Calculated and Empirical Values of Vibronic Transition Dipole Moments of Reactive Chemical Intermediates for Determination of Concentrations.

Absorption spectroscopy has long been known as a technique for making molecular concentration measurements and has received enhanced visibility in recent years with the advent of new techniques, like cavity ring-down spectroscopy, that have increased its sensitivity. To apply the method, it is necessary to have a known molecular absorption cross section for the species of interest, which typically is obtained by measurements of a standard sample of known concentration. However, this method fails if the species is highly reactive, and indirect means for attaining the cross section must be employed. The HO2 and alkyl peroxy radicals are examples of reactive species for which absorption cross sections have been reported. This work explores and describes for these peroxy radicals the details of an alternative approach for obtaining these cross sections using quantum chemistry methods for the calculation of the transition dipole moment upon whose square the cross section depends. Likewise, details are given for obtaining the transition moment from the experimentally measured cross sections of individual rovibronic lines in the near-IR Ã-X̃ electronic spectrum of HO2 and the peaks of the rotational contours in the corresponding electronic transitions for the alkyl (methyl, ethyl, and acetyl) peroxy radicals. In the case of the alkyl peroxy radicals, good agreement for the transition moments, ≈20%, is found between the two methods. However, rather surprisingly, the agreement is significantly poorer, ≈40%, for the HO2 radical. Possible reasons for this disagreement are discussed.

A combined experimental and computational study on the transition of the calcium isopropoxide radical as a candidate for direct laser cooling.

Vibronically resolved laser-induced fluorescence/dispersed fluorescence (LIF/DF) and cavity ring-down (CRD) spectra of the electronic transition of the calcium isopropoxide [CaOCH(CH3)2] radical have been obtained under jet-cooled conditions. An essentially constant energy separation of 68 cm-1 has been observed for the vibrational ground levels and all fundamental vibrational levels accessed in the LIF measurement. To simulate the experimental spectra and assign the recorded vibronic bands, Franck-Condon (FC) factors and vibrational branching ratios (VBRs) are predicted from vibrational modes and their frequencies calculated using the complete-active-space self-consistent field (CASSCF) and equation-of-motion coupled-cluster singles and doubles (EOM-CCSD) methods. Combined with the calculated electronic transition energy, the computational results, especially those from the EOM-CCSD calculations, reproduced the experimental spectra with considerable accuracy. The experimental and computational results suggest that the FC matrix for the studied electronic transition is largely diagonal, but transitions from the vibrationless levels of the à state to the X̃-state levels of the CCC bending (ν14 and ν15), CaO stretch (ν13), and CaOC asymmetric stretch (ν9 and ν11) modes also have considerable intensities. Transitions to low-frequency in-plane [ν17(a')] and out-of-plane [ν30(a'')] CaOC bending modes were observed in the experimental LIF/DF spectra, the latter being FC-forbidden but induced by the pseudo-Jahn-Teller (pJT) effect. Both bending modes are coupled to the CaOC asymmetric stretch mode via the Duschinsky rotation, as demonstrated in the DF spectra obtained by pumping non-origin vibronic transitions. The pJT interaction also induces transitions to the ground-state vibrational level of the ν10(a') mode, which has the CaOC bending character. Our combined experimental and computational results provide critical information for future direct laser cooling of the target molecule and other alkaline earth monoalkoxide radicals.

Electronic spectroscopy of the A1̃2A''/A2̃2A'-X̃2A' transitions of jet-cooled calcium ethoxide radicals: Vibronic structure of alkaline earth monoalkoxide radicals of Cs symmetry.

