Preoperative chemoradiotherapy in older patients with rectal cancer guided by comprehensive geriatric assessment within a multidisciplinary team-a multicenter phase II trial.

BACKGROUND: The purpose of this study was to evaluate the safety and efficacy of preoperative concurrent chemoradiotherapy (preCRT) for locally advanced rectal cancer in older people who were classified as "fit" by comprehensive geriatric assessment (CGA). METHODS: A single-arm, multicenter, phase II trial was designed. Patients were eligible for this study if they were aged 70 years or above and met the standards of "fit" (SIOG1) as evaluated by CGA and of the locally advanced risk category. The primary endpoint was 2-year disease-free survival (DFS). Patients were scheduled to receive preCRT (50 Gy) with raltitrexed (3 mg/m2 on days 1 and 22). RESULTS: One hundred and nine patients were evaluated by CGA, of whom eighty-six, eleven and twelve were classified into the fit, intermediate and frail category. Sixty-eight fit patients with a median age of 74 years were enrolled. Sixty-four patients (94.1%) finished radiotherapy without dose reduction. Fifty-four (79.3%) patients finished the prescribed raltitrexed therapy as planned. Serious toxicity (grade 3 or above) was observed in twenty-four patients (35.3%), and fourteen patients (20.6%) experienced non-hematological side effects. Within a median follow-up time of 36.0 months (range: 5.9-63.1 months), the 2-year overall survival (OS), cancer-specific survival (CSS) and disease-free survival (DFS) rates were 89.6% (95% CI: 82.3-96.9), 92.4% (95% CI: 85.9-98.9) and 75.6% (95% CI: 65.2-86.0), respectively. Forty-eight patients (70.6%) underwent surgery (R0 resection 95.8%, R1 resection 4.2%), the corresponding R0 resection rate among the patients with positive mesorectal fascia status was 76.6% (36/47). CONCLUSION: This phase II trial suggests that preCRT is efficient with tolerable toxicities in older rectal cancer patients who were evaluated as fit based on CGA. TRIAL REGISTRATION: The registration number on ClinicalTrials.gov was NCT02992886 (14/12/2016).

A prospective phase II clinical trial of total neoadjuvant therapy for locally advanced gastric cancer and gastroesophageal junction adenocarcinoma.

To investigate the safety and efficacy of the neoadjuvant chemoradiotherapy (NCRT) followed by neoadjuvant consolidation chemotherapy (NCCT) and surgery for locally advanced gastric cancer (GC) or gastroesophageal junction (GEJ) adenocarcinoma. Patients diagnosed as locally advanced GC or Siewert II/III GEJ adenocarcinoma with clinical stage T3-4 and/or N positive were prospectively enrolled. Patients underwent NCRT (45 Gy/25 fractions) with concurrent S-1, followed by NCCT (4 to 6 cycles of the SOX regimen) 2 to 4 weeks after NCRT. Gastric cancer radical resection with D2 lymph node dissection was performed 4 to 6 weeks after the total neoadjuvant therapy. The study was conducted from November 2019 to January 2023, enrolling a total of 46 patients. During the NCRT, all patients completed the treatment without dose reduction or delay. During the NCCT, 32 patients (69.6%) completed at least 4 cycles of chemotherapy. Grade 3 or higher adverse events in NCRT (5 cases) were non-hematological. During the course of NCCT, a notable occurrence of hematological toxicities was observed, with grade 3 or higher leukopenia (9.7%) and thrombocytopenia (12.2%) being experienced. A total of 28 patients (60.9%) underwent surgery, achieving R0 resection in all cases. A significant proportion of cases (71.4%) exhibited pathological downstaging to ypT0-2, while 10 patients (35.7%) demonstrated a pathologic complete response (pCR). The total neoadjuvant therapy comprising NCRT followed by NCCT and surgery demonstrates a low severe adverse reactions and promising efficacy, which could be considered as a viable treatment for locally advanced GC or GEJ adenocarcinoma.Trial registration: Clinicaltrials.gov (registration number: NCT04062058); the full date of first trial registration was 20/08/2019.

Treatment outcome, toxicity, and quality of life of patients with bronchus-associated lymphoid tissue lymphoma.

