Sequential Schedule Research Articles

Treatment sequences and survival outcomes in advanced HR + HER2- breast cancer patients: a real-world cohort.

Palliative treatment options for HR + HER2- advanced breast cancer (ABC) patients have increased, but data is lacking about the optimal treatment sequence. We used real-world data from a comprehensive cancer center to describe applied treatment sequences and we determined treatment-related and survival outcomes. Patients aged 18 years and older with HR + HER2- ABC treated with systemic treatment were included in this historic cohort study. Sequential treatment schedules, time to treatment discontinuation, time to chemotherapy, and overall survival (OS) were determined, stratified by first-line treatment. 202 patients were included. They received a total of 650 treatment lines (median 3; range: 1-11). 91 (45%), 25 (12%), 24 (12%), 28 (14%), 22 (11%) and 12 (6%) patients started first-line treatment with non-steroidal aromatase inhibitors (NSAI), NSAI + cyclin dependent kinase 4/6-inhibitors (CDK4/6i), fulvestrant + CDK4/6i, tamoxifen, chemotherapy and other treatment, respectively. 10, 13, and 14 different treatment regimens were given in first, second and third-line, respectively. Of the patients who started first-line NSAI monotherapy (n = 91), 3 (3%) died before receiving second-line treatment. In this real-world cohort, we observed a wide variety of different treatment sequences applied in daily clinical practice, some of which were in discordance with the current guidelines. Fear that patients may never get around to treatment with CDK4/6i if a patient did not start with a CDK4/6i was not supported by our study results.

Sensitization of melanoma cells to standard chemotherapy: G-quadruplex binders as synergistic agents.

The use of chemotherapeutics has achieved considerable success in cancer therapy; however, their toxicity can severely impact patients' health. In this study, aiming to reduce the doses and potential side effects of traditional chemotherapeutics, we systematically treated A375MM human melanoma cells with seven clinically approved antineoplastic drugs, in combination with three well-characterized G-quadruplex (G4) ligands, using either simultaneous or sequential dosing schedules. Interestingly, the G4binders synergized with most of the investigated anticancer drugs, with the degree of synergism being strictly dependent on both the treatment schedule and the drug sequence employed. Notably, some of the synergistic combinations showed selective toxicity towardmelanoma cells over nontumorigenic human keratinocytes. Furthermore, immunofluorescence experiments highlighted the potential implication of G4 structures in the molecular mechanisms driving the synergistic interaction between some chemotherapeutics and G4 binders. Overall, our systematic study supports the combination of G4-interacting molecules with standard antineoplastic drugs as a promising antitumor strategy.

Assessing the mucosal intestinal and systemic humoral immunity of sequential schedules of inactivated poliovirus vaccine and bivalent oral poliovirus vaccine for essential immunization in Bangladesh: An open-label, randomized controlled trial

In 2012, the Strategic Advisory Group of Experts on Immunization (SAGE) recommended introduction of at least one inactivated poliovirus vaccine (IPV) dose in essential immunization programs. We evaluated systemic humoral and intestinal mucosal immunity of a sequential IPV-bivalent oral poliovirus vaccine (bOPV) schedule compared with a co-administration IPV + bOPV schedule in an open-label, randomized, controlled, non-inferiority, inequality trial in Dhaka, Bangladesh. Healthy infants aged 6 weeks were randomized to either: (A) IPV and bOPV at 6 and bOPV at 10 and 14 weeks (IPV + bOPV-bOPV-bOPV); or (B) IPV at 6 and bOPV at 10 and 14 weeks (IPV-bOPV-bOPV). Of 456 participants enrolled and randomly assigned during May–August 2015, 428 (94%) were included in the modified intention-to-treat analysis (arm A: 211, arm B: 217). Humoral immune responses did not differ at 18 weeks between study arms: type 1 (98% versus 96%; p = 0.42), type 2 (37% versus 39%; p = 0.77), and type 3 (97% versus 93%; p = 0.07). Virus shedding one week after the bOPV challenge dose in arm B was non-inferior to arm A (type 1 difference = −3% [90% confidence interval: −6 − 0.4%]; type 3 difference: −3% [−6 to −0.2%]). Twenty-six adverse events including seven serious adverse events were reported among 25 participants including one death; none were attributed to study vaccines.An IPV-bOPV-bOPV sequential schedule induced comparable systemic humoral immunity to all poliovirus types and types 1 and 3 intestinal mucosal immunity as an IPV + bOPV-bOPV-bOPV co-administration schedule.

