy, either for recurrence or osteoradionecrosis, a different, progressive level of vessel injury may be encountered. STUDY DESIGN: Case series with chart review. SETTING: Tertiary referral academic medical center practice. SUBJECTS AND METHODS: Eighty-four patients received primary treatment for advanced head and neck squamous cell carcinoma with HYPERRADPLAT. Of these, 8 patients (10%) underwent free tissue transfer reconstruction and a total of 11 free flaps. RESULTS: Wound breakdown, fistula, or both occurred postoperatively in 50% (4/8) of these patients. No complications of the venous anastomoses occurred. Fifty percent (4/8) of patients required return to surgery for arterial failure due to thrombosis of the anastomosis. Two cases of these flaps could not be salvaged. CONCLUSION: Microvascular reconstruction following HYPERRADPLAT appears to result in a high number of arterial related complications. This experience implies an important delayed treatment effect of HYPERRADPLAT occurs upon recipient arteries. The manner in which this effect may occur in recipient arteries in the setting of more conventional chemoradiation requires further study.

How bilateral iliolumbar fusion increases the stability of horizontal osteosynthesis in unstable pelvic ring injuries?

OBJECTIVE: In type C pelvic ring injuries, the operative stabilization of the posterior ring is absolutely indicated. There exist four different types of operative methods: iliosacral screw fixation, transsacral plate synthesis, ventral plate fixation (primarily for sacroiliac luxations), and local plate synthesis performed on the dorsal cortex of the sacrum. In our current article, we analyzed the stability of fixation methods used together with bilateral iliolumbar techniques. METHODS: We analyzed a finite element pelvic model attached to lumbar 4-5 vertebrae. By imitating a standing position on two feet, we measured the differences in tension and displacement in T1 and T2 thoracic vertebrae fractures with and without iliolumbar fusion in cases of iliosacral screw fixation, transsacral plate synthesis and KFI-H (small fragment-H) plate synthesis. RESULTS: The osteosynthesises reinforced via Galveston technique were rather stable; the amount of displacement measured in the fracture gap was significantly less than in the cases without iliolumbar fusion. The tension in the implants were below the allowed values, therefore they were capable of withstanding the imposed loads without permanent deformation. CONCLUSIONS: In unilateral pelvis injuries, if a non-weight bearing status cannot be achieved on the injured side, unilateral iliolumbar fusion reinforcement is justified, since the contralateral lower limb must also be non-weight bearing due to the pelvis injury itself. In the case of the most unstable sacrum fracture--"jumper's fracture", bilateral iliolumbar fusion is necessary, in which case the patient will be able to bear weight during the early postoperative period.

Vitamin D receptor activation in a diabetic-like environment: potential role in the activity of the endothelial pro-inflammatory and thioredoxin pathways.

High blood and tissue concentrations of glucose and advanced glycation end products (AGEs) are thought to play an important role in the development of diabetic vascular complications. Thioredoxin interacting protein (TXNIP) is up-regulated in response to high levels of glucose and is an endogenous inhibitor of thioredoxin (TRX), and may play a contributory role in the occurrence of diabetic-related vascular diseases. Vitamin D inhibits endothelial proliferation and is a cardiovascular protective agent. The present study evaluated the impact of paricalcitol and calcitriol on the endothelial inflammatory and TXNIP pathways in cultured endothelial cells exposed to a diabetic-like environment. Fresh human umbilical vein cord endothelial cells (HUVEC) were treated for 24h with 200 µg/ml AGE-HSA and 250 mg/dl glucose concentrations, with paricalcitol or calcitriol. IL6, IL8, NFκB (p50/p65), receptor of AGE (RAGE), TXNIP, and TRX expressions were evaluated at the levels of mRNA, protein, and TRX activity. Calcitriol and paricalcitol significantly down-regulated the markers involved in the inflammatory responses. Only paricalcitol induced a significant decrease in TXNIP mRNA and protein expressions. Neither paricalcitol nor calcitriol affected TRX reductase activity or TRX mRNA and protein expressions. Our findings indicate that in an endothelial diabetic-like environment, paricalcitol and calcitriol significantly decreased the expression of genes involved in the inflammatory pathway. In this in vitro study, it seems that the TRX antioxidant system was not involved. The different effects found between paricalcitol and calcitriol might reflect the selectivity of vitamin D receptor (VDR) activation.