The disease failure patterns and optimal treatment of bronchus-associated lymphoid tissue (BALT) lymphoma are unknown. This retrospective study involved 71 patients with primary BALT lymphoma who had received radiotherapy (RT), surgery, immunochemotherapy (IC), or observation. The median follow-up time was 66 months. The 5-year overall survival and lymphoma-specific survival were 91.2% and 96.1%, respectively, and were not significantly different among treatments. The 5-year cumulative incidence of overall failure for RT, surgery, IC, and observation was 0%, 9.7% (p = .160), 30.8% (p = .017), and 31.3% (p = .039). There was no grade ≥3 toxicity in RT group according to the CTCAE 5.0 reporting system. Quality of life (QoL) was at similarly good levels among the treatment groups. BALT lymphoma had a favorable prognosis but persistent risk of relapse after IC or observation. Given the very low disease failure risk and good QoL, RT remains an effective initial treatment for BALT lymphoma.

BALT lymphoma has a favorable prognosis but a persistent progression and relapse risk.Radiotherapy is associated with lower failure of disease progression and relapse, low toxicity and good quality of life.

Disparities in mortality risk after diagnosis of hematological malignancies in 185 countries: A global data analysis.

This study was to report proxy measures for mortality risk in patients with hematological malignancies across 185 countries globally and explore its association with their socioeconomic status and treatment. The incidence, mortality, and 5-year prevalence data were extracted from the GLOBOCAN database. The data regarding the human development index (HDI), gross national income (GNI), vulnerability index, and concordance with cancer Essential Medicines List (EML) were obtained from open-source reports. The ratio of mortality to 5-year-prevalence (MPR) and that of mortality to incidence (MIR) were calculated and age-standardized using Segi's world standard population. Finally, the possible associations were assessed using Pearson correlation analyses. In 2020, the global incidence, mortality, and 5-year prevalence of HMs were 1,278,362, 711,840, and 3,616,685, respectively. Global age-standardized MPR and MIR were 0.15 and 0.44, respectively; they varied significantly among 6 regions, 185 countries, 4 HM types, and 4 HDI groups worldwide. Older populations always had higher ratios. The correlation of MPRs and MIRs with HDI, GNI, and concordance with cancer EML was negative, whereas it was positive with the vulnerability index (lower was better). Increasing access to cancer drugs in resource-limited regions with a focus on vulnerable children may aid in reducing HM-related mortality risk.

Optimizing the prognostic capacity of baseline 18F-FDG PET/CT metabolic parameters in extranodal natural killer/T-cell lymphoma by using relative and absolute thresholds.

Objectives: To investigate the prognostic capacity of baseline 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) metabolic parameters in extranodal natural killer/T-cell lymphoma (ENKTCL), and the influence of relative thresholds (RT) and absolute thresholds (AT) selection on prognostic capacity. Materials and methods: Metabolic tumor volume (MTV)-based parameters were defined using RTs (41 % or 25 % of maximum standardized uptake value [SUVmax]), ATs (SUV 2.5, 3.0, 4.0, or mean liver uptake) in 133 patients. Metabolic parameters were classified into avidity-related parameters (SUVmax, mean SUV [SUVmean], standard deviation of SUV [SUVsd]), volume-related parameters (RT-MTV), and avidity- and volume-related parameters (total lesion glycolysis [TLG] and AT-MTV). The prognostic capacity of the metabolic parameters and the effects of different threshold types (RT vs. AT) were evaluated. Results: All metabolic parameters were moderately associated with prognosis. However, the area under the receiver operating characteristic curve of MTV and TLG was slightly higher than that of avidity-related parameters for predicting 5-year progression-free survival (PFS) (0.614-0.705 vs. 0.563-0.609) and overall survival (OS) (0.670-0.748 vs. 0.562-0.593). Correlations of MTV and avidity-related parameters differed between RTs (r < 0.06, P = 0.324-0.985) and ATs (r 0.56-0.84, P ≤ 0.001). AT-MTV was the optimal predictor for PFS and OS, while RT-TLG was the optimal predictor for PFS, and the combination of RT-MTV with SUVmax was the optimal predictor for OS. Conclusion: The incorporation of volume and avidity significantly improved the prognostic capacity of PET in ENKTCL. Composite parameters that encompassed both avidity and volume were recommended.

Prediction of 5-year overall survival of diffuse large B-cell lymphoma on the pola-R-CHP regimen based on 2-year event-free survival and progression-free survival.

