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Multiple prospective trials have integrated immune checkpoint blockade (ICB) into treatment paradigms involving radiotherapy (RT) for head and neck cancer. Dosimetric predictors of hypothyroidism after RT is not well understood in this context. In this secondary analysis, we evaluate the association of radiation dose-volume metrics with hypothyroidism after definitive treatment with or without ICB for HPV-related oropharyngeal cancer (OPC). This was a dosimetric secondary analysis of locally advanced HPV+ OPC treated on two prospective phase II de-escalation trials (OPTIMA / NCT02258659) and OPTIMA II / NCT03107182) and an associated expansion cohort on registry (OPTIMA-like). On OPTIMA and OPTIMA-like, patients received induction chemotherapy (platinum doublet x 3 cycles) followed by response-adapted de-escalated RT (+/- chemotherapy). On OPTIMA II, nivolumab was added to induction chemotherapy and offered adjuvantly for 6 months. After RT, hypothyroidism was defined as elevated TSH and being prescribed levothyroxine or demonstrating clinical signs/symptoms. Demographic and treatment variables were recorded, notably mean thyroid dose (Gy) and thyroid volume receiving a minimum of 30-70 Gy (V30 Gy - V70 Gy). Hypothyroidism was analyzed as a time-to-event outcome using cumulative incidence (with death and salvage reirradiation as competing risks). Optimal dosimetric cut points were defined as those with maximum Youden index. 134 patients met inclusion criteria (median follow-up 5.6 years, median age 61 years, 95% men). 50 patients (37%) received ICB. The mean thyroid dose was 23 Gy (median across patients; range: 0.5 – 61 Gy). Hypothyroidism occurred in 26% (n = 35) of patients (median time 0.8 years; range: 0.03 - 4.0 years). For mean thyroid dose, the optimal cut point was 35.5 Gy (31% sensitivity, 89% specificity). Across all dosimetric predictors, the optimal cut point by Youden index was V50 Gy ≥ 31.7% (43% sensitivity, 89% specificity). The cumulative incidence of hypothyroidism is displayed in Table 1. On multivariable Fine-Gray competing risks regression, V50 Gy was associated with hypothyroidism (sHR = 1.02 per % thyroid gland; 95% CI, 1.01 to 1.03; P = 0.001), while ICB (P = 0.15), age (P = 0.41), and sex (P = 0.34) were not. There was no interaction effect between thyroid dose and ICB. The percentage of thyroid gland receiving at least 50 Gy was associated with hypothyroidism (optimal cut point V50 Gy > 31.7%). ICB was not significantly associated with hypothyroidism and did not interact with dosimetric predictors. These findings inform potential thyroid dose constraints to utilize in future trials, including those integrating ICB. [ABSTRACT FROM AUTHOR]