Integrated scheduling of production and material delivery for the intelligent manufacturing system

This paper addresses the issue of integrated scheduling of production and material delivery in an intelligent manufacturing system. The system includes multiple flexible flowlines and a fleet of automated guided vehicles (AGVs), whose capacity is shared among the flowlines. Multiple orders from different customers are processed on the flowlines, with AGVs delivering materials in different batch sizes based on varying product quantities of orders and limited load capacity. The problem is formulated as a mixed-integer linear programming model to minimise total order delays and the number of used AGVs. To handle the complexity caused by the uneven temporal coupling relationship between production and material delivery, a bi-level neighbourhood search solution algorithm is proposed. This algorithm uses variable neighbourhood search for production scheduling and adaptive large neighbourhood search for material delivery scheduling. Extensive numerical experiments using real-case-based instances are conducted to demonstrate the satisfactory performance of our proposed algorithm. Furthermore, we emphasise the advantages of integrated scheduling compared to traditional sequential scheduling across various problem settings.

DRL-Based Sequential Scheduling for IRS-Assisted MIMO Communications

DRL-Based Sequential Scheduling for IRS-Assisted MIMO Communications

Multi-Channel Cooperative Spectrum Sensing and Scheduling for Cognitive IoT Networks

This paper presents a novel multi-channel cooperative spectrum sensing and scheduling (MC$_2$S$_3$) framework for spectrum and energy harvesting cognitive Internet of Things (IoT) networks. We address the challenge of maximizing network throughput by formulating a combinatorial problem that jointly optimizes the sensing scheduling of primary channels (PCs), the assignment of IoT devices for sensing scheduled PCs, and the clustering and allocation of IoT nodes to efficiently use discovered idle PCs; subject to spectrum utilization and collision avoidance constraints. Recognizing the inherent complexity of the underlying NP-hard mixed-integer non-linear programming (MINLP) problem, we propose a decomposition strategy that decouples the master problem into PC exploration and exploitation sub-problems. In the exploration phase, we derive closed-form solutions for optimal sensing durations and detection thresholds that satisfies spectrum utilization and collision avoidance constraints, which are then used to develop a priority metric to rank PCs. The proposed PC ranking informs a sequential PC scheduling and IoT sensing assignment approach that exploits a linear bottleneck assignment (LBA) strategy, proceeding until further scheduling does not enhance network utility. For the exploitation phase, we leverage a non-orthogonal multiple access (NOMA) strategy to multiplex multiple IoT nodes on a single PC, employing an iterative linear sum assignment (LSA) method for efficient allocation to maximize utilization of idle PCs. Numerical results validate the efficacy of our proposed methodologies, reaching an accuracy of approximately 99% in the order of milliseconds, significantly outperforming time complexity of brute-force benchmarks.

Antibody-Drug Conjugate Sacituzumab Govitecan Enables a Sequential TOP1/PARP Inhibitor Therapy Strategy in Patients with Breast Cancer.