This study aimed to predict the 5-year overall survival (OS) benefit of pola-R-CHP versus R-CHOP in the POLARIX trial based on the 2-year event-free survival (EFS) and progression-free survival (PFS) rates in diffuse large B-cell lymphoma (DLBCL). We identified randomized controlled trials (RCT) published before 31 May 2023. The correlation between the logarithmic (log) hazard ratio (HR) for EFS (HREFS ) or PFS (HRPFS ) and the HR for OS (HROS ) was estimated at the trial-level. Correlation analysis was performed between 2-year PFS or EFS and 5-year OS rates at the treatment arm-level. Linear regression models were used to calculate the 5-year OS of pola-R-CHP and R-CHOP. In the included 20 RCTs, a linear correlation between HREFS (r = 0.765) or HRPFS (r = 0.534) and HROS was observed at the trial- level. Two-year EFS (r = 0.918) or 2-year PFS (r = 0.865) correlated linearly with 5-year OS. Linear regression analysis between 2-year EFS/PFS and 5-year OS gave estimated 5-year OS rates between pola-R-CHP and R-CHOP of 6.4% and 6.3%, respectively. Two-year EFS and PFS are feasible early endpoints in patients with DLBCL treated primarily with immunochemotherapy. The pola-R-CHP regimen is expected to improve 5-year OS.

[A case of neonatal Netherton syndrome]. / 新生儿Netherton综合征1例.

A male infant, aged 6 days, was admitted to the hospital due to respiratory distress and systemic desquamative rash after birth. The infant presented with erythema and desquamative rash, respiratory failure, recurrent infections, chronic diarrhea, hypernatremic dehydration, and growth retardation. Comprehensive treatment, including anti-infection therapy, intravenous immunoglobulin administration, and skin care, resulted in improvement of the rash, but recurrent infections persisted. Second-generation sequencing revealed a homozygous mutation in the SPINK5 gene, consistent with the pathogenic variation of Netherton syndrome. The family opted for palliative care, and the infant died at the age of 2 months after discharge. This report documents a case of Netherton syndrome caused by the SPINK5 gene mutation in the neonatal period, and highlights multidisciplinary diagnosis and therapy for this condition.

Cellulose-based bi-layer hydrogel evaporator with a low evaporation enthalpy for efficient solar desalination.

Interfacial evaporation through hydrogel-based evaporators is emerging as a sustainable and cost-effective strategy for drinkable water production. Herein, a specially designed bi-layer hydrogel evaporator was fabricated and used for efficient solar water desalination. With cotton linter as cellulose precursor, it was dispersed in a highly concentrated ZnCl2 (65 %) solution, and cross-linked by epichlorohydrin to prepare cellulose composite hydrogel. After removing inorganic salts by salt-leaching, polyaniline (PANi) with broadband and wide-range light absorption was then integrated into the top surface of hydrogel through in situ polymerization to construct a bi-layer evaporator. As a solar evaporator, the water could be evaporated with a low-energy demand, and the heat from the sunlight could be confined at the interface to achieve efficient water evaporation. Therefore, the hydrogel evaporator demonstrates an optimal water evaporation rate of 3.02 kg m-2 h-1 and photothermal conversion efficiency of 89.09 % under 1 sun (1 kW m-2) irradiation. This work provides new possibilities for efficient solar water purification systems with assured water quality.

Diagnostic performance and clinical impacts of metagenomic sequencing after allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Metagenomic Next-Generation Sequencing (mNGS) is a rapid, non-culture-based, high-throughput technique for pathogen diagnosis. Despite its numerous advantages, only a few studies have investigated its use in patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). METHODS: We conducted a retrospective analysis of 404 mNGS tests performed on 264 patients after allo-HSCT. The tests were divided into three groups (Phase A, B, C) based on the time spent hospitalized post-transplantation, and we evaluated the analytical performance of mNGS in comparison with conventional microbiological tests (CMT), while also analyzing its clinical utility for clinical impacts. RESULTS: Metagenomic sequencing demonstrated a significantly higher rate of positive microbiological findings as compared to CMT (334/404 (82.7 %) vs. 159/404 (39.4 %), respectively, P < 0.001). The detection rates by both mNGS and CMT varied across the three-phase (mNGS: A-60/89 (67.4 %), B-147/158 (93.0 %), C-125/157 (79.6 %), respectively, P < 0.001; CMT: A-21/89 (23.6 %), B-79/158 (50.0 %), C-59/157 (37.6 %), respectively, P < 0.001). The infection sites and types of pathogens were also different across the three phases. Compared to non-GVHD cases, mNGS detected more Aspergillus spp. and Mucorales in GVHD patients (Aspergillus: 12/102 (11.8 %) vs. 8/158 (5.1 %), respectively, P = 0.048; Mucorales: 6/102 (5.9 %) vs. 2/158 (1.3 %), respectively, P = 0.035). Forty-five (181/404) percent of mNGS tests yielded a positive impact on the clinical diagnosis, while 24.3 % (98/404) of tests benefited the patients in antimicrobial treatment. CONCLUSION: mNGS is an indispensable diagnostic tool in identifying pathogens and optimizing antibiotic therapy for hematological patients receiving allo-HSCT.