Laser-induced fluorescence/dispersed fluorescence (LIF/DF) and cavity ring-down spectra of the A1̃2A''/A2̃2A'-X̃2A' electronic transition of the calcium ethoxide (CaOC2H5) radical have been obtained under jet-cooled conditions. An essentially constant Ã2-Ã1 energy separation for different vibronic levels is observed in the LIF spectrum, which is attributed to both the spin-orbit (SO) interaction and non-relativistic effects. Electronic transition energies, vibrational frequencies, and spin-vibrational eigenfunctions calculated using the coupled-cluster method, along with results from previous complete active space self-consistent field calculations, have been used to predict the vibronic energy level structure and simulate the recorded LIF/DF spectra. Although the vibrational frequencies and Franck-Condon (FC) factors calculated under the Born-Oppenheimer approximation and the harmonic oscillator approximation reproduce the dominant spectral features well, the inclusion of the pseudo-Jahn-Teller (pJT) and SO interactions, especially those between the A1̃2A″/A2̃2A' and the B̃2A' states, induces additional vibronic transitions and significantly improves the accuracy of the spectral simulations. Notably, the spin-vibronic interactions couple vibronic levels and alter transition intensities. The calculated FC matrix for the A1̃2A''/A2̃2A'-X̃2A' transition contains a number of off-diagonal matrix elements that connect the vibrational ground levels to the levels of the ν8 (CO stretch), ν11 (OCC bending), ν12 (CaO stretch), ν13 (in-plane CaOC bending), and ν21 (out-of-plane CaOC bending) modes, which are used for vibrational assignments. Transitions to the ν21(a″) levels are allowed due to the pJT effect. Furthermore, when LIF transitions to the Ã-state levels of the CaOC-bending modes, ν13 and ν21, are pumped, A1̃2A''/A2̃2A'→X̃2A' transitions to the combination levels of these two modes with the ν8, ν11, and ν12 modes are also observed in the DF spectra due to the Duschinsky mixing. Implications of the present spectroscopic investigation to laser cooling of asymmetric-top molecules are discussed.

Rotational and fine structure of open-shell molecules in nearly degenerate electronic states. II. Interpretation of experimentally determined interstate coupling parameters of alkoxy radicals.

Rotationally and fine-structure resolved B̃←X̃ laser-induced fluorescence (LIF) spectra of alkoxy radicals have been simulated with a "coupled two-states model" [J. Liu, J. Chem. Phys. 148, 124112 (2018)], in which the nearly degenerate X̃ and à states are considered together. These two electronic states are separated by the "difference potential" and coupled by the spin-orbit (SO) interaction and the Coriolis interaction. Molecular constants determined in fitting the LIF spectra using the coupled two-states model provide quantitative insight into the SO and Coriolis interactions, as well as other intramolecular dynamics, including the pseudo-Jahn-Teller effect. The spectroscopic model also allows semi-quantitative prediction of effective spin-rotation constants using molecular geometry and SO constants, which can be calculated ab initio with considerable accuracy. The dependence of fit values of molecular constants on the size and conformation of alkoxy radicals is discussed.

Development and Validation of a Prognostic, Risk-Adjusted Scoring System for Operative Upper-Extremity Infections.

PURPOSE: Acute infections of the distal upper extremity (UE) can require one and possibly multiple debridements. We aimed to develop and validate a prognostic scoring system based on patient, infection, and microbiology risk factors to help with operative planning and patient counseling. METHODS: We studied all acute surgical UE infections distal to the elbow joint over a 5-year period. A split-sample design was created with 1:1 randomization into development and validation samples. The primary outcome was infection persistence, defined as the need for additional operative drainage according to usual indications. Multivariable logistic regression identified risk factors for persistent infections in the development sample, which was translated to a simple clinical scoring system derived from regression coefficients. The model was then tested separately against the validation sample. RESULTS: A total of 602 patients were included; 31% of all infections exhibited persistence. Independent risk factors from the development sample included diabetes (3 points), smoking (2 points), leukocytosis at presentation (2 points), animal bite mechanism (3 points), osteomyelitis (4 points), tenosynovitis (7 points), pyarthrosis (3 points), necrotizing fasciitis (11 points), and methicillin-resistant Staphylococcus aureus (3 points). These were all confirmed in the validation sample. Infections were categorized into 3 groups based on risk for persistent infection: low (less than 8 points), medium (8-11 points), and high (12 points or more). In the validation sample, the probability of persistent infection for these 3 groups was 23%, 57%, and 79%, respectively. The c statistic for the model in the validation sample was 0.79. CONCLUSIONS: Persistence of acute surgical distal UE infections is mediated by patient and microbiology factors, as well as infection mechanism and type. Surgeons can use this risk-adjusted prognostic scoring system to anticipate which infections may require additional therapeutic debridement and plan operative schedules and counsel patients accordingly. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic II.

First-Principles Calculation of Jahn-Teller Rotational Distortion Parameters.