A new approach to local hardness.

The applicability of the local hardness as defined by the derivative of the chemical potential with respect to the electron density is undermined by an essential ambiguity arising from this definition. Further, the local quantity defined in this way does not integrate to the (global) hardness-in contrast with the local softness, which integrates to the softness. It has also been shown recently that with the conventional formulae, the largest values of local hardness do not necessarily correspond to the hardest regions of a molecule. Here, in an attempt to fix these drawbacks, we propose a new approach to define and evaluate the local hardness. We define a local chemical potential, utilizing the fact that the chemical potential emerges as the additive constant term in the number-conserving functional derivative of the energy density functional. Then, differentiation of this local chemical potential with respect to the number of electrons leads to a local hardness that integrates to the hardness, and possesses a favourable property; namely, within any given electron system, it is in a local inverse relation with the Fukui function, which is known to be a proper indicator of local softness in the case of soft systems. Numerical tests for a few selected molecules and a detailed analysis, comparing the new definition of local hardness with the previous ones, show promising results.

Treatment of the displaced femoral neck fractures: indications and limits of osteosynthesis.

PURPOSE: Opinions about the optimal treatment of displaced femoral neck fractures in the elderly are still divided. The two main options are internal fixation and arthroplasty. The aim of our study was to determine the most adequate surgical procedure for displaced, Garden type III-IV femoral neck fractures: which patients should undergo an osteosynthesis or primary arthroplasty, with the least prospect of complications? METHODS: We analyzed 489 femoral neck fractures treated by percutaneous osteosynthesis. We also compared the results of displaced fractures treated with primary arthroplasty versus secondary arthroplasty performed due to the failure of primary osteosynthesis. RESULTS: The rate of redisplacement in the Garden type III group was 7.6%, and in the Garden type IV group, it was 25.5%, mainly in the case of subcapital fractures. Also, walking ability was examined 4 months after injury. In the ASA score II-III group, most of the patients were able to walk with or without walking aids, but in the case of ASA score IV, most of them were immobile or died during the hospital or posthospital phase. Our research also proved that, in cases of femoral neck fractures treated with primary arthroplasty, the complication rate is lower than after secondary arthroplasty due to failure of the primary osteosynthesis. CONCLUSIONS: Based on our results, we recommend osteosynthesis in the case of Garden type III femoral neck fractures and, in turn, arthroplasty with respect to the high rate of early redisplacement in the case of Garden type IV fractures, especially in the case of subcapital fractures. For patients confined to a bed and in poor general condition (ASA score IV), the first choice treatment option is the minimally invasive percutaneous osteosynthesis.

Energy surface, chemical potentials, Kohn-Sham energies in spin-polarized density functional theory.

On the basis of the zero-temperature grand canonical ensemble generalization of the energy E[N,N(s),v,B] for fractional particle N and spin N(s) numbers, the energy surface over the (N,N(s)) plane is displayed and analyzed in the case of homogeneous external magnetic fields B(r). The (negative of the) left-/right-side derivatives of the energy with respect to N, N(↑), and N(↓) give the fixed-N(s), spin-up, and spin-down ionization potentials/electron affinities, respectively, while the derivative of E[N,N(s),v,B] with respect to N(s) gives the (signed) half excitation energy to the lowest-lying state with N(s) increased (or decreased) by 2. The highest occupied and lowest unoccupied Kohn-Sham spin-orbital energies are identified as the corresponding spin-up and spin-down ionization potentials and electron affinities. The excitation energies to the lowest-lying states with N(s)±2 can be obtained as the differences between the lowest unoccupied and the opposite-spin highest occupied spin-orbital energies, if the (N,N(s)) representation of the Kohn-Sham spin-potentials is used. The cases where the convexity condition on the energy does not hold are also discussed. Finally, the discontinuities of the energy derivatives and the Kohn-Sham potential are analyzed and related.

Reconstruction of the through-and-through oral cavity defect with the fibula free flap.

OBJECTIVE: To evaluate our experience with reconstruction of anterior and lateral through-and-through defects of the oral cavity using the fibula osteocutaneous flap. STUDY DESIGN: Case series with chart review. METHODS: Review of patients undergoing reconstruction of through-and-through oral cavity defects between August 2006 and July 2008. Defect size, complications, and need for additional reconstruction were examined. RESULTS: Twelve patients were identified with through-and-through oromandibular defects reconstructed with the fibula. Soft tissue defects were successfully closed using a de-epithelialized segment to create two skin paddles. Four patients required additional pectoralis major flap reconstruction for secondary fibula skin loss (1), neck skin breakdown (1), delayed flap loss (1), and need for additional tissue for closure (1). CONCLUSION: The versatility of the fibula for through-and-through defects of the oral cavity is underestimated, and in most cases it is appropriate to reserve second flaps for salvage reconstruction.

Nonuniqueness of magnetic fields and energy derivatives in spin-polarized density functional theory.

The effect of the recently uncovered nonuniqueness of the external magnetic field B(r) corresponding to a given pair of density n(r) and spin density n(s)(r) on the derivative of the energy functional of spin-polarized density functional theory, and its implications for the definition of chemical reactivity descriptors, is examined. For ground states, the nonuniqueness of B(r) implies the nondifferentiability of the energy functional E(v,B)[n,n(s)] with respect to n(s)(r). It is shown, on the other hand, that this nonuniqueness allows the existence of the one-sided derivatives of E(v,B)[n,n(s)] with respect to n(s)(r). Although the N-electron ground state can always be obtained from the minimization of E(v,B)[n,n(s)] without any constraint on the spin number N(s)=integraln(s)(r)dr, the Lagrange multiplier mu(s) associated with the fixation of N(s) does not vanish even for ground states. Mu(s) is identified as the left- or right-side derivative of the total energy with respect to N(s), which justifies the interpretation of mu(s) as a (spin) chemical potential. This is relevant not only for the spin-polarized generalization of conceptual density functional theory, the spin chemical potential being one of the elementary reactivity descriptors, but also for the extension of the thermodynamical analogy of density functional theory for the spin-polarized case. For higher-order reactivity indices, B(r)'s nonuniqueness has similar implications as for mu(s), leading to a split of the indices with respect to N(s) into one-sided reactivity descriptors.

Incidence of oral cavity and pharynx cancer in Kentucky.

BACKGROUND: Oral cavity and pharyngeal (OCOP) cancer is strongly associated with tobacco use and alcohol consumption. Kentucky consistently has one of the highest rates of tobacco use in the United States. The purpose of this study was to examine the differences in incidence rates in Kentucky as compared to nationwide data as well as regional differences within the state. METHOD: Oral and pharyngeal cancer incidence data for the years 1995-2004 in Kentucky were obtained from Kentucky Cancer Registry (KCR). Data for the same time period for the United States were approximated using SEER*Stat 6.3.5 provided by the Surveillance, Epidemiology, and End Results (SEER) Program. Age-adjusted incidence rates and smoothed incidence rates by county were examined. RESULTS: The overall incidence of oral cavity and pharyngeal cancer in Kentucky was 12.1/100,000. This was significantly higher than the rate seen in the SEER data of 11.3/100,000 population (p < 0.05). This difference was more pronounced for males in Kentucky, where a 20% higher rate (19.2 vs 16.3/100,000 SEER) was observed. The vast majority of cases (62.1%) had a documented smoking history, and this number was higher in advanced stage disease (73%). Rates were lower in Appalachian regions (11.4/100,000) compared to non-Appalachian regions (12.4/10/ 100,000), p < 0.01, with additional geographic variations observed. CONCLUSION: Kentucky has a higher incidence rate for oral cavity and pharyngeal cancer than the national average. The high prevalence of tobacco use in the state is likely a strong contributing factor. The etiology of regional patterns of incidence rates statewide requires further study.