A case of neonatal Netherton syndrome / 中国当代儿科杂志

A male infant, aged 6 days, was admitted to the hospital due to respiratory distress and systemic desquamative rash after birth. The infant presented with erythema and desquamative rash, respiratory failure, recurrent infections, chronic diarrhea, hypernatremic dehydration, and growth retardation. Comprehensive treatment, including anti-infection therapy, intravenous immunoglobulin administration, and skin care, resulted in improvement of the rash, but recurrent infections persisted. Second-generation sequencing revealed a homozygous mutation in the SPINK5 gene, consistent with the pathogenic variation of Netherton syndrome. The family opted for palliative care, and the infant died at the age of 2 months after discharge. This report documents a case of Netherton syndrome caused by the SPINK5 gene mutation in the neonatal period, and highlights multidisciplinary diagnosis and therapy for this condition.

Quality assurance in a phase III, multicenter, randomized trial of POstmastectomy radioThErapy in Node posiTive breast cancer with or without Internal mAmmary nodaL irradiation (POTENTIAL): a planning benchmark case.

PURPOSE: To report the planning benchmark case results of the POTENTIAL trial-a multicenter, randomized, phase 3 trial-to evaluate the value of internal mammary nodal (IMN) irradiation for patients with high-risk breast cancer. METHODS: All participating institutions were provided the outlines of one benchmark case, and they generated radiation therapy plans per protocol. The plans were evaluated by a quality assurance team, after which the institutions resubmitted their revised plans. The information on beams arrangement, skin flash, inhomogeneity corrections, and protocol compliance was assessed in the first and final submission. RESULTS: The plans from 26 institutions were analyzed. Some major deviations were found in the first submission. The protocol compliance rates of dose coverage for the planning target volume of chest wall, supraclavicular fossa plus axilla, and IMN region (PTVim) were all significantly improved in the final submission, which were 96.2% vs. 69.2%, 100% vs. 76.9%, and 88.4% vs. 53.8%, respectively. For OARs, the compliance rates of heart Dmean, left anterior descending coronary artery V40Gy, ipsilateral lung V5Gy, and stomach V5Gy were significantly improved. In the first and final submission, the mean values of PTVim V100% were 79.9% vs. 92.7%; the mean values of heart Dmean were 11.5 Gy vs. 9.7 Gy for hypofractionated radiation therapy and 11.5 Gy vs. 11.0 Gy for conventional fractionated radiation therapy, respectively. CONCLUSION: The major deviations were corrected and protocol compliance was significantly improved after revision, which highlighted the importance of planning benchmark case to guarantee the planning quality for multicenter trials.

Decreased lymphoma-related deaths and improved long-term relative survival with radiotherapy for early-stage diffuse large B-cell lymphoma in the rituximab era.

BACKGROUND: We aimed to investigate the incidence of lymphoma-related death (LRD) and the long-term net survival benefit of radiotherapy (RT) for early-stage diffuse large B-cell lymphoma (DLBCL) in the rituximab era. METHODS: 10,841 adults diagnosed with early-stage DLBCL between 2002-2015 were retrospectively analyzed using data from the Surveillance, Epidemiology, and End Results database. Primary therapy was categorized into combined-modality treatment (CMT, n = 3,631) and chemotherapy alone (n = 7,210). Competing risk analysis was used to evaluate the cumulative incidence of mortality. Inverse probability of treatment weighting (IPTW) was used to balance groups. The net survival benefit of RT was estimated through relative survival (RS), standardized mortality ratio (SMR), and transformed Cox regression, while controlling for background mortality. RESULTS: Patients initially treated with CMT had a lower cumulative incidence of LRD compared to those who received chemotherapy alone (HR 0.63, 95%CI: 0.57-0.69; P < 0.001). The 10-year overall survival (OS), RS, and SMR for CMT were 66.1%, 85.0%, and 1.71 respectively, which were significantly better than those for chemotherapy alone (53.0%; 69.8%; 2.62; all P < 0.001). IPTW and multivariable analysis revealed that the addition of RT led to better OS (HR 0.67, 95%CI: 0.62-0.71; P < 0.001) and RS (HR 0.69, 95%CI: 0.65-0.74; P < 0.001). Moreover, compared with chemotherapy alone, the benefit of OS and RS for CMT increased over time within 10 years of diagnosis. CONCLUSION: RT reduced LRD and improved the long-term net survival in early-stage DLBCL in the rituximab era. Further prospective studies are warranted to assess the specific patient population that would benefit the most from consolidative RT in early-stage DLBCL.

Effect of low-temperature stress on the survival of Meloidogyne incognita and its application in greenhouse of northern China.

We examined the effects of low temperature on egg hatching and killing rate of the 2nd instars of Meloi-dogyne incognita (J2) in the laboratory. We further evaluated the effects of two soil treatment methods on the survival rate of M. incognita in northern China in a field experiment. The results of laboratory experiment showed that survival rate of J2 was 0 after being subjected to -7 ℃ for 24 hours, and that egg hatching was completely inhibited 24 hours after being subjected to -9 ℃. The survival rate of J2 was 0 after being subjected to -1, -2, -3, and -4 ℃ for 8, 5, 3, and 1.5 d, respectively. Egg hatching was completely inhibited after being subjected to -2, -3, -4, and -5 ℃ for 9, 6, 4, and 1 d, respectively. Results of the fitting analysis showed that both the relationships between the temperature and the lethal time of J2 as well as the temperature and the non-hatching time of the eggs followed exponential functions. The results of field test showed that death rate of M. incognita in 0-50 cm soil layer after ridging treatment and 0-30 cm soil layer after leveling treatment could reach 100%, while the disease index of the former in 30-40 cm and 40-50 cm was 84.9% and 75.8%, respectively, which was lower than that in the greenhouse. Our results suggest that preventing and controlling M. incognita in greenhouses through low-tempe-rature in winter could achieve a better control effect in Yulin City and the northward region. The proposed technique is convenient and has high potential for popularization.

Copper sulfide integrated functional cellulose hydrogel for efficient solar water purification.

Hydrogels are emerging materials for solar steam generation to alleviate water scarcity. Herein, a semiconductor of copper sulfide (CuS) was integrated into cellulose hydrogel to fabricate a solar steam evaporator. Sustainable and low-cost cotton linter (cellulose) was regenerated by NaOH/urea solvent. Epichlorohydrin was added as a cross-linking agent to enhance the mechanical robustness of the composite hydrogel, and CuS crystals were tightly attached to cellulose fibers and uniformly distributed in the hydrogel matrix. Under simulated solar light, a heating zone was established at the top surface of the composite hydrogel, and CuS can efficiently absorb and convert light into heat. The hydrophilic cellulose network affords an adequate water supply and a low water vaporization enthalpy. By tuning the CuS loadings, the optimized evaporation rate and solar-to-vapor efficiency could reach 2.2 kg/m2/h and 87 %, respectively, under 1 sun irradiation. The evaporation rate remained above 2.1 kg/m2/h after 48 h of irradiation. Moreover, the hydrogels (with a CuS loading of 30 wt%) showed a efficiently photocatalytic degradation of 95 % for methylene blue and 92 % for Rhodamine B. Such functional hydrogel evaporator holds great potential for practical water treatment and solar-driven applications.

Breast-conserving surgery versus mastectomy for treatment of breast cancer after neoadjuvant chemotherapy.