The antibody-drug conjugate (ADC) sacituzumab govitecan (SG) comprises the topoisomerase 1 (TOP1) inhibitor (TOP1i) SN-38, coupled to a monoclonal antibody targeting trophoblast cell surface antigen 2 (TROP-2). Poly(ADP-ribose) polymerase (PARP) inhibition may synergize with TOP1i and SG, but previous studies combining systemic PARP and TOP1 inhibitors failed due to dose-limiting myelosuppression. Here, we assess the proof-of-mechanism and clinical feasibility for SG and talazoparib (TZP) employing an innovative sequential dosing schedule. In vitro models tested pharmacodynamic endpoints, and in a phase 1b clinical trial (NCT04039230), 30 patients with metastatic triple-negative breast cancer (mTNBC) received SG and TZP in a concurrent (N = 7) or sequential (N = 23) schedule. Outcome measures included safety, tolerability, preliminary efficacy, and establishment of a recommended phase 2 dose. We hypothesized that tumor-selective delivery of TOP1i via SG would reduce nontumor toxicity and create a temporal window, enabling sequential dosing of SG and PARP inhibition. In vitro, sequential SG followed by TZP delayed TOP1 cleavage complex clearance, increased DNA damage, and promoted apoptosis. In the clinical trial, sequential SG/TZP successfully met primary objectives and demonstrated median progression-free survival (PFS) of 7.6 months without dose-limiting toxicities (DLT), while concurrent dosing yielded 2.3 months PFS and multiple DLTs including severe myelosuppression. While SG dosed concurrently with TZP is not tolerated clinically due to an insufficient therapeutic window, sequential dosing of SG followed by TZP proved a viable strategy. These findings support further clinical development of the combination and suggest that ADC-based therapy may facilitate novel, mechanism-based dosing strategies.

Abstract PO5-03-09: Concurrent versus sequential use of adjuvant capecitabine and radiation in patients with triple-negative breast cancer with residual disease: A retrospective review

Abstract Background: The CREATE-X trial demonstrated benefit of adjuvant capecitabine for patients with triple-negative breast cancer (TNBC) with residual disease after neoadjuvant chemotherapy and surgery. In clinical practice however, physician discretion determines the sequence of capecitabine relative to radiation therapy (RT), as well as the treatment dose. Therefore, our study aimed to assess the treatment patterns and tolerance of capecitabine and RT in patients with residual TNBC at our institution after publication of the CREATE-X study. Methods: This was a retrospective IRB-approved study that included patients with TNBC who had residual disease following neoadjuvant chemotherapy and surgery and received both adjuvant loco-regional RT and capecitabine at our institution between July 1, 2017 and June 30, 2021. Patient characteristics and treatment regimens were abstracted from medical charts. For this study, we defined optimally-delivered capecitabine to be a starting dose of 1250 mg/m2 twice per day on days 1-14 every 3 weeks as per the CREATE-X trial, and all planned cycles completed without dose reductions or discontinuation. RT was defined as optimally delivered when patients completed the prescribed dose without a treatment break of > 1 week or discontinuation of planned RT. We used descriptive statistics to report our observations. Results: Thirty-four patients met our eligibility criteria. The median age at diagnosis was 56 years (range: 30-77 years) and the median follow up time was 48 months. Of the 27 patients who received sequential RT and capecitabine, the median starting dose of capecitabine was 1000 mg/m2. Of the 7 patients who received concomitant RT and capecitabine, the median starting dose during RT was 800 mg/m2; after completion of RT, patients completed 6 additional cycles of capecitabine at a median dose of 1000 mg/m2. We observed a greater residual breast tumor burden in patients prescribed concomitant RT and capecitabine; 71.4% were ypT2/T3 compared to only 18.5% ypT2/T3 in sequentially treated patients (OR 11.0; 95% CI, 1.64 to 73.97; p=0.05). There was no significant difference in the positive lymph node status between the 2 groups (42.9% and 40.7%, respectively). A median RT dose of 50 Gy in 25 fractions was delivered in both schedules. No patients discontinued RT due to intolerance. In the 27 sequentially treated patients, the majority (73%) received RT before capecitabine. Among these, 14 patients (51.9%) required a dose reduction and 6 patients (22.2%) discontinued capecitabine due to intolerance. Of the 7 patients receiving concomitant RT and capecitabine, 2 patients (28.5%) discontinued capecitabine due to intolerance (one during RT and one following completion of RT). The concomitant RT and capecitabine regimen was not associated with higher odds of prematurely discontinuing capecitabine compared to the sequential schedule (OR 1.15; 95% CI, 0.18 to 7.34). Conclusion: In this study, most patients received a sequential schedule and those with a higher residual disease burden were more likely to be prescribed concomitant RT and capecitabine. The starting dose of capecitabine in both schedules was lower than the starting dose in the CREATE X trial but consistent with the practice standard in the US. Our early experience did not demonstrate any signal to suggest a difference in the tolerance of capecitabine administered sequentially or concurrently. Further studies are needed to evaluate the optimal sequence of RT and capecitabine in the adjuvant setting. Citation Format: Catherine Yu, Alaina Kessler, Theresa Shao, Sarah Cate, Paula Klein, Manjeet Chadha. Concurrent versus sequential use of adjuvant capecitabine and radiation in patients with triple-negative breast cancer with residual disease: A retrospective review [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-03-09.