A theoretical and computational framework is presented for the parameters h1 and h2 that appear in the rotational Hamiltonian for molecules subject to the Jahn-Teller effect. Expressions that relate h1 and h2 to first and second moments of the degenerate normal coordinates as well as derivatives of the inertia tensor are presented in detail for both cylindrical and Cartesian coordinate systems. The method is demonstrated for three situations in which experimental information about h1 (and/or h2) is available: the ground 2E1″ and 2E states of the cyclopentadienyl (C5H5) and methoxy (CH3O) radicals, respectively, and the excited 2E″ state of the nitrate (NO3) radical. Results for h1 and h2 parametrized by ab initio calculations exhibit good agreement with measured values, and they are demonstrably superior to those obtained with an approach based on first-order perturbation theory. The computational technology developed for h1 and h2 can be used to benchmark quantum chemistry calculations for molecules with Jahn-Teller effects and facilitate the analysis of their spectra.

Laser-induced fluorescence and dispersed-fluorescence spectroscopy of the Ã2E-X̃2A1 transition of jet-cooled calcium methoxide (CaOCH3) radicals.

Laser-induced fluorescence (LIF) and dispersed fluorescence (DF) spectra of the Ã2E-X̃2A1 electronic transition of the calcium methoxide (CaOCH3) radical have been obtained under jet-cooled conditions. Complete active space self-consistent field and coupled-cluster calculations on the free radical were performed to aid the assignment of vibronic transitions observed in the LIF/DF spectra. In addition to dominant spectral features that are well reproduced by vibrational frequencies and Franck-Condon (FC) factors calculated ab initio, the FC matrix for the Ã2E-X̃2A1 electronic transition contains considerable off-diagonal elements that connect (i) the CaO-stretch (ν4) mode and non-CaO stretch modes and (ii) the asymmetric CaOC stretch (ν3) and the CaOC bending (ν8) modes. The Jahn-Teller and pseudo-Jahn-Teller interactions involving the Ã2E state as well as the spin-orbit interaction induce additional vibronic transitions that are not allowed under the Born-Oppenheimer approximation. Additionally, anharmonic vibrational terms in the ground state induce transitions that are forbidden in the harmonic-oscillator approximation. Spin-orbit splitting has been observed for several vibrational levels of the Ã2E state, and an essentially constant value was measured at all levels accessed in the LIF experiment. Implications of the present spectroscopic investigation to the proposed schemes of laser-cooling MOCH3 (M = alkaline earth metals) molecules and detection of time-reversal-symmetry-violating interactions are discussed.

Quantifying the Effect of Diabetes on Surgical Hand and Forearm Infections.

PURPOSE: Diabetes has long been established as a risk factor for hand and forearm infections. The purpose of this study was to review the effect of glycemic factors on outcomes among diabetic patients with surgical upper-extremity infections. We hypothesized that diabetic inpatients may benefit from stronger peri-infection glycemic control. METHODS: A prospective cohort study enrolled diabetic and nondiabetic surgical hand and forearm infections over 3 years. Glycemic factors included baseline glycosylated hemoglobin, blood glucose (BG) at presentation, and inpatient BG. Poor baseline control was defined as glycosylated hemoglobin of 9.0% or greater and poor inpatient control as average BG of 180 mg/dL or greater. The main outcome of interest was the need for repeat therapeutic drainage. Multivariable logistic regression quantified the association between diabetic factors and this outcome. RESULTS: The study involved 322 patients: 76 diabetic and 246 nondiabetic. Diabetic infections were more likely than nondiabetic infections to result from idiopathic mechanisms, occur in the forearm, and present as osteomyelitis, septic arthritis, and necrotizing fasciitis. Diabetic microbiology was more likely polymicrobial and fungal. After first drainage, diabetic patients were more likely to require repeat drainage and undergo eventual amputation. Among diabetic patients, poor inpatient control was associated with need for repeat drainage. CONCLUSIONS: Diabetes exacerbates the burden of surgical upper-extremity infections: specifically, more proximal locations, deeper involved anatomy at presentation, broader pathogenic microbiology, increased need for repeat drainage, and higher risk for amputation. Among diabetic patients, poor inpatient glycemic control is associated with increased need for repeat drainage. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic I.

Vaginal Laxity, Sexual Distress, and Sexual Dysfunction: A Cross-Sectional Study in a Plastic Surgery Practice.