Background: To compare recurrence and survival outcomes between breast-conserving surgery (BCS) and mastectomy after neoadjuvant chemotherapy (NACT). Methods: The data of 730 patients who underwent NACT between 2000 and 2014 were retrospectively reviewed. A total of 104 (14.2%) patients received BCS and 626 (85.8%) received mastectomy. Locoregional recurrence (LRR), distant metastases (DM), disease-free survival (DFS), breast cancer-specific survival (BCSS), and overall survival (OS) were analyzed using the Kaplan-Meier method. The impact of BCS versus mastectomy on outcomes was assessed by multivariate Cox models. Inverse probability of treatment weighting (IPTW) was used to balance covariates between the two groups. Results: The median follow-up of BCS and mastectomy groups were 86.5 and 87.4 months, respectively. There were significant differences in distribution of most baseline characteristics between two groups. Compared with those who underwent mastectomy, the patients with BCS had similar 5-year LRR, DM, and DFS rates, but had significantly higher 5-year BCSS (98.9% vs. 90.4%, P = 0.005) and OS (98.9% vs. 90.1%, P = 0.003) rates. Multivariate analysis also showed that BCS significantly improved BCSS (HR = 0.27, 95% CI: 0.08-0.85, P = 0.025) and OS (HR = 0.25, 95% CI: 0.08-0.79, P = 0.018). After IPTW adjustment, the LRR, DM, DFS, BCSS and OS between two groups had no significant differences. Conclusions: The recurrence and survival outcomes are comparable with BCS and mastectomy. Thus, BCS is a safe treatment option for selected breast cancer patients after NACT.

Outcome and risk prediction of early progression in patients with extranodal natural killer/T cell lymphoma from the CLCG study.

Recently, progression-free survival at 24 months (PFS24) was defined as clinically relevant for patients with extranodal NK/T cell lymphoma. Herein, the clinical data from two independent random cohorts (696 patients each in the primary and validation datasets) were used to develop and validate a risk index for PFS24 (PFS24-RI), and evaluate its ability to predict early progression. Patients achieving PFS24 had a 5-year overall survival (OS) of 95.8%, whereas OS was only 21.2% in those failing PFS24 (P<0.001). PFS24 was an important predictor of subsequent OS, independent of risk stratification. The proportion of patients achieving PFS24 and 5-year OS rates correlated linearly among risk-stratified groups. Based on multivariate analysis of the primary dataset, the PFS24-RI included five risk factors: stage II or III/IV, elevated lactate dehydrogenase, Eastern Cooperative Oncology Group score ≥2, primary tumor invasion, and extra-upper aerodigestive tract. PFS24-RI stratified the patients into low-risk (0), intermediate-risk (1-2), high-risk (≥3) groups with different prognoses. Harrell's C-index of PFS24-RI for PFS24 prediction was 0.667 in the validation dataset, indicating a good discriminative ability. PFS24-RI calibration indicated that the actual observed and predicted probability of failing PFS24 agreed well. PFS24-RI provided the probability of achieving PFS24 at an individual patient level.

Voluntary Deep Inspiration Breath-Hold (VDIBH) Whole-Breast Irradiation Assisted by Optical Surface Monitoring System (OSMS) in Patients With Left-Sided Breast Cancer: A Prospective Phase II Study.

Objectives: To investigate the dosimetric advantages of the voluntary deep inspiration breath-hold technique assisted by optical surface monitoring system for whole breast irradiation in left breast cancer after breast-conserving surgery and verify the reproducibility and acceptability of this technique. Methods: Twenty patients with left breast cancer receiving whole breast irradiation after breast-conserving surgery were enrolled in this prospective phase II study. Computed tomography simulation was performed during both free breathing and voluntary deep inspiration breath-hold for all patients. Whole breast irradiation plans were designed, and the volumes and doses of the heart, left anterior descending coronary artery, and lung were compared between free breathing and voluntary deep inspiration breath-hold. Cone beam computed tomography was performed for the first 3 treatments, then weekly during voluntary deep inspiration breath-hold treatment to evaluate the accuracy of the optical surface monitoring system technique. The acceptance of this technique was evaluated with in-house questionnaires completed by patients and radiotherapists. Results: The median age was 45 (27-63) years. All patients received hypofractionated whole breast irradiation using intensity-modulated radiation therapy up to a total dose of 43.5 Gy/2.9 Gy/15f. Seventeen of the 20 patients received concomitant tumor bed boost to a total dose of 49.5 Gy/3.3 Gy/15f. Voluntary deep inspiration breath-hold showed a significant decrease in the heart mean dose (262 ± 163 cGy vs 515 ± 216 cGy, P < .001) and left anterior descending coronary artery (1191 ± 827 cGy vs 1794 ± 833 cGy, P < .001). The median delivery time of radiotherapy was 4 (1.5-11) min. The median deep breathing cycles were 4 (2-9) times. The average score for acceptance of voluntary deep inspiration breath-hold by patients and radiotherapists was 8.7 ± 0.9 (out of 12) and 10.6 ± 3.2 (out of 15), respectively, indicating good acceptance by both. Conclusions: The voluntary deep inspiration breath-hold technique for whole breast irradiation after breast-conserving surgery in patients with left breast cancer significantly reduces the cardiopulmonary dose. Optical surface monitoring system-assisted voluntary deep inspiration breath-hold is reproducible and feasible and showed good acceptance by both patients and radiotherapists.