Abstract PO4-03-07: The impact of chemotherapy relative dose intensity on pathological complete response in patients with triple negative breast cancer treated with neoadjuvant chemotherapy

Abstract Background: Neoadjuvant chemotherapy (NACT) is the preferred treatment approach for early-stage triple negative breast cancer (TNBC). Achieving pathologic complete response (pCR) after NACT is associated with improved event-free survival and overall survival in patients with TNBC. Major research efforts have been deployed to identify predictive biomarkers for pCR in TNBC. However, the values of chemotherapy (CT) relative dose intensity (RDI) in predicting pCR remain unclear. Methods: A retrospective analysis was conducted among 96 consecutive patients with early stage TNBC who received NACT between February 2018 and January 2023 at the University of Naples Federico II (Naples, Italy). Patients’ demographics, clinical-pathological features, and type of CT schedules were retrieved from electronic medical records. pCR was defined as the absence of residual invasive or in situ carcinoma in primary tumor and/or lymph nodes, upon chemotherapy administration. RDI was calculated as the ratio of delivered to planned CT dose intensity. RDI was defined as low if < 85% or high if ≥85%, respectively. Univariate and multivariate logistic regression were used to evaluate the association between age, tumor stage, RDI, CT regimen dose type, and pCR. Results: All patients were included in the analysis. Median age at diagnosis was 51 years (range 28-75). Sixty-five (68%) and 31 (32%) patients were diagnosed with stage II and stage III TNBC, respectively. Nineteen (19%) patients received a sequential schedule of anthracycline plus cyclophosphamide (AC) and a taxane (T). Sixty-one (64%) patients received AC followed by concurrent carboplatin-paclitaxel (CaP). Sixteen (17%) patients received the anti-PD1 pembrolizumab in addition to ACCaP chemotherapy backbone (ACCaP-Pem). Fifty-four (56%) patients received a dose-dense AC-based CT. A pCR was achieved in 59 (61%) patients. Interestingly, patients who received a dose-dense AC based neoadjuvant CT had higher chance to achieve a pCR compared with those treated with a non dose-dense AC based CT (70% vs 46%, p = 0.03). Overall, 79 (82%) and 17 (18%) patients received a RDI high and RDI low CT, respectively. No difference in terms of age, body mass index, performance status, tumor stage, type of chemotherapy was observed between the two groups (Table 1). At univariate analysis RDI high (OR 5.18, 95%CI: 1.65-16.31, p=0.005) and dose dense AC-based CT (OR 2.42, 95%CI: 0.18-0.97, p=0.04) were significantly associated with pCR. In a multivariate model including RDI, age, tumor stage, and AC regimen dose type, RDI was the only variable independently associated with pCR (OR 4.60, 95% CI: 1.40-15.06, p = 0.01). Conclusion: A chemotherapy RDI≥ 85% independently predicts pCR in early stage TNBC patients treated with standard NACT. In our cohort, one in five patients received a suboptimal chemotherapy dose intensity affecting at least in part tumor response. Studies with larger TNBC patient populations are warranted to confirm the impact of RDI on pCR and long-term outcomes. Table 1 Citation Format: Roberto Buonaiuto, Giuseppe Neola, Aldo Caltavituro, Paola Trasacco, Federica Pia Mangiacotti, Giovanna Pecoraro, Matteo Lambertini, Erica Pietroluongo, Pietro De Placido, Sabino De Placido, Valeria Forestieri, Mario Giuliano, Grazia Arpino, Carmine De Angelis. The impact of chemotherapy relative dose intensity on pathological complete response in patients with triple negative breast cancer treated with neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-03-07.