BACKGROUND: Sexual health issues can be characterized by vaginal laxity (VL), sexual distress, and sexual dysfunction. The epidemiology of these issues in plastic surgery patients, and especially breast cancer survivors, remains poorly understood. OBJECTIVES: To prospectively assess sexual health issues in a plastic surgery patient population with and without breast cancer. METHODS: A prospective cohort study was created in our practice from June to August 2017 with administration of a survey including the vaginal laxity questionnaire (VLQ), female sexual distress scale-revised (FSDS-R), and female sexual function index (FSFI). Multivariate logistic regression identified the controlled effect of patient variables on development of sexual health issues. RESULTS: Of 291 patients solicited, 239 completed the survey (37.7% breast cancer survivors vs 62.3% without). Prevalence of VL was nearly 1 in 6 women. Of these, 46.0% met criteria for sexual distress (FSDS-R ≥ 11.0) and 64.8% had sexual dysfunction (FSFI ≤ 26.5). Breast cancer survivors exhibited significantly greater overall sexual dysfunction (P < 0.001) and greater dysfunction within all FSFI domains of desire, arousal, lubrication, orgasm, satisfaction, and pain (all P < 0.02). On multivariate regression, number of vaginal deliveries predicted development of VL (OR 1.87, P < 0.001), presence of VL predicted sexual distress (OR 3.01, P = 0.007), while history of breast cancer predicted sexual dysfunction (OR 1.87, P < 0.05). CONCLUSIONS: Sexual health issues are prevalent amongst plastic surgery patients. Aesthetic practices can improve patients' quality of life by focusing on these areas. Potential therapeutic options to address sexual health issues should consider addressing vaginal laxity.

Nonsurgical Facial Rejuvenation: Outcomes and Safety of Neuromodulator and Soft-Tissue Filler Procedures Performed in a Resident Cosmetic Clinic.

BACKGROUND: The ability to perform nonsurgical facial rejuvenation procedures is a core competency requirement for plastic surgery residents. However, limited data exist on training models to achieve competency in nonsurgical facial rejuvenation and on outcomes of these procedures performed by residents. The purpose here is to evaluate patient-reported outcomes and safety of nonsurgical facial rejuvenation procedures performed by plastic surgery residents. METHODS: We prospectively enrolled 50 patients undergoing neuromodulator and/or soft-tissue filler injections in a resident cosmetic clinic between April and August 2016. Patients completed FACE-Q modules pre-procedure, and at 1 week and 1 month post-procedure. Paired t-tests were used to calculate statistical significance of changes between pre- and post-procedure scores. Effect sizes were calculated to assess clinical improvement from pre- to post-procedure. The magnitude of change was interpreted using Cohen's arbitrary criteria (small 0.20, moderate 0.50, large 0.80). RESULTS: Forty-five patients completed the study. Patients experienced significant improvements (p < 0.001) in all FACE-Q domains, including aging appearance appraisal (improved from 49.7 ± 29.4 to 70.1 ± 21.6, effect size 0.79), psychological well-being (44.0 ± 14.6-78.6 ± 20.7, effect size 1.93), social functioning (48.6 ± 16.6-75.5 ± 21.7, effect size 1.20), and satisfaction with facial appearance (50.1 ± 13.7-66.2 ± 19.7, effect size 0.95). At 1 month, overall satisfaction with outcome and decision were 75.8 ± 20.7 and 81.1 ± 20.4, respectively. No patients experienced complications. CONCLUSIONS: Nonsurgical facial rejuvenation procedures performed by residents can improve patients' quality of life and provide high satisfaction without compromising safety. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors http://www.springer.com/00266 .

Impact of Time Interval between Radiation and Free Autologous Breast Reconstruction.

Background To evaluate whether the timing of surgery after radiation in autologous breast reconstruction affects major complications. Methods We performed a retrospective review of 454 free flaps (331 patients) for breast reconstruction at a single institution from 2003 to 2014. Charts were reviewed for age, BMI, laterality, flap type (TRAM, msTRAM, DIEP), surgeon, donor vessels (IMA, TD), chemotherapy, smoking, diabetes, hypertension, DVT, venous anastomoses, vein size, and time from radiation (none, < 12 months, or ≥ 12 months). The primary outcome of major complications was defined as partial/total flap loss, thrombosis, ischemia, or hematoma requiring return to the operating room. To identify independent predictors of major complications, a multivariate logistic regression was constructed. Alpha = 0.05 indicated significance in all tests. Results Average age was 47.4 ± 8.4. Free flaps consisted of msTRAM (41.1%), TRAM (29.6%), or DIEP (29.3%). The donor vessel was IMA in 66.9% of flaps or TD in 33.0% of patients with 90.7% using only one vein and 9.3% with two veins. The average IMA/TDV size was 2.5 cm ± 0.5. Preoperative radiation occurred in 31.2% of flaps. There were 54 flaps with at least one major complication (11.7%). On multivariate regression, only flap type (OR =4.04, p < .01) and vein size (OR = 0.13, p = 0.02) independently predicted major complications. Conclusion There was no significant difference in major complications between flaps who had reconstruction within 12 months and greater than 12 months after radiation. Only having a more muscle sparing technique or smaller vein size were independent risk factors for major complications.