Riluzole in Spinal Cord Injury Study (RISCIS)-Pharmacokinetic (PK) Sub-Study: An Analysis of Pharmacokinetics, Pharmacodynamics, and Impact on Axonal Degradation of Riluzole in Patients With Traumatic Cervical Spinal Cord Injury Enrolled in the RISCIS Phase III Randomized Controlled Trial.

To date, no drug therapy has shown significant efficacy in improving functional outcomes in patients with acute spinal cord injury (SCI). Riluzole is an approved benzothiazole sodium channel blocker to attenuate neurodegeneration in amyotrophic lateral sclerosis (ALS) and is of interest for neuroprotection in SCI. In a Phase I clinical trial (ClinicalTrials.gov Identifier: NCT00876889), riluzole was well tolerated with a 2-week treatment at the dose level approved for ALS and exhibited potential efficacy in patients with SCI. The acute and progressive nature of traumatic SCI and the complexity of secondary injury processes alter the pharmacokinetics (PK) of therapeutics. In the PK sub-study of the multi-center, randomized, placebo-controlled, double-blinded Riluzole in Spinal Cord Injury Study (RISCIS) Phase II/III trial (ClinicalTrials.gov Identifier: NCT01597518), a total of 32 SCI patients were enrolled, and most of our patients were middle-age Caucasian males with head and neck injuries. We studied the PK and pharmacodynamics (PD) of riluzole on motor recovery, measured by International Standards for Neurological Classification of SCI (ISNCSCI) Motor Score at injury and at 3-month and 6-month follow-ups, along with levels of the axonal injury biomarker phosphorylated neurofilament heavy chain (pNF-H), during the 2-week treatment. PK modeling, PK/PD correlations were developed to identify the potential effective exposure of riluzole for intended PD outcomes. The longitudinal impacts of SCI on the PK of riluzole are characterized. A time-varying population PK model of riluzole is established, incorporating time-varying clearance and volume of distribution from combined data of Phase I and Phase II/III trials. With the developed model, a rational, optimal dosing scheme can be designed with time-dependent modification to preserve the required therapeutic exposure of riluzole. The PD of riluzole and the relationship between PK and neurological outcomes of the treatment were established. The time course of efficacy in total motor score improvement (ΔTMS) and pNF-H were monitored. A three-dimensional (3D) PK/PD correlation was established for ΔTMS at 6 months with overall riluzole exposure area under the curve for Day 0-Day14 (AUCD0-D14) and baseline TMS for individual patients. Patients with baseline TMS between 1 and 36 benefited from the optimal exposure range of 16-48 mg*h/mL. The PD models of pNF-H revealed the riluzole efficacy, as treated subjects exhibited a diminished increase in progression of pNF-H, indicative of reduced axonal breakdown. The independent parameter of area between effective curves (ABEC) between the time profiles of pNF-H in placebo and treatment groups was statistically identified as a significant predictor for the treatment effect on the biomarker. A mechanistic clinical outcomes (CO)/PD (pNF-H) model was established, and the proposed structure demonstrated the feasibility of PK/PD/CO correlation model. No appreciable hepatic toxicity was observed with the current riluzole treatment regimen. The development of effective treatment for SCI is challenging. However, the future model-informed and PK-guided drug development and regimen modification can be rationally executed with the optimal dosing regimen design based on the developed 3D PK/PD model. The PK/PD/CO model can serve as a rational guide for future drug development, PKPD model refinement, and extension to other studies in SCI settings.