Effect of Load on Sequential Imperfect Preventive Maintenance and Replacement Schedules of Mechanically Repairable Machines

This paper examines the impact of load on the operational time and maintenance cost of mechanically repairable machines. Three different levels of load with multiplicative impact on the hazard rate of the failure distribution were applied to the working of a cassava grinding machine using a two-parameter Weibull distribution with respective hazard and cumulative hazard functions. Their effect on the preventive maintenance (PM) and replacement schedules revealed that at above maximum load level, the length of the machine’s operational time decreased drastically compared to the decrease at maximum load level and relative decrease at the below maximum load level when compared to the machine’s operational time at the minimum load level. The application of load also results in frequent preventive maintenance actions and an increase in machine downtime for a given cost ratio. This implies that the influence of load on the PM and replacement maintenance schedule of mechanically repairable machines is essential to the design and operation of such machines. The results also provide maintenance engineers with an operational guide for PM and replacement maintenance actions in order to prevent failure maintenance and increase the machine’s availability for enhanced productivity.

E2E-AT: A Unified Framework for Tackling Uncertainty in Task-Aware End-to-End Learning

Successful machine learning involves a complete pipeline of data, model, and downstream applications. Instead of treating them separately, there has been a prominent increase of attention within the constrained optimization (CO) and machine learning (ML) communities towards combining prediction and optimization models. The so-called end-to-end (E2E) learning captures the task-based objective for which they will be used for decision making. Although a large variety of E2E algorithms have been presented, it has not been fully investigated how to systematically address uncertainties involved in such models. Most of the existing work considers the uncertainties of ML in the input space and improves robustness through adversarial training. We extend this idea to E2E learning and prove that there is a robustness certification procedure by solving augmented integer programming. Furthermore, we show that neglecting the uncertainty of COs during training causes a new trigger for generalization errors. To include all these components, we propose a unified framework that covers the uncertainties emerging in both the input feature space of the ML models and the COs. The framework is described as a robust optimization problem and is practically solved via end-to-end adversarial training (E2E-AT). Finally, the performance of E2E-AT is evaluated by a real-world end-to-end power system operation problem, including load forecasting and sequential scheduling tasks.

Immune persistence after different polio sequential immunization schedules in Chinese infants

Trivalent oral poliovirus vaccine (tOPV) has been withdrawn and instead an inactivated poliovirus vaccine (IPV) and bivalent type 1 and type 3 OPV (bOPV) sequential immunization schedule has been implemented since 2016, but no immune persistence data are available for this polio vaccination strategy. This study aimed to assess immune persistence following different polio sequential immunization schedules. Venous blood was collected at 24, 36, and 48 months of age from participants who had completed sequential schedules of combined IPV and OPV in phase III clinical trials. The serum neutralizing antibody titers against poliovirus were determined, and the poliovirus-specific antibody-positive rates were evaluated. A total of 1104 participants were enrolled in this study. The positive rates of poliovirus type 1- and type 3-specific antibodies among the sequential immunization groups showed no significant difference at 24, 36, or 48 months of age. The positive rates of poliovirus type 2-specific antibody in the IPV-IPV-tOPV group at all time points were nearly 100%, which was significantly higher than the corresponding rates in other immunization groups (IPV-bOPV-bOPV and IPV-IPV-bOPV). Immunization schedules involving one or two doses of IPV followed by bOPV failed to maintain a high positive rate for poliovirus type 2-specific antibody.