Preoperative Paravertebral Block Improves Postoperative Pain Control and Reduces Hospital Length of Stay in Patients Undergoing Autologous Breast Reconstruction after Mastectomy for Breast Cancer.

BACKGROUND: Postoperative pain is a major challenge for patients undergoing breast reconstruction after surgical treatment of breast cancer, resulting in prolonged hospitalizations and additional resource utilization. Evidence on the efficacy of techniques to minimize postoperative pain in autologous breast reconstruction is lacking. We sought to determine whether preoperative paravertebral block (PVB), a regional anesthetic technique, affects postoperative pain control and hospital length of stay (LOS) in patients undergoing autologous breast reconstruction. METHODS: Consecutive patients undergoing postmastectomy autologous breast reconstruction between 2012 and 2015 were identified from a prospectively collected database to compare those who received PVB to those who did not. Primary outcomes included self-reported pain score, time to oral-only narcotic usage (TTON), and LOS. Sample differences were compared using Wilcoxon rank-sum and Chi square tests for continuous and categorical variables. Kaplan-Meier analysis was used to evaluate TTON and LOS, with Mantel-Cox test used to compare groups. RESULTS: Of 78 patients, 39 received PVB and 39 did not. Study groups did not differ regarding age, body mass index, American Society of Anesthesiologists class, mastectomy type, flap type, or cancer stage (p > 0.05). Patients in the PVB group reported significantly lower postoperative pain at 2 (p < 0.01) and 24 h (p < 0.01) and shorter median TTON (66 vs. 76 h, p < 0.01). Importantly, median LOS was reduced for patients receiving a PVB in both hours (95 vs. 116, p < 0.01) and hospital nights (4 vs. 5, p = 0.05). CONCLUSIONS: Preoperative PVB is associated with improved postoperative pain control and shorter hospitalizations for patients with breast cancer undergoing postmastectomy autologous reconstruction.

Impact of Neoadjuvant and Adjuvant Chemotherapy on Immediate Tissue Expander Breast Reconstruction.

BACKGROUND: Delayed wound healing or infection leads to premature tissue expander (TE) explantation after immediate postmastectomy breast reconstruction. A large study with sufficient duration of follow-up focusing on the impact of chemotherapy (CT) on premature TE removal after immediate breast reconstruction is lacking. METHODS: A retrospective review of patients undergoing immediate TE reconstruction was conducted. Multivariate analyses identified factors contributing to premature removal of TEs including neoadjuvant and adjuvant CT, specific chemotherapeutic regimens, and other factors like cancer stage, body mass index, smoking, radiation, and age. Kaplan-Meier curves were plotted to study the timing of premature TE removal. RESULTS: Of 899 patients with TEs, 256 received no, 295 neoadjuvant, and 348 adjuvant CT. Premature removal occurred more frequently in the neoadjuvant (17.3 %) and adjuvant (19.9 %) cohorts than the no-CT (12.5 %) cohort (p = 0.056). Premature TE removal occurred earlier (p = 0.005) in patients who received no CT than those with adjuvant CT. Radiation in patients receiving neoadjuvant CT prolonged the mean time to premature removal (p = 0.003). In the absence of radiation, premature removal occurred significantly sooner with neoadjuvant than adjuvant CT (p = 0.035). DISCUSSION: Premature removal of a TE occurs more commonly in patients treated with neoadjuvant or adjuvant CT and is most commonly observed 2-3 months after placement-well after the follow-up period recorded by the American College of Surgeons National Surgery Quality Improvement Program (NSQIP) database. These findings can be used to aid preoperative counseling and guide the timing of follow-up for these patients.

Pair-eigenstates and mutual alignment of coupled molecular rotors in a magnetic field.

We examine the rotational states of a pair of polar (2)Σ molecules subject to a uniform magnetic field. The electric dipole-dipole interaction between the molecules creates entangled pair-eigenstates of two types. In one type, the Zeeman interaction between the inherently paramagnetic molecules and the magnetic field destroys the entanglement of the pair-eigenstates, whereas in the other type it does not. The pair-eigenstates exhibit numerous intersections, which become avoided for pair-eigenstates comprised of individual states that meet the selection rules ΔJi = 0, ± 1, ΔNi = 2n (n = 0, ±1, ±2,…), and ΔMi = 0, ± 1 imposed by the electric dipole-dipole operator. Here Ji, Ni and Mi are the total, rotational and projection angular momentum quantum numbers of molecules i = 1, 2 in the absence of the electric dipole-dipole interaction. We evaluate the mutual alignment of the pair-eigenstates and find it to be independent of the magnetic field, except for states that undergo avoided crossings, in which case the alignment of the interacting states is interchanged at the magnetic field corresponding to the crossing point. We present an analytic model which provides ready estimates of the pairwise alignment cosine that characterises the mutual alignment of the pair of coupled rotors.

Prospects for quantum computing with an array of ultracold polar paramagnetic molecules.

Arrays of trapped ultracold molecules represent a promising platform for implementing a universal quantum computer. DeMille [Phys. Rev. Lett. 88, 067901 (2002)] has detailed a prototype design based on Stark states of polar (1)Σ molecules as qubits. Herein, we consider an array of polar (2)Σ molecules which are, in addition, inherently paramagnetic and whose Hund's case (b) free-rotor pair-eigenstates are Bell states. We show that by subjecting the array to combinations of concurrent homogeneous and inhomogeneous electric and magnetic fields, the entanglement of the array's Stark and Zeeman states can be tuned and the qubit sites addressed. Two schemes for implementing an optically controlled CNOT gate are proposed and their feasibility discussed in the face of the broadening of spectral lines due to dipole-dipole coupling and the inhomogeneity of the electric and magnetic fields.

A multicenter phase I dose escalation trial to evaluate safety and tolerability of intra-arterial temozolomide for patients with advanced extremity melanoma using normothermic isolated limb infusion.

BACKGROUND: L-phenylalanine mustard (LPAM) has been the standard for use in regional chemotherapy (RC) for unresectable in-transit melanoma. Preclinical data demonstrated that regional temozolomide (TMZ) may be more effective. METHODS: Patients with AJCC Stage IIIB or IIIC extremity melanoma who failed previous LPAM-based RC were treated with TMZ via isolated limb infusion (ILI) according to a modified accelerated titration design. Drug pharmacokinetic (PK) analysis, tumor gene expression, methylation status of the O6-methylguanine methyltransferase (MGMT) promoter, and MGMT expression were evaluated. Primary objectives were to (1) determine dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of TMZ via ILI and (2) explore biomarker correlates of response. RESULTS: 28 patients completed treatment over 2.5 years at 3 institutions. 19 patients were treated at the MTD defined as 3,200 mg/m(2) [multiplied by 0.09 (arm), 0.18 (leg)]. Two of five patients had DLTs at the 3,600 mg/m(2) level while only grade 1 (n = 15) and grade 2 (n = 4) clinical toxicities occurred at the MTD. At 3-month post-ILI, 10.5 % (2/19) had CR, 5.3 % (1/19) had PR, 15.8 % (3/19) had SD, and 68.4 % (13/19) had PD. Neither PK parameters of TMZ nor MGMT levels were associated with response or toxicity. CONCLUSION: In this first ever use of intra-arterial TMZ in ILI for melanoma, the MTD was determined. While we could not define a marker for TMZ response, the minimal toxicity of TMZ ILI may allow for repeated treatments to increase the response rate as well as clarify the role of MGMT expression.

SRC family kinase inhibition as a novel strategy to augment melphalan-based regional chemotherapy of advanced extremity melanoma.