Early changes in the tensile strength and morphology of primary sutured skin wounds in rats.

The specific aim of this study was to measure the TS of rat skin wounds during the first week following surgical injury. Biomechanical and histological data were collected daily (days 1 to 7 following surgery) from separate groups of Sprague-Dawley rats (N = 12) each with two 3 cm long parallel skin incisions on the back. The wounds were immediately closed by four simple sutures. A control group (N = 15) was used to obtain TS measurements of unwounded skin. TS was measured by applying a ramp load until wound separation and estimated by dividing the yield strength by the wound area. The time course of biomechanical recovery followed a step-plateau pattern with the largest increase in TS observed one day after surgery (0 - 1.60 g/cm(2)). The plateau stage extended from day 1 to 5 (1.60 - 3.88 g/cm(2)). The final step (day 5-7) indicated a period of rapid rise in wound TS (3.88 - 11.57 g/cm(2)). Since even on day 7 the mean TS was only 4% of unwounded skin, the wound had to be protected from tensile loads. Histological analysis confirmed that the early changes in TS (day 1) correlated with the fibrin accumulation of the wound edges followed by a plateau stage caused by the tissue proliferation. The rapid increase in wound TS was characterized by cross-linking the incisions with collagen fibres with escalating organization. We conclude that from a biomechanical perspective, sutures can be removed during the "plateau phase", but the wound must be protected from tensile loads.

Protein interaction of nucleosome assembly protein 1 and casein kinase 2 during desiccation response in the insect-killing nematode Steinernema feltiae IS-6.

The change in gene expression induced by desiccation in the semiarid, entomopathogenic nematode Steinernema feltiae IS-6, includes induction of transcription of a nucleosome assembly protein, NAP1 homolog, and of casein kinase 2 (CK2) genes. Therefore, one of the events during the dehydration response of S. feltiae IS-6 may be transcriptional activation by S. feltiae IS-6 NAP1 homolog (Sf-Nap1), which is regulated by S. feltiae IS-6 CK2 (Sf-CK2). This regulation necessitates physical interaction between the Sf-Nap1 and Sf-CK2 proteins. In the present study we used yeast 2-hybrid analysis to demonstrate physical interaction between the 2 proteins, thus confirming the involvement of a protein interaction-based step in the desiccation response mechanism of S. feltiae IS-6.

Does epirubicin affect left ventricular systolic performance in oncologic patients?

PURPOSE: In the present study the left ventricular diastolic and systolic functions were evaluated in patients treated with lower total doses of epirubicin using Doppler echocardiography. PATIENTS AND METHODS: Seventeen patients with different malignant tumors treated with epirubicin up to 450 mg/m(2) (study group), and a gender-and age-matched group of 29 patients diagnosed with tumors, who had not started treatment yet (control group), were assessed by echocardiography. Left ventricular diastolic function was assessed by measuring the Doppler transmitral flow. We measured the maximal velocity of the E wave (rapid filling) and A wave (atrial filling). The ratio of Emax/Amax, the pressure half time (PHT) of the E wave and the iso-volumic relaxation time (IVRT) were also calculated. The left ventricular systolic performance was assessed by measuring the global ejection fraction (EF). RESULTS: The left ventricular diastolic performance was altered in the study group. In this group we noticed a significant decrease ( p < 0.001) of Emax. A wave was significantly increased in the study group compared to the control group ( p < 0.001). The mitral E/A ratio was subunitary in the study group. The E wave PHT was prolonged in the epirubicin-treated group in comparison to the controls (p<0.001). The IVRT was prolonged in the study group in comparison to the controls (p<0.05). The left ventricular systolic performance was not significantly altered in the study group compared to the control group. Although the EF was lower in the study group the difference did not reach statistical significance. CONCLUSION: Our Doppler echocardiography study documented an impaired left ventricular diastolic performance in patients with various malignancies treated with lower total doses of epirubicin. This impairment is due to poor left ventricular compliance.