Entanglement Purification with Quantum LDPC Codes and Iterative Decoding

Recent constructions of quantum low-density parity-check (QLDPC) codes provide optimal scaling of the number of logical qubits and the minimum distance in terms of the code length, thereby opening the door to fault-tolerant quantum systems with minimal resource overhead. However, the hardware path from nearest-neighbor-connection-based topological codes to long-range-interaction-demanding QLDPC codes is likely a challenging one. Given the practical difficulty in building a monolithic architecture for quantum systems, such as computers, based on optimal QLDPC codes, it is worth considering a distributed implementation of such codes over a network of interconnected medium-sized quantum processors. In such a setting, all syndrome measurements and logical operations must be performed through the use of high-fidelity shared entangled states between the processing nodes. Since probabilistic many-to-1 distillation schemes for purifying entanglement are inefficient, we investigate quantum error correction based entanglement purification in this work. Specifically, we employ QLDPC codes to distill GHZ states, as the resulting high-fidelity logical GHZ states can interact directly with the code used to perform distributed quantum computing (DQC), e.g. for fault-tolerant Steane syndrome extraction. This protocol is applicable beyond the application of DQC since entanglement distribution and purification is a quintessential task of any quantum network. We use the min-sum algorithm (MSA) based iterative decoder with a sequential schedule for distilling 3-qubit GHZ states using a rate 0.118 family of lifted product QLDPC codes and obtain an input fidelity threshold of ≈0.7974 under i.i.d. single-qubit depolarizing noise. This represents the best threshold for a yield of 0.118 for any GHZ purification protocol. Our results apply to larger size GHZ states as well, where we extend our technical result about a measurement property of 3-qubit GHZ states to construct a scalable GHZ purification protocol.

Management of Fruit and Shoot Borer, Leucinodes orbonalis (Guenee) in Brinjal through Sequential Application of Selected Insecticides and Biorationals

Leucinodes orbonalis Guenee (Lepidoptera: Crambidae), commonly known as brinjal shoot and fruit borer is a dreaded pest in India. The bio efficacy of insecticides and biorationals has been test verified in managing fruit and shoot borer through logical sequential schedules. The results of the present field experiment conducted during Summer 2023 in Agricultural and Horticultural research Station (AHRS), Bavikere revealed the most effective insecticidal schedule among the tested sequences. The sequence containing Chlorantraniliprole 18.5 SC @ 0.3 ml/L - Spinosad 45 SC @ 0.4 ml/L - Lufenuron 5 EC @ 1.0 ml/L - Bacillus thuringiensis var. kurstaki @ 2.0 g/L demonstrated remarkable success in reducing the damage caused by L. orbonalis along with economic viability and high cost-benefit ratio.

Enrichment of circulating helper-T (Th) and unswitched memory-B (NSwM-B) cell populations and responsiveness to immune checkpoint blockade (ICB) in microsatellite-stable (MSS)/mismatch repair-proficient (pMMR) colorectal cancer (CRC).

