Elephantiasis nostras verrucosa: an atypical presentation following intrapelvic lymphoma

Elephantiasis nostras verrucosa is a progressively debilitating and disfiguring disease commonly presenting with verrucous, cobblestone-like papules, nodules, or plaques with nonpitting edema in the lower extremities. Histopathology is marked by hyperkeratosis and dermal or subcutaneous fibrosis as a result of chronic lymphedema. Risk factors include obesity, recurrent cellulitis, chronic venous insufficiency, congestive heart failure, scleroderma, radiation, trauma, and tumors. We report a 72-year-old man who presented to the dermatology clinic for an 11-year history of edematous legs, occasionally associated with ulcerations. The findings developed within a year of intrapelvic non-Hodgkin lymphoma and progressed gradually over 10 years after lymphoma remission. Physical examination revealed atypical features including compressible cysts and pitting edema extending from the lower legs to the thighs bilaterally. The patient was noncompliant for the recommended compressive devices and the condition progressively worsened over the course of 7 months of follow-up. Early interdisciplinary management using compressive devices and a lymphatic pump are recommended. Underlying causative factors should be assessed with regular follow-up to optimize treatment outcomes

Inter-patient variations in relative biological efectiveness for craniospinal irradiation with protons

Cranio-spinal irradiation (CSI) using protons has dosimetric advantages compared to photons and is expected to reduce risk of adverse effects. The proton relative biological effectiveness (RBE) varies with linear energy transfer (LET), tissue type and dose, but a variable RBE has not replaced the constant RBE of 1.1 in clinical treatment planning. We examined inter-patient variations in RBE for ten proton CSI patients. Variable RBE models were used to obtain RBE and RBE-weighted doses. RBE was quantified in terms of dose weighted organ-mean RBE (RBEd = mean RBE-weighted dose/mean physical dose) and effective RBE of the near maximum dose (D2%), i.e. RBED2% = D2%,RBE/D2%,phys, where subscripts RBE and phys indicate that the D2% is calculated based on an RBE model and the physical dose, respectively. Compared to the median RBEd of the patient population, differences up to 15% were observed for the individual RBEd values found for the thyroid, while more modest variations were seen for the heart (6%), lungs (2%) and brainstem (<1%). Large inter-patient variation in RBE could be correlated to large spread in LET and dose for these organs at risk (OARs). For OARs with small inter-patient variations, the results show that applying a population based RBE in treatment planning may be a step forward compared to using RBE of 1.1. OARs with large inter-patient RBE variations should ideally be selected for patient-specific biological or RBE robustness analysis if the physical doses are close to known dose thresholds.publishedVersio

Reduction of PTV margins for elective pelvic lymph nodes in online adaptive radiotherapy of prostate cancer patients

Background Cone beam CT (CBCT) based online adaptive radiotherapy (oART) is a new development in radiotherapy. With oART, the requirements for planning target volume (PTV) margins differ from standard therapy because motion occurs during a session. In this study, we aim to evaluate a margin reduction for locally advanced prostate patients treated with oART. Material and methods Intrafraction motion of the elective pelvic lymph nodes was evaluated by two radiation therapists (RTTs) for 150 fractions from 10 prostate patients treated with oART. PTV margins of 3, 4 and 5 mm where added to these lymph nodes for all patients. The seven first patients were treated with 5 mm PTV margin, while the last three patients were treated with 4 mm margin. After treatment, the RTTs reviewed the verification CBCTs and evaluated whether the various PTV margins would have covered the adapted clinical target volume, scoring each fraction as approved, inconclusive or rejected. Couch shifts corresponding to the rigid prostate match between the CBCTs were analyzed with respect to the RTT evaluation. Results The RTTs approved a 4 mm margin in 95% of the fractions, while 2% of the fractions were rejected. For a 3 mm margin, 57% of the fractions were approved, while 5% were rejected. The scoring from the two RTTs was consistent; e.g., for 3 mm, one RTT approved 58% of the fractions, while the other approved 55%. If the couch was moved less than 2 mm in any direction, 70% of the fractions were approved for a 3 mm margin, compared to 32% for shifts greater than 2 mm. Conclusion It is safe to reduce the PTV margin from 5 to 4 mm for the elective pelvic lymph nodes for prostate patients treated with oART. Further margin reductions can be motivated for patients presenting little intrafraction motion.publishedVersio

The Organ Sparing Potential of Different Biological Optimization Strategies in Proton Therapy

Purpose Variable relative biological effectiveness (RBE) models allow for differences in linear energy transfer (LET), physical dose, and tissue type to be accounted for when quantifying and optimizing the biological damage of protons. These models are complex and fraught with uncertainties, and therefore, simpler RBE optimization strategies have also been suggested. Our aim was to compare several biological optimization strategies for proton therapy by evaluating their performance in different clinical cases. Methods and Materials Two different optimization strategies were compared: full variable RBE optimization and differential RBE optimization, which involve applying fixed RBE for the planning target volume (PTV) and variable RBE in organs at risk (OARs). The optimization strategies were coupled to 2 variable RBE models and 1 LET-weighted dose model, with performance demonstrated on 3 different clinical cases: brain, head and neck, and prostate tumors. Results In cases with low in the tumor, the full RBE optimization strategies had a large effect, with up to 10% reduction in RBE-weighted dose to the PTV and OARs compared with the reference plan, whereas smaller variations (<5%) were obtained with differential optimization. For tumors with high the differential RBE optimization strategy showed a greater reduction in RBE-weighted dose to the OARs compared with the reference plan and the full RBE optimization strategy. Conclusions Differences between the optimization strategies varied across the studied cases, influenced by both biological and physical parameters. Whereas full RBE optimization showed greater OAR sparing, awareness of underdosage to the target must be carefully considered.publishedVersio

Combined RBE and OER optimization in proton therapy with FLUKA based on EF5-PET

Introduction Tumor hypoxia is associated with poor treatment outcome. Hypoxic regions are more radioresistant than well-oxygenated regions, as quantified by the oxygen enhancement ratio (OER). In optimization of proton therapy, including OER in addition to the relative biological effectiveness (RBE) could therefore be used to adapt to patient-specific radioresistance governed by intrinsic radiosensitivity and hypoxia. Methods A combined RBE and OER weighted dose (ROWD) calculation method was implemented in a FLUKA Monte Carlo (MC) based treatment planning tool. The method is based on the linear quadratic model, with α and β parameters as a function of the OER, and therefore a function of the linear energy transfer (LET) and partial oxygen pressure (pO2). Proton therapy plans for two head and neck cancer (HNC) patients were optimized with pO2 estimated from [18F]-EF5 positron emission tomography (PET) images. For the ROWD calculations, an RBE of 1.1 (RBE1.1,OER) and two variable RBE models, Rørvik (ROR) and McNamara (MCN), were used, alongside a reference plan without incorporation of OER (RBE1.1). Results For the HNC patients, treatment plans in line with the prescription dose and with acceptable target ROWD could be generated with the established tool. The physical dose was the main factor modulated in the ROWD. The impact of incorporating OER during optimization of HNC patients was demonstrated by the substantial difference found between ROWD and physical dose in the hypoxic tumor region. The largest physical dose differences between the ROWD optimized plans and the reference plan was 12.2 Gy. Conclusion The FLUKA MC based tool was able to optimize proton treatment plans taking the tumor pO2 distribution from hypoxia PET images into account. Independent of RBE-model, both elevated LET and physical dose were found in the hypoxic regions, which shows the potential to increase the tumor control compared to a conventional optimization approach.publishedVersio

Acute Wounding Alters the Beta2-Adrenergic Signaling and Catecholamine Synthetic Pathways in Keratinocytes

Keratinocyte migration is critical for wound re-epithelialization. Previous studies showed that epinephrine activates the beta2-adrenergic receptor (B2AR), impairing keratinocyte migration. Here, we investigated the keratinocyte catecholamine synthetic pathway in response to acute trauma. Cultured keratinocytes were scratch wounded and expression levels of the B2AR and catecholamine synthetic enzymes tyrosine hydroxylase and phenylethanolamine-N-methyltransferase were assayed. The binding affinity of the B2AR was measured. Wounding downregulated B2AR, tyrosine hydroxylase, and phenylethanolamine-N-methyltransferase expression, but pre-exposure to timolol, a beta-adrenergic receptor antagonist, delayed this effect. In wounded keratinocytes, B2AR-binding affinity remained depressed even after its expression returned to prewounding levels. Keratinocyte-derived norepinephrine increased after wounding. Norepinephrine impaired keratinocyte migration; this effect was abrogated with B2AR-selective antagonist ICI-118,551 but not with B1AR-selective antagonist bisoprolol. Finally, for clinical relevance, we determined that norepinephrine was present in freshly wounded skin, thus providing a potential mechanism for impaired healing by local B2AR activation in wound-edge keratinocytes. Taken together, the data show that keratinocytes modulate catecholamine synthetic enzymes and release norepinephrine after scratch wounding. Norepinephrine appears to be a stress-related mediator that impairs keratinocyte migration through activation of the B2AR. Future therapeutic strategies evaluating modulation of norepinephrine-related effects in the wound are warranted

Optimized EGFR blockade strategies in <i>EGFR</i> addicted gastroesophageal adenocarcinomas

Purpose: Gastric and gastroesophageal adenocarcinomas represent the third leading cause of cancer mortality worldwide. Despite significant therapeutic improvement, the outcome of patients with advanced gastroesophageal adenocarcinoma is poor. Randomized clinical trials failed to show a significant survival benefit in molecularly unselected patients with advanced gastroesophageal adenocarcinoma treated with anti-EGFR agents.Experimental Design: We performed analyses on four cohorts: IRCC (570 patients), Foundation Medicine, Inc. (9,397 patients), COG (214 patients), and the Fondazione IRCCS Istituto Nazionale dei Tumori (206 patients). Preclinical trials were conducted in patient-derived xenografts (PDX).Results: The analysis of different gastroesophageal adenocarcinoma patient cohorts suggests that EGFR amplification drives aggressive behavior and poor prognosis. We also observed that EGFR inhibitors are active in patients with EGFR copy-number gain and that coamplification of other receptor tyrosine kinases or KRAS is associated with worse response. Preclinical trials performed on EGFR-amplified gastroesophageal adenocarcinoma PDX models revealed that the combination of an EGFR mAb and an EGFR tyrosine kinase inhibitor (TKI) was more effective than each monotherapy and resulted in a deeper and durable response. In a highly EGFR-amplified nonresponding PDX, where resistance to EGFR drugs was due to inactivation of the TSC2 tumor suppressor, cotreatment with the mTOR inhibitor everolimus restored sensitivity to EGFR inhibition.Conclusions: This study underscores EGFR as a potential therapeutic target in gastric cancer and identifies the combination of an EGFR TKI and a mAb as an effective therapeutic approach. Finally, it recognizes mTOR pathway activation as a novel mechanism of primary resistance that can be overcome by the combination of EGFR and mTOR inhibitors

Elephantiasis nostras verrucosa: an atypical presentation following intrapelvic lymphoma

Elephantiasis nostras verrucosa is a progressively debilitating and disfiguring disease commonly presenting with verrucous, cobblestone-like papules, nodules, or plaques with nonpitting edema in the lower extremities. Histopathology is marked by hyperkeratosis and dermal or subcutaneous fibrosis as a result of chronic lymphedema. Risk factors include obesity, recurrent cellulitis, chronic venous insufficiency, congestive heart failure, scleroderma, radiation, trauma, and tumors. We report a 72-year-old man who presented to the dermatology clinic for an 11-year history of edematous legs, occasionally associated with ulcerations. The findings developed within a year of intrapelvic non-Hodgkin lymphoma and progressed gradually over 10 years after lymphoma remission. Physical examination revealed atypical features including compressible cysts and pitting edema extending from the lower legs to the thighs bilaterally. The patient was noncompliant for the recommended compressive devices and the condition progressively worsened over the course of 7 months of follow-up. Early interdisciplinary management using compressive devices and a lymphatic pump are recommended. Underlying causative factors should be assessed with regular follow-up to optimize treatment outcomes

Cellular versus acellular matrix devices in treatment of diabetic foot ulcers: study protocol for a comparative efficacy randomized controlled trial

Abstract Background Diabetic foot ulcers (DFUs) represent a significant source of morbidity and an enormous financial burden. Standard care for DFUs involves systemic glucose control, ensuring adequate perfusion, debridement of nonviable tissue, off-loading, control of infection, local wound care and patient education, all administered by a multidisciplinary team. Unfortunately, even with the best standard of care (SOC) available, only 24% or 30% of DFUs will heal at weeks 12 or 20, respectively.The extracellular matrix (ECM) in DFUs is abnormal and its impairment has been proposed as a key target for new therapeutic devices. These devices intend to replace the aberrant ECM by implanting a matrix, either devoid of cells or enhanced with fibroblasts, keratinocytes or both as well as various growth factors. These new bioengineered skin substitutes are proposed to encourage angiogenesis and in-growth of new tissue, and to utilize living cells to generate cytokines needed for wound repair.To date, the efficacy of bioengineered ECM containing live cellular elements for improving healing above that of a SOC control group has not been compared with the efficacy of an ECM devoid of cells relative to the same SOC. Our hypothesis is that there is no difference in the improved healing effected by either of these two product types relative to SOC. Methods/Design To test this hypothesis we propose a randomized, single-blind, clinical trial with three arms: SOC, SOC plus Dermagraft® (bioengineered ECM containing living fibroblasts) and SOC plus Oasis® (ECM devoid of living cells) in patients with nonhealing DFUs. The primary outcome is the percentage of subjects that achieved complete wound closure by week 12. Discussion If our hypothesis is correct, then immense cost savings could be realized by using the orders-of-magnitude less expensive acellular ECM device without compromising patient health outcomes. The article describes the protocol proposed to test our hypothesis. Trial registration ClinicalTrials.gov: NCT01450943. Registered: 7 October 201