VTd-PACE and VTd-PACE-like regimens are effective salvage therapies in difficult-to-treat relapsed/refractory multiple myeloma: a single-center experience.

Although treatment options for multiple myeloma (MM) are rapidly evolving, there still remain difficult-to-treat situations, especially in relapsed and/or refractory (r/r) disease. When modern therapies are exhausted, or emergency treatment is needed for high tumor burden, classic chemotherapy combination regimens like the VTd-PACE regimen and its modifications (PACE-M) may also be beneficial as bridging to subsequent treatment options. This single-center retrospective analysis aimed to investigate the outcome of VTd-PACE and PACE-M salvage therapy in 31 heavily pretreated r/r MM patients. The primary objective was the overall response rate (ORR). Secondary objectives were median progression-free survival (mPFS), median overall survival (mOS), safety, and renal response. Median age was 59 years (range 39-75), and 71% of patients were male. R-ISS stratification showed high-risk MM in 48%. The median number of prior therapies was 3, with 23 patients being triple- and 12 penta-refractory (74% and 39%). ORR was 71%, including 23% of patients achieving a very good partial response. Median duration of follow-up was 15 months (range 0-29 months). mPFS and mOS were 3 months (95% CI 0.27-5.74) and 11 months (95% CI 3.66-18.35), respectively. In 26 patients (83.9%), at least one subsequent treatment (stem cell transplant or BCMA-directed) was administered. Renal function significantly improved after VTd-PACE or PACE-M treatment (p = 0.032). Non-hematological adverse events ≥ grade 3 were predominantly infections. VTd-PACE and PACE-M are effective salvage therapies in difficult-to-treat situations in heavily pre-treated r/r MM, including patients with impaired renal function. VTd-PACE and PACE-M can be successfully used as bridging therapy for subsequent treatment.

Real-world clinical outcomes in patients with relapsed and refractory multiple myeloma receiving VTD-PACE treatment in the era of monoclonal antibodies.

Bortezomib (Velcade), thalidomide, dexamethasone, platinum (cisplatin), adriamycin (doxorubicin), cyclophosphamide, and etoposide (VTD-PACE) are commonly used as salvage treatment for patients with relapsed/refractory multiple myeloma (RRMM). However, its outcomes in the era of monoclonal antibodies remain unclear. Therefore, this retrospective cohort study assessed the clinical outcomes of 60 patients with RRMM (median four prior treatment lines) administered VTD-PACE. The median follow-up period was 11.1 months, during which they received a median of two cycles of VTD-PACE. The overall response rate (ORR) was 66.7%; ORRs of 53.1 and 82.1% were noted in patients with ≥ 4 and ≤ 3 prior lines (P = 0.027), respectively. The median overall survival (OS) was 17 months, with a median progression-free survival (PFS) of 9.8 months. Using the 3-month time point after VTD-PACE treatment as a landmark, 54 patients were still alive. Landmark analysis was conducted for PFS and OS of patients who received or did not receive HSCT or CART after VTD-PACE treatment. Patients who underwent subsequent hematopoietic stem cell transplantation (HSCT) or chimeric antigen receptor T-cell therapy (CART) following VTD-PACE showed a trend of longer PFS and OS than those who did not undergo subsequent HSCT or CART. The median OS in patients with and without renal dysfunction was 10.7 months and 21.5 months, respectively (P = 0.0091). Therefore, VTD-PACE is useful as a bridging therapy for HSCT or CART, as a response can be expected regardless of organ damage, disease risk, or history of anti-CD38 antibody use.

A Multi-Task Fusion Strategy-Based Decision-Making and Planning Method for Autonomous Driving Vehicles.

The autonomous driving technology based on deep reinforcement learning (DRL) has been confirmed as one of the most cutting-edge research fields worldwide. The agent is enabled to achieve the goal of making independent decisions by interacting with the environment and learning driving strategies based on the feedback from the environment. This technology has been widely used in end-to-end driving tasks. However, this field faces several challenges. First, developing real vehicles is expensive, time-consuming, and risky. To further expedite the testing, verification, and iteration of end-to-end deep reinforcement learning algorithms, a joint simulation development and validation platform was designed and implemented in this study based on VTD-CarSim and the Tensorflow deep learning framework, and research work was conducted based on this platform. Second, sparse reward signals can cause problems (e.g., a low-sample learning rate). It is imperative for the agent to be capable of navigating in an unfamiliar environment and driving safely under a wide variety of weather or lighting conditions. To address the problem of poor generalization ability of the agent to unknown scenarios, a deep deterministic policy gradient (DDPG) decision-making and planning method was proposed in this study in accordance with a multi-task fusion strategy. The main task based on DRL decision-making planning and the auxiliary task based on image semantic segmentation were cross-fused, and part of the network was shared with the main task to reduce the possibility of model overfitting and improve the generalization ability. As indicated by the experimental results, first, the joint simulation development and validation platform built in this study exhibited prominent versatility. Users were enabled to easily substitute any default module with customized algorithms and verify the effectiveness of new functions in enhancing overall performance using other default modules of the platform. Second, the deep reinforcement learning strategy based on multi-task fusion proposed in this study was competitive. Its performance was better than other DRL algorithms in certain tasks, which improved the generalization ability of the vehicle decision-making planning algorithm.

Radiographic vertical tracheal diameter assessment at different levels along the trachea as an alternative method for the evaluation of the tracheal diameter in non-brachycephalic small breed dogs.

BACKGROUND: Tracheal narrowing due to congenital tracheal hypoplasia, acquired tracheal stenosis and tracheal collapse can lead to life-threatening respiratory distress. Tracheal hypoplasia has been identified in brachycephalic dog breeds, predominantly English Bulldogs, by measuring the tracheal diameter compared to the diameter of the thoracic inlet and creating a ratio. However, reference ranges for tracheal diameter have not been established for non-brachycephalic small breed dogs. It would be advantageous to have established tracheal diameters for non-brachycephalic small breed dogs, as these are the dogs most at risk of tracheal collapse. The main objective, of this study was to radiographically evaluate vertical tracheal diameter (VTD) at three standardized locations along the trachea of non-brachycephalic small breed dogs, in an attempt to further establish a screening diagnostic protocol for canine tracheal hypoplasia. Medical records and thoracic radiographs of non-brachycephalic small breed dogs without respiratory disease were reviewed. Right lateral radiographs were reviewed. The absolute and average VTDs at three locations (location A: caudal cervical VTD; location B thoracic inlet VTD; location C: intrathoracic VTD) were standardized by manubrium length (ML), as well as by the previously utilized thoracic inlet distance (Ti-D) and proximal 3rd rib width (PR3-W) to calculate manubrium-tracheal index (M-TI), thoracic inlet-tracheal index (Ti-TI), and proximal R3-tracheal score (PR3-TS), respectively. Correlations between averaged tracheal diameter and each of the ML, Ti-D, and PR3-W, and between M-TI and each of Ti-TI and PR3-TS were calculated. RESULTS: Eighty-one healthy dogs met the criteria for inclusion. Significant differences (P < 0.0001) were identified among the mean values of the absolute and standardized VTDs at levels A, B, and C. The smallest tracheal diameter was identified at the level of the thoracic inlet (Level B). The average VTD correlated better with ML (rs = 0.82, P < 0.0001) compared to Ti-D and PR3-W. A relatively strong correlation (rs = 0.77, P < 0.0001) was identified between the averaged manubrium tracheal index (M-TI) and thoracic inlet tracheal index (Ti-TI). CONCLUSION: M-TI is an appropriate alternative to Ti-TI and PR3-TS to radiographically evaluate VTD in dogs. M-TI < 0.43, < 0.34, or < 0.38 at level A, B, or C, respectively, may indicate tracheal hypoplasia in non-brachycephalic small breed dogs. Screening of canine VTD could be achieved using M-TI.

Phase II clinical trial of personalized VCD-VTD sequential therapy using the Vulnerable Elders Survey-13 (VES-13) for transplant-ineligible patients with newly diagnosed multiple myeloma.

The Vulnerable Elders Survey-13 (VES-13) is a well-studied simplified frailty screening tool for elderly patients in the oncology setting. We conducted a prospective clinical trial to evaluate the efficacy and safety of dose-adjusted treatment based on the VES-13 in transplant-ineligible patients with newly diagnosed multiple myeloma (MM). In the Fit group (VES-13 <3), patients were treated with 4 cycles of standard-dose VCD (bortezomib, cyclophosphamide, and dexamethasone) followed by 4 cycles of standard-dose VTD (bortezomib, thalidomide, and dexamethasone). In the Frail group (VES-13 ≥3), patients were treated with 4 cycles of reduced-dose VCD followed by 4 cycles of reduced-dose VTD. The median age was 75 years (66-86 years), and 34% of the cases were classified as PS 3. Among the Fit group (n=16), the overall response rate (ORR) was 87.5%. Among the Frail group (n=31), the ORR was 87.1%. There were no significant differences in progression-free survival (PFS) and overall survival (OS) between the Fit and Frail groups (3-year PFS: 68.8% vs 53.3%, P = 0.658; 3-year OS: 70.0% vs 77.6%, P = 0.919). Personalized VCD-VTD sequential therapy based on the VES-13 was associated with high response rates and showed acceptable safety in elderly frail patients with MM. The study is registered as UMIN000011235.

Comparison of vocal fatigue and vocal tract discomfort between teachers of normal pupils and teachers of mentally disabled pupils.

PURPOSE: This study aims to study the comparison of vocal fatigue and vocal tract discomfort between teachers of normal pupils and teachers of mentally disabled pupils. STUDY DESIGN: Cross-sectional study METHODS: Participants were 179 teachers (50 male, 129 female) and 30 non-teachers (14 male, 16 female) who participated in the current study. The teachers work in elementary schools. Furthermore, 87 of the teachers work for mentally disabled pupils at special elementary schools. Non-teachers were Ahvaz Jundishapur University of Medical Sciences employees who consider as the control group. They completed the Persian VFI and VTDp questionnaires three times, at the beginning, middle, and end of their office hours for 1 workday. RESULTS: The current study's findings indicate that the Persian VFI and VTD scores of non-teachers were significantly lower than teachers' scores. Furthermore, teachers of mentally disabled pupils demonstrated higher values from teachers of normal pupils based on the Persian VFI and VTDp scores CONCLUSION: The study results showed that teachers experienced more vocal fatigue and vocal tract discomfort than non-teachers. Furthermore, teachers of mentally disabled pupils indicated more vocal fatigue, the larynx's physical discomfort, and vocal tract discomfort, but this difference was practically small.

Real world outcomes with Bortezomib Thalidomide dexamethasone and Cyclophosphamide Bortezomib dexamethasone induction treatment for transplant eligible multiple myeloma patients in a Latin American country. A Retrospective Cohort Study from Grupo Argentino de Mieloma Múltiple.

Data about treatment outcomes and toxicity in Latin America are scarce. There are differences with central countries based on access to healthcare system and socioeconomic status. Argentinean Society of Hematology recommends bortezomib-based triplets for induction treatment of transplant eligible newly diagnosed multiple myeloma patients. Most common options are CyBorD (cyclophosphamide, bortezomib and dexamethasone) and VTD (bortezomib, thalidomide and dexamethasone). Main goal of our retrospective, multicentric study was to compare very good partial response rate (VGPR) or better after induction treatment in a real-world setting in Argentina. Secondary objectives included comparison of complete response (CR) post-induction and after bone marrow transplantation, grade 3-4 adverse events (AEs), progression-free survival (PFS) and overall survival (OS). Three hundred twenty-two patients were included (median age at diagnosis: 57 years; 52% male; 28% had ISS3; 14% with high-risk cytogenetics; median follow up: 34 months). CyBorD was indicated in 74% and 26% received VTD. In VTD arm, 72.62% of patients achieved at least VGPR vs 53.36% receiving CyBorD (odds ratio, OR: 1.96 [95% confidence interval, CI: 1.08-3.57; P = .026] after adjusting by age, ISS [International Staging System], lactate dehydrogenase levels (LDH) and cytogenetic risk. Difference in VGPR was 19.26% (95% CI: 15-24). CR rate were 35.92% (VTD) vs 22.55% (CyBorD) (adjusted OR: 2.13 [95% CI: 1.12-4.05]). Difference in CR was 13.37% (95% CI: 9.6-17.53). Adverse events (AEs) were more common with VTD (69.05% vs 55.46% for CyBorD; P = .030), especially grade 3-4 neuropathy (P = .005) and thrombosis (P = .001). Thromboprophylaxis was inadequate in 20.24% of patients. Hematological AEs were more common with CyBorD, especially thrombocytopenia (P = .017). PFS and OS at 24 months were not different between treatments. In this real-world setting, VTD was associated with better CR and VGPR than CyBorD. Nevertheless, CyBorD continues to be the preferred induction regimen in Argentina, based on safety profile. Frontline autologous stem cell transplantation improves quality of responses, especially in countries with limited access to new drugs.

[Pretesting of the German Vocal Fatigue Index (VFI-D)-transcultural translation and cross validation]. / Prätestung des deutschen Vocal Fatigue Index (VFI-D) ­ transkulturelle Übersetzung und Kreuzvalidierung.

BACKGROUND: In clinical routine, vocal fatigue is a common symptom in patients with dysphonia. OBJECTIVE: The aim of this study was to conduct a transcultural translation of the Vocal Fatigue Index (VFI), a standardized subjective questionnaire. Furthermore, pretesting and prevalidation were performed in 20 subjects, with comparison to the Voice Handicap Index (VHI­9i) and the Vocal Tract Discomfort Scale (VTD). MATERIALS AND METHODS: The translation, content review, and pretest of the German Vocal Fatigue Index (VFI-D) was divided into four sections: 1. transcultural translation, 2. expert voting on comprehensibility, 3. test of comprehensibility through cognitive interviews in 15 participants, 4. pretest of the VFI­D with cross validation compared to VHI­9i and VTD in 20 subjects. This process corresponds to current standards for transcultural translation and adaptation of questionnaires. RESULTS: According to expert voting and cognitive testing, the VFI­D is correct and comprehensible (intercoder reliability κ = 0.66). The factor analysis revealed three distinguishable parts: VFI­D part 1 correlates strongly with VHI­9i and VTD, VFI­D part 2 with VTD only (rho ≈ 0.800 each), and VFI­D part 3 correlates only weakly with VHI­9i and VTD (rho ≈ 0.585). Thus, convergence and divergence validity are proven. CONCLUSION: The first German version of the VFI­D might be a base for further research on symptoms, causes, and treatment options in vocal fatigue. Particularly patients in voice-intensive professions may benefit.

A comparison of salvage infusional chemotherapy regimens for recurrent/refractory multiple myeloma.

BACKGROUND: Despite the impact of proteasome inhibitors and immunomodulatory agents, infusional chemotherapy regimens continue to be used for patients with multiple myeloma. To the authors' knowledge, contemporary data regarding salvage chemotherapy regimens are sparse, with no direct comparisons. METHODS: The authors performed a single-institution study comparing 3 salvage chemotherapy regimens in 107 patients with recurrent/refractory multiple myeloma: dexamethasone, cyclophosphamide, etoposide, and cisplatin (DCEP) in 52 patients; bortezomib, thalidomide, dexamethasone, cisplatin, doxorubicin, cyclophosphamide, and etoposide (VTD-PACE) in 22 patients; and cyclophosphamide, vincristine, doxorubicin, and dexamethasone (CVAD) in 33 patients. RESULTS: Differences between treatment groups existed, including higher baseline creatinine for patients treated with CVAD (P<.001) and greater prior use of infusional chemotherapy for those receiving VTD-PACE (P<.001). There was no significant difference in response noted among the 3 regimens: 55% overall (P = .18). For the intent-to-transplant population, a similar percentage were successfully bridged to transplant without further therapy (62%; P = .9). There was no difference in survival observed across the 3 regimens, with an overall median progression-free survival of 4.5 months (95% confidence interval, 3.6-5.5 months [P = .8]) and a median overall survival of 8.5 months (95% confidence interval, 6.1-11 months [P = .8]). Furthermore, there was no statistically significant difference noted among clinically relevant adverse events, although there was a suggestion of fewer adverse events with DCEP. Patients treated with the intent to transplant had superior outcomes for response (odds ratio, 3.40; P = .01), progression-free survival (hazard ratio, 0.28; P<.001), and overall survival (hazard ratio, 0.19; P<.001). CONCLUSIONS: The 3 salvage regimens demonstrated similar responses, survival, and adverse events. Given the short response durations observed in the recurrent/refractory disease setting, infusional chemotherapy is best suited for cytoreduction before more definitive therapy is administered.

The Relation Between Endoscopic and Subjective Laryngopharyngeal Reflux Signs, Vocal Tract Discomfort, Voice Handicap, and Voice Disorder Type: Same Yet Different?

OBJECTIVES: This study aimed to investigate the relation between subjective voice-related symptoms and endoscopic findings in patients with different etiology of voice disorder and vocally healthy subjects with and without laryngopharyngeal reflux (LPR). STUDY DESIGN: Retrospective cross-sectional study. METHODS: The study involved 149 participants (106 female, 43 male) including 125 with various voice disorders (functional, structural, and neurogenic) and 24 vocally healthy individuals. For self-rating the German versions of the Voice Handicap Index (VHI), Vocal Tract Discomfort (VTD) Scale, and Reflux Symptom Index (RSI) were applied, while endoscopic evaluations utilized the Reflux Finding Score (RFS) and Reflux Sign Assessment (RSA). Statistical analyses incorporated ANOVA with Bonferroni posthoc tests to identify group variations. Correlations between VTD Scale, VHI, RSI, RFS, and RSA were evaluated using Pearson's correlation coefficient. To examine test sensitivity and specificity for the VTD Scale and RSA, we performed a receiver operating characteristics analysis. Youden's-Index was applied to determine the cut-off-value with best discriminatory abilities. The diagnosis of LPR was assumed when the criteria of RFS > 7 AND RSI > 13 was met. RESULTS: Significant differences for all voice diagnosis groups and vocally healthy individuals for RFS and all three self-rating questionnaires were found. Moreover, there was significant correlation between VTD Scale and VHI and RSI as well as RSI and RFS, which was moderate, negative in the group of persons with LPR. However, there was no significant difference for RSA results between the vocally healthy or any diagnosis group. CONCLUSION: Thus, the RFS may be more suitable to predict reflux and voice-related symptoms. The VTD Scale is a useful instrument in screening voice disorders but also LPR and can therefore be used as a tool for decision-making when transferring to a specialist.