The new FIGO 2023 staging for endometrial cancer intends to improve concordance of clinical outcomes with pathological features. The goal of this study is to report outcomes with the new FIGO 2023 staging system and assess stage migration. The study hypothesis is stage migration will provide more accurate prognostication for disease free survival (DFS). An IRB approved retrospective review was performed in patients (FIGO 2009: FIGO 1A-4B/ FIGO 2023: Stage 1A-4C) treated definitively for endometrial cancer with hysterectomy followed by radiation therapy +/-chemotherapy at a single institution. Patients who could not be fully staged were excluded. Extent of LVSI was not available for 10 patients. Patients were staged based on both FIGO 2009 and FIGO 2023 staging systems. Stage migration was defined as, if a change in stage number occurred (example: stage 1A to 2C was considered stage migration, while stage 1A to 1C was not). The Kaplan–Meier method estimated DFS. From 2012-2021, 111 patients received EBRT alone 27.0% (n = 30), vaginal cuff brachytherapy alone 34.2% (n = 38), or both 38.7% (n = 43). Mean age at diagnosis was 66.5 (range = 30.4-87.6). Median follow up was 61.5 months from radiation (range = 0.5-188 months). 66.6% (n = 74) of patients had a high-risk histology: grade 3 or undifferentiated endometrioid adenocarcinoma (n = 27), serous (n = 22), clear cell (n = 6), carcinosarcoma (n = 18), or high grade neuroendocrine (n = 1). FIGO 2009 staging results: 1A(n = 34), 1B (n = 18), 2 (n = 12), 3A (n = 10), 3B (n = 2), 3C1 (n = 16), 3C2 (n = 12), 4A (n = 1), 4B (n = 6). Restaging based on the FIGO 2023 classification system: 1A2 (n = 7), 1A3 (n = 1), 1B (n = 12), 1C (n = 8), 2A (n = 6), 2C (n = 31), 3A1 (n = 1), 3A2 (n = 7), 3B1 (n = 2), 3B2 (n = 1), 3C1 (n = 16), 3C2 (n = 12), 4A (n = 1), 4B (n = 3), 4C (n = 3). In patients initially staged 1A or 1B (n = 52), stage migration to 2C occurred in 48.1 % (n = 25) of patients. Stage migration occurred in 23.4% (n = 26) of patients and primarily occurred from stage 1A/1B to 2C. Based on the 2009 FIGO staging system, 2-yr DFS was 80.4%, 58.3%, 72.4%, and 28.6% for stages 1,2,3, and 4, respectively. Based on the 2023 FIGO staging system, 2-yr DFS was 85.3%, 69.9%, 71.7%, and 28.6% for stages 1,2,3, and 4, respectively. No significant difference in recurrence rates between patients originally staged in 2009 as FIGO stage 1A/1B and migrated to FIGO stage 2C under the 2023 staging system compared to patients that were originally staged FIGO stage 1A/1B in 2009 and did not have stage migration (Recurrence rates: 36% vs. 18.5%, p = 0.215). A significant proportion of 2009 FIGO IA-B patients had stage migration to 2023 FIGO II. The 2023 classification showed trend to higher DFS for Stage I-II patients and greater ability to prognosticate disease outcomes. Further study is needed when recommending adjuvant therapy in the context of prior studies using the 2009 staging system. [ABSTRACT FROM AUTHOR]

Hartmann's procedure is the surgical treatment of choice for perforated acute diverticulitis. Hartmann's reversal (HR) that is performed at a later stage may be challenging. The optimal timing for HR is still a subject for controversy. The aim of this study is to assess whether the timing of HR affects surgical outcome. A retrospective-cohort multi-center study was conducted, including all patients who underwent HR for acute diverticulitis from January 2004 to June 2015 in 5 medical centers. Patient data included demographics, surgical data and post-operative outcome. One hundred and twenty-two patients were included in the database. Median time from Hartmann's procedure to reversal was 182.7 days, with the majority of patients (76 patients, 62.2%) operated 60 to 180 days from the Hartmann's procedure. Fifty-seven patients (46.7%) had post-operative complications, most commonly wound infections (27 patients, 22.1%). Receiver operating characteristic (ROC) curve and a propensity score match analysis (P = 0.43) correlating between days to HR from the index procedure showed no specific cut-off point regarding post-operative complications (P = 0.16), Major (Clavien–Dindo score of 3 or more) complications (P = 0.19), Minor (Clavien Dindo 1-2) and no complications (P = 0.14). Median length of stay was 10.9 days (range 3-90) and Pearson correlation failed to demonstrate a correlation between timing of surgical intervention and length of stay (P = 0.4). Hartmann's Reversal is a complex surgical procedure associated with high rates of complications. In our series, timing of surgery did not affect surgical complications rate or severity or the length of hospital stay. [ABSTRACT FROM AUTHOR]