150 Background: The anti-tumor activity of ICB in MSS/pMMR-CRC is limited. However, recent studies have highlighted the possibility of inducing ICB responsiveness by oxaliplatin-based chemotherapy. The understanding of underlying mechanisms and identification of rational biomarkers are major focus areas in immuno-oncology. Methods: Patients with previously untreated, unresectable abdominal metastases from MSS/pMMR-CRC were randomly assigned to the oxaliplatin-based standard Nordic FLOX regimen (control arm) or 2 FLOX cycles followed by 2 ICB (nivolumab) cycles in a repeat sequential schedule (experimental arm). Radiologic response assessment was done every 8 weeks, and the study arms reached identical primary endpoint – median progression-free survival (PFS) 9.3 months. Experimental-arm patients at one study center had peripheral blood mononuclear cells (PBMC) prepared at study entry (V1), after the initial 2 FLOX cycles (V3), and after the succeeding 2 nivolumab cycles (V5). The PBMC were incubated with 19 cell-surface antibodies and analyzed by mass cytometry. Patients were categorized in PFS >9.3 months (improved; n = 7) or PFS <9.3 months (shortened; n = 6). Live cell clusters were identified by hierarchically applying automated 1D gates to the available lineage markers. After gating, all cells were assigned to soft clusters according to phenotypes. The cluster sizes were used to compute the differential abundance of immune-cell populations and a Peacock test assessed multivariate changes between the improved and shortened PFS groups. Results: Circulating CD4+ (Th) cells and CD27+IgD+ (NSwM-B) cells were concurrently enriched in the improved PFS group. After the initial 2 FLOX cycles (V3), median increase (from V1) was 2.89% (of lymphocyte count) for Th cells and 0.54% (of leukocyte count) for NSwM-B cells (p < 0.001). Continued responses occurred over the succeeding 2 nivolumab cycles (until V5) with median increase of 1.19% for Th cells and 0.19% for NSwM-B cells (p < 0.001). The association between the immune-cell alterations and PFS was validated by categorizing the cases in above or below the median increase in Th and NSwM-B cell populations from V1 to V5. The high-increase group achieved median PFS 15.0 months (95% CI, 10.8-19.2) compared to 4.0 months (95% CI, 1.9-22.1) for the low-increase group (log-rank; p = 0.002). Conclusions: This unsupervised analysis of high-dimensional PBMC data from a limited case number revealed that circulating Th and NSwM-B cell populations may mediate ICB responsiveness invoked by short-course oxaliplatin-based chemotherapy in patients with abdominal metastases from MSS/pMMR-CRC. Owing to weaknesses of such a post-hoc analysis, further studies are needed to confirm the generalizability of these findings. Clinical trial information: NCT003388190 .

Swift Carrier Scheduling for Battery-free Sensor Tags with Sensing Chain Requirements

Battery-free sensor tags extensively enhance sensing capabilities of IoT in a cost-effective manner, which are provided energy from unmodulated carriers of other IoT devices. Passive tag scheduling algorithms have been proposed to achieve battery-free sensor tag group scheduling through coloring active devices/nodes for carrier sharing. However, existing passive tag scheduling works realize scheduling each sensor tag once, missing chain-like scheduling requirements in scenarios such as pipeline safety detection. Besides, the existing active node coloring manner leads to frequent re-coloring since carrier conflicts change after part of tags are scheduled. In this paper, we are the first to propose the concept of sensing chain, which represents scheduling multiple battery-free sensor tags in a specific order. Then, we formulate the scheduling problem as a pure integer programming problem to jointly optimize carrier generation and energy consumption. To address this NP-hard problem, we present three types of carrier sharing coloring strategies, and develop an efficient scheduling algorithm with one-time tag (ordinary and sensing chain tag) coloring. Extensive experiments demonstrate that our proposed algorithm significantly reduces energy consumption compared to sequential scheduling. Besides, our solution is close to optimal while reducing execution time by over 40% with or without the sensing chain than state-of-arts.

Sequential clinical scheduling with stochastic patient re-entrance: Case of Mohs Micrographic Surgery