BACKGROUND: Src kinase inhibition has been shown to augment the efficacy of chemotherapy. Dasatinib, a dual Src/Abl kinase inhibitor approved for the treatment of CML, is under investigation as monotherapy for tumors with abnormal Src signaling, such as melanoma. The goal of this study was to determine if Src kinase inhibition using dasatinib could enhance the efficacy of regionally administered melphalan in advanced extremity melanoma. METHODS: The mutational status of c-kit and patterns of gene expression predictive of dysregulated Src kinase signaling were evaluated in a panel of 26 human melanoma cell lines. The effectiveness of dasatinib was measured by quantifying protein expression and activation of Src kinase, focal adhesion kinase, and Crk-associated substrate (p130(CAS)), in conjunction with in vitro cell viability assays using seven melanoma cell lines. Utilizing a rat model of regional chemotherapy, we evaluated the effectiveness of systemic dasatinib in conjunction with regional melphalan against the human melanoma cell line, DM443, grown as a xenograft. RESULTS: Only the WM3211 cell line harbored a c-kit mutation. Significant correlation was observed between Src-predicted dysregulation by gene expression and sensitivity to dasatinib in vitro. Tumor doubling time for DM443 xenografts treated with systemic dasatinib in combination with regional melphalan (44.8 days) was significantly longer (p = 0.007) than either dasatinib (21.3 days) or melphalan alone (24.7 days). CONCLUSIONS: Systemic dasatinib prior to melphalan-based regional chemotherapy markedly improves the efficacy of this alkylating agent in this melanoma xenograft model. Validation of this concept should be considered in the context of a regional therapy clinical trial.

Bevacizumab and wound-healing complications: mechanisms of action, clinical evidence, and management recommendations for the plastic surgeon.

Reflecting the growing understanding of vascular endothelial growth factor (VEGF) in cancer survival and growth, the anti-VEGF antibody bevacizumab (Avastin) is increasingly used to treat advanced malignancy. However, because VEGF also mediates proper wound healing, bevacizumab may lead to potentially severe wound-healing complications (WHCs). Because bevacizumab expands in use, the plastic surgeon will increasingly be entrusted to manage such WHCs successfully. Therefore, this review summarizes the pathophysiological evidence, systematically reviews the available clinical evidence, and provides management guidelines for bevacizumab-related WHCs. Bevacizumab produces WHCs by disrupting vasodilation, increased vascular permeability, and angiogenesis. Current clinical evidence suggests that bevacizumab may increase WHC risk. This risk seems higher with neoadjuvant than adjuvant bevacizumab use and may be decreased by extending the bevacizumab-surgery interval. Further research is required to quantify the exact bevacizumab-related WHC incidence and optimize the bevacizumab-surgery interval. We propose management guidelines for bevacizumab-related WHCs by indication that should be integrated with clinical judgment, input from the oncology team, and patient wishes when making therapeutic decisions.

A multi-institution experience comparing the clinical and physiologic differences between upper extremity and lower extremity melphalan-based isolated limb infusion.

BACKGROUND: Although studies of melphalan-based isolated limb infusion (ILI) combine data from upper extremity (UE) treatments with those from lower extremity (LE) treatments, differences between the 2 may be clinically important. METHODS: Candidates for UE ILI (n = 51) and LE ILI (n = 192) were identified from prospective databases at 2 institutions. The Response Evaluation Criteria in Solid Tumors and Wieberdink toxicity scale were used as appropriate. RESULTS: The following patients had indications for UE ILI: melanoma, 36 of 47 patients (77%); sarcoma, 5 of 47 patients (11%); Merkel cell sarcoma, 3 of 47 patients (6%), and squamous cell carcinoma, 3 of 47 patients (6%). The patients who underwent UE ILI, as expected, had lower limb volumes (mean, 2.5 L vs 8.6 L; P < .001) and lower mean melphalan doses (20.7 mg vs 49.5 mg; P < .001). On perfusate blood gas analysis, the mean base excess at 30 minutes (-13.9 vs -9.1; P < .001) and the mean pH at 30 minutes (7.06 vs 7.15; P < .001) were lower for UE procedures than for LE procedures, although the mean ischemic time was longer in LE procedures (67.2 minutes) than in UE procedures (61.6 minutes; P = .03). The rate of regional toxicity grade ≥3 for UE ILI was 7% compared with 24% (P = .005) for LE ILI. There was no difference in the complete response rate for melanoma UE procedures (28%; 95% confidence interval, 16%-44%) compared with LE ILI procedures (32%; 95% confidence interval, 25%-39%). CONCLUSIONS: ILI for UE disease was associated with similar complete response rates but lower toxicity than ILI for LE disease and with different physiologic sequelae despite comparable methods. The UE appears relatively resistant to toxic effects of melphalan-based ILI as currently performed, which suggests a potential for further optimization of drug dosing for UE ILI.