Combined stereotactic body radiotherapy (SBRT) and immune checkpoint inhibitors (ICI) may work synergistically to improve both locoregional and systemic disease control. However, prognostic markers to identify patients most likely to benefit from combined SBRT and ICI (SBRT+ICI) are lacking. Prior work demonstrated that a validated CD8 T cell radiomics score (RS) is correlated with clinical outcomes in patients undergoing SBRT+ICI. We hypothesize this RS remains associated with clinical outcomes in an expanded cohort of patients from three phase I clinical trials using different ICIs. Patients with metastatic solid tumors treated on three trials of multi-site SBRT with concurrent or sequential ICI were evaluated. Up to 4 metastases per patient were treated with SBRT (30-50 Gy in 3-5 fractions). ICI agents included pembrolizumab or nivolumab combined with either ipilimumab, cabiralizumab, or urelumab. A RS was calculated for each metastasis using 8 variables, including 5 radiomics features extracted from pretreatment CT scans. An average RS was calculated for each patient using all irradiated lesions. A predefined cutoff was used to stratify RS scores and groups of patients as low or high RS. Local failure (LF) of irradiated metastases was analyzed using cumulative incidence with death as a competing risk. Competing risk regression was used to evaluate the association between LF and RS. The Kaplan-Meier method was used to estimate progression free survival (PFS) and overall survival (OS), and Cox proportional hazards models were used to evaluate associations with RS. We evaluated 183 patients with 427 metastases treated with SBRT+ICI. The majority of patients had NSCLC (57%). The median follow-up was 9 months. The cumulative incidence of LF was 7.6% (95% CI = 5.3-10.5%) overall, 4.5% (95% CI = 2.5-7.3%) for high-RS metastases, and 16.1% (95% CI = 10.0-23.5%) for low-RS metastases. Low-RS metastases had a higher risk of LF compared to high-RS metastases (HR = 3.2, 95% CI = 1.6 – 6.2, p = 0.001). On a continuous scale, there was a decreased risk of LF with increasing RS (HR = 0.1, 95% CI = 0.01-0.7, p = 0.016). For all patients at 12-months, PFS was 19.4% (95% CI = 13.6-25.9%) and OS was 49.1% (95% CI = 41.2-56.5%). Comparison of low vs. high RS groups was not significant for PFS (HR = 1.1, 95% CI = 0.8-1.5, p = 0.758) or OS (HR = 1.2, 95% CI = 0.8-1.7, p = 0.449). RS on a continuous scale did not correlate significantly with PFS (HR = 1.1, 95% CI = 0.5-2.3, p = 0.895) or OS (HR = 1.0, 95% CI = 0.4-2.3, p = 0.975). Our results support the prognostic utility of this CD8 T cell RS in patients undergoing SBRT+ICI. Future work will investigate using the RS for treatment selection in patients with advanced solid tumors. [ABSTRACT FROM AUTHOR]

Abstract: Aims: The administration of a high dose of rTNF-α (3–4mg) and Melphalan via isolated limb perfusion (ILP) for patients with locally advanced limb STS was shown to be effective. Reports that a low dose of TNF (1mg) is as effective, led to the adoption of the low dose regimen as the treatment of choice. The purpose of this study was to compare two groups of patients with locally advanced limb STS, that was treated with high and low dose TNF-ILP, in terms of limb preservation. Methods: Retrospective study of 41 patients who underwent ILP, with “high dose” (HD) and “low dose” (LD) TNF. ILP/TNF was performed on candidates to either amputation or significantly mutilating surgery without this treatment. In both groups, all patients, with the exception of three in each group, underwent resection of the residual tumor or tumor bed or limb 8–12 weeks after the procedure. Results: In the HD group, marked tumor softening occurred within 48h, and in tumors protruding through the skin, hemorrhagic necrosis was evident within 24h. The overall response rate was 65.2%. Five patients achieved a CR and 10 had a PR; in five of these patients >90% necrosis of the tumor occurred. In eight patients, only minimal regression was observed (stabilization of disease). The rate of limb sparing was 69.5%. In the LD group, the overall response rate was 30.7%. CR was achieved in one patient. PR was observed in two. Two patients were lost to follow up. Of the remaining 15 patients, limb preservation was achieved in 53.3%. Conclusion: Despite the retrospective comparison and possible selection bias, it is possible to raise the concern that at least some patients may benefit from a higher TNF dose perfusion in ILP for advanced limb STS. [Copyright &y& Elsevier]

Abstract: We study the chaotic dynamics of a heterogeneous reaction–diffusion medium composed of two uniform regions: one oscillatory, and the other excitable. It is shown that, by altering the diffusion coefficient, local chaotic oscillations can be induced at the interface between regions, which in turn, generate different chaotic sequences of pulses traveling in the excitable region. We analyze the properties of the local chaotic driver, as well as the diffusion-induced transitions. A procedure based on the abnormal frequency-locking phenomenon is proposed for controlling such sequences. Relevance of the obtained results to cardiac dynamics is briefly discussed. [Copyright &y& Elsevier]

Contouring guidelines for stereotactic body radiotherapy (SBRT) to bone metastases, especially to non-spine sites, are an evolving area. Inadequate CTV margins may lead to marginal failures or failures within the boney compartment. Here, we report the local control outcomes for spine and non-spine bone metastases treated with SBRT and immunotherapy across three prospective phase I trials. Between 2016 and 2020, patients with widely metastatic solid malignancies were treated on three phase I trials (n = 213) combining multi-site SBRT with immunotherapy (regimens included pembrolizumab, ipilimumab with nivolumab, urelumab with nivolumab, or cabiralizumab with nivolumab; administered concurrently or sequentially). In this secondary analysis, patients that received SBRT to a bone metastasis were included. CTV expansions were 0mm for non-spine sites and anatomically defined per NRG-BR001 for spine sites. Local failure (LF) was defined as progression (per SPINO response assessment recommendations and imaging review by Radiation Oncology and Radiology) within the 95% isodose line. Marginal failure was considered progression within the 20%-95% isodose line. Outcomes were analyzed utilizing cumulative incidence with death as a competing risk. Univariable and multivariable Fine-Gray models were utilized to correlate LF rates with tumor, patient, and treatment-related variables, such as age, anatomical site, histology, GTV volume (cc), and PTV V95% (%). 29 patients (median age 58 years; median OS 8.1 months) received SBRT to 37 bone metastases (25 [68%] non-spine; 12 [32%] spine; 95% received 30 Gy in 3 fractions). Non-spine sites included the chest (n = 12), pelvis (n = 11), and femur (n = 1). The two most common histologies were lung (13 lesions [35%]) and breast (6 lesions [16%]). Median GTV volume was 7cc and PTV V95% was 98%. There were 4 (10.8%) local failures and zero marginal failures (or bone compartment failures) among treated lesions (median follow-up 8.1 months). In the multivariable Fine-Gray model, both lesion location (P < 0.001) as well as histology (P < 0.001) were associated with LF, driven by lesions in the chest and spine. Cumulative incidence of LF is presented in Table 1. In widely metastatic patients receiving immunotherapy, the rate of local failure was low and marginal failures were not observed after SBRT to bone metastases, even with 0mm CTV expansions for non-spine lesions. Both histology and lesion location were associated with local failure. These findings inform adequate target delineation for future trials utilizing SBRT to non-spine and spine bone metastases. [ABSTRACT FROM AUTHOR]

Observations on the phenology of Quercus ithaburensis were carried out during three consecutive years in Yahudia Nature Reserve, Israel. Bud-break occurred mostly in February with minor bud breaks in March-April, May and September-October. Trees shed leaves in October through January with a peak in December-January, but even during these months at least 10% of the trees remained evergreen. Branch growth took place during February-April. Shedding of 1-year old branches was recorded in half of the observations, accompanied by the formation of abscission tissue. Acorns generally began to ripen in November and shedding extended from December until January. The percentage of acorns attaining full ripeness varied considerably from branch to branch and from year to year, reaching approx. 20% of the number of acorns found in May. Ripe acorns appeared exclusively on 2-year old branches. The degree of fire damage to trees greatly depended on the intensity of the fire, which in turn depended on weather conditions, quantity of drypasture vegetation, and the location of the tree relative to cairns.Most trees were located within cairns. which constituted insulation belts, as no herbaceous vegetation grows on them. The effect of grazing intensity was decisive to the extent that fire damaged trees. Reduction of the bulk of dry pasture vegetation, affected the number of trees harmed, both as to their revival and their re-budding potential.Heavy grazing reduced to nearly half the number of trees suffering damage. After an early summer fire, budding was monitored, but not after a late summer fire. (C) 1999 Elsevier Science B.V. [ABSTRACT FROM AUTHOR]

Abstract: Spiral pair creation and dynamics is a widely occurring phenomenon in nature. It can appear in the heart tissue, causing severe arrhythmia, known as a figure-eight reentry. We consider the appearance of a spiral pair source, its minimal strength for survival, and the possible results of its interaction with a plane wave. In particular, its ability to outlast such an encounter is of interest. We also consider the question of exposing the source to a train of pulses, in terms of the frequency and angle of encounter. Results show different regimes of behavior, e.g. source annihilation, motion of the source away from, or towards the origin of the plane waves, its breaking and multiplication. Relevance of these results to heart arrhythmia and their possible cancellation by external pacing are briefly discussed. [Copyright &y& Elsevier]

Series-none compensated induction wireless power delivery link (SN-IPDL) was recently shown to be capable of achieving minimal complexity receiver with reduced losses in case of strong coupling, typical for applications such as power delivery into enclosed compartments such as industrial glove boxes and close-range inductive heating. Common practical applications often feature power delivery to varying loads which require a stable operational voltage. Operation at LIVO frequency allows establishing potentially feedback-free wireless power delivery with constant output voltage for varying loads. The paper reveals that due to nonzero equivalent series resistances and invalidity of the first-harmonic-approximation (FHA) based equivalent circuit, the output voltage remains affected by the load despite operation at LIVO frequency, residing within a certain range of values, lower and upper bounds of which correspond to rated and zero loading, respectively. This must be considered during SN-IPDL system design in order to assure that output voltage stays within allowed bounds for relevant loading conditions. This paper derives analytical expressions for output voltage bounds of a power-loaded series-to SN-IPDL, functioning at load-independent-voltage-output (LIVO) frequency. Time domain differential equations (DE)-based analysis is applied to derive the two bounds and allows (as a by-product) establishing an alternative FHA-based equivalent circuit of SN-IPDL operating in continuous conduction mode. Simulations and experiments based on 380V, 1.2 kW-rated prototype demonstrate excellent matching with analytical outcomes, validating the proposed analysis. • SN-IPTL operating at LIVO frequency is discussed. • Modified equivalent circuit is proposed. • Analytic expressions for output voltage range bounds are derived. • Simulations and experiments demonstrate close matching. [ABSTRACT FROM AUTHOR]

Background Kidney graft torsion and subsequent acute kidney injury is a rare yet potentially devastating complication of intraperitoneal kidney transplant. We report a case of this elusive diagnosis and describe kidney salvage by using laparoscopic fixation. Case Report A 49-year-old male patient presented with multiple episodes of anuric acute kidney injury 16 months after an uneventful combined orthotopic liver and kidney transplantation. After a thorough investigation, a diagnosis of kidney torsion was made, and the patient was urgently operated. Upon surgery, a complete torsion of a viable kidney was found. Laparoscopic fixation was achieved by using an absorbable mesh “pocket.” The patient has experienced no similar episodes in the subsequent year. Conclusions Nephrologists and surgeons should be aware of this rare complication. Prompt diagnosis and operative repair are crucial to save the graft. Prophylactic nephropexy should be considered in all intraperitoneal transplantations. [ABSTRACT FROM AUTHOR]

Abstract: This work presents results of particle mass, number and size measurements inside passenger cars (PCs), vans and urban buses. Effects of the in-cabin air purifier on particle concentrations and average size inside a vehicle are studied. Use of the air purifier leads to a dramatic reduction, by 95–99%, in the measured ultrafine particles number concentration inside a vehicle compared with outside readings. Extremely low particle concentrations may be reached without a danger of vehicle occupants'' exposure to elevated CO2 levels. The lowest values of particle concentrations inside a PC without air purifier are registered under the recirculation ventilation mode, but the issue of CO2 accumulation limits the use of this mode to very short driving events. Lower PM concentrations are found inside newer cars, if this ventilation mode is used. Great differences by a factor of 2.5–3 in PM10 concentrations are found between the PCs and the buses. Smoking inside a car leads to a dramatic increase, by approximately 90 times, in PM2.5 concentrations. [Copyright &y& Elsevier]

The energy expenditure (EE) of grazing cows and the metabolizable energy (ME) content of the pasture were measured over the course of 3 years under 29 representative treatments of grazing seasons, two different stocking rates, and two periods of confinement. Ten cows were used per treatment. Individual faecal output (FO) was measured for six of the grazing periods, and the metabolizable energy intake (MEI) was calculated from faecal output and in vitro digestibility. EE was estimated from measurements of daily heart rate (HR) and oxygen consumption, calibrated against oxygen consumption per heart beat (O2 pulse). The EE of lactating beef cows on lush pasture in the early spring reached 1260±31 kJ per (kg BW0.75 day); with that of non-lactating cows in the summer decreased to 481±53 kJ per (kg BW0.75 day). The EE and O2 Pulse increased with increasing MEI and ME. The diurnal and annual EE patterns were affected mainly by the herbage quality and intake. A high stocking rate resulted in a decrease in the cows'' body condition score (BCS), associated with a reduction in the EE of the cows in confinement. The effects of animal and field conditions on HR, EE, retained energy (RE) and skin temperatures (Tsk) were studied for the grazing periods, and not those from the confinement. Skin temperature was negatively associated with BCS. The HR, EE and retained energy (RE) were highly correlated with MEI (P<0.001). These dependencies can be used to predict MEI and RE from HR measurements. The high dependencies of the energy balance variables on the herbage ME and biomass and on the cows'' reproductive state offers a tool for predicting the cows'' RE from these simple measurements. [Copyright &y& Elsevier]

Intake and digesta kinetics of free-ranging beef cows in two stocking rates were estimated during the course of the grazing seasons, February through June 1998 and 1999. Area allocations were 0.9 and 1.8 ha/cow in the high (HSR) and low stocking rates (LSR), respectively. Cows with their calves were introduced to the plots from January to July and the calves were weaned in May each year. Intake measurements were carried out in eight cows in each plot three times in 1998 and twice in 1999. The herbage in the plots was sampled and analysed for chemical composition and in vitro digestibility at each time of measurements, and the standing biomass in the plot was determined at the same times. Intake and digesta kinetics were estimated from faecal concentrations of chromium and cobalt, following a single dose of Cr-mordanted NDF and Co-EDTA to the rumen. Dry matter and digestible matter intakes were calculated from the faecal output (FO) and in vitro DM digestibility. The effects of herbage composition and standing biomass on intake and digesta kinetics are presented and discussed. Dry and digestible matter intakes decreased, and digesta retention time increased as the season progressed from winter lush to summer dry herbage. The effect of stocking rate on intake was small and insignificant, but retention time of particles was numerically shorter in the high than in the low stocking rate in all the measurements, and those of solutes were shorter in the high than in the low stocking rate only in the winter. Intake was larger, and mean retention time of digesta was shorter in lactating then in non-lactating cows. [Copyright &y& Elsevier]