We study the problem of appointment scheduling for outpatient clinics with stochastic patient re-entrance. It is motivated by the scheduling problem for Mohs Micrographic Surgery, which is a popular technique for the excision of skin cancers. Re-entrance occurs when a patient repeats upstream processes during the single-day outpatient appointment, usually after a medical test. In some surgical procedures, the number of re-entrances for each patient is unknown until medical test results become available, causing long patient waiting time and clinic overtime. To address these challenges, we develop a stochastic slot model, SMART, that captures the key characteristics of the appointment processes and stochastic re-entrance, utilizing a delay before possible re-entrance. We then design a sequential scheduling algorithm that balances patient waiting, clinic overtime and patient throughput while considering stochastic complications such as no-shows, processing time variability, and the number of re-entrances per patient. We establish several theoretical properties of the algorithm, including the optimality of the resulting schedules for the sequential scheduling setting. We apply SMART to appointment scheduling for Mohs clinics, where patients may have same-day re-entrance due to repetitive skin excisions. We compare SMART schedules to others that ignore re-entrance and to current scheduling practices via simulation studies under a more realistic setting. Numerical experiments show that SMART schedules dominate other schedules, and ignoring re-entrance can cost huge loss in efficiency. Furthermore, SMART schedules exhibit a special ‘stair-stepping’ pattern for the number of appointments, with most patients assigned to the early slots and many empty slots at the end.

Regorafenib Plus Vincristine and Irinotecan in Pediatric Patients With Recurrent/Refractory Solid Tumors: An Innovative Therapies for Children With Cancer Study.

This phase Ib study defined the safety, maximum tolerated dose (MTD), and recommended phase II dose (RP2D) of regorafenib combined with vincristine and irinotecan (VI). Secondary objectives were evaluation of antitumor activity and pharmacokinetics (PK) of regorafenib and irinotecan. Patients aged 6 months to <18 years with relapsed/refractory solid malignancies (≥50% with rhabdomyosarcoma [RMS]) received regorafenib (starting dose 72 mg/m2/day) concomitantly or sequentially with vincristine 1.5 mg/m2 on days 1 and 8 and irinotecan 50 mg/m2 on days 1-5 (21-day cycle). Adverse events (AEs) and tumor response were assessed. PK (regorafenib and irinotecan) were evaluated using a population PK model. We enrolled 21 patients (median age 10 years; 12 RMS; five Ewing sarcoma [EWS]). The MTD/RP2D of regorafenib in the sequential schedule was 82 mg/m2. The concomitant dosing schedule was discontinued because of dose-limiting toxicities in 2/2 patients treated. Most common grade 3/4 (>30% of patients) AEs were neutropenia, anemia, thrombocytopenia, and leukopenia. The overall response rate was 48% and disease control rate (complete response/partial response/stable disease/non-CR/non-PD) was 86%. Median progression-free survival was 7.0 months (95% CI, 2.9 to 14.8) and median overall survival was 8.7 months (95% CI, 5.5 to 16.3). When combined with VI, regorafenib PK were comparable to single-agent PK in children and adults (treated with regorafenib 160 mg/day). Regorafenib can be combined sequentially with standard dose VI in pediatric patients with relapsed/refractory solid tumors with appropriate dose modifications. Clinical activity was observed in patients with RMS and EWS (clinicaltrials.gov NCT02085148).

Cost-utility analysis of the use of the 20-valent anti-pneumococcal vaccine (PCV20) in adults older than 60 years in Spain

Background and objectivesA cost-utility analysis was conducted to assess the efficiency of implementing a PCV20 vaccination strategy in the Spanish adult population older than 60 years, for the prevention of non-bacteremic pneumococcalpneumonia (NBP) and invasive pneumococcal disease (IPD). MethodsA Markov model, with annual cycles and a time horizon of 10 years was used. The analysis population was stratified by age and risk groups. The comparator was the sequential vaccination with the 15-valent pneumococcal conjugate vaccine (PCV15) followed by one dose of the pneumococcal polysaccharide vaccine (PPV23). The base case analysis was performed from the National Healthcare System (NHS) perspective including direct costs (€2018) and applying a discount of 3% to future costs and outcomes. Alternative scenarios explored a shorter time horizon (5 years), the societal perspective and other available vaccination strategies. All the parameters and assumptions were validated by a panel of experts. To evaluate the robustness of the model, deterministic and probabilistic sensitivity analyses (PSA) were carried out. ResultsThe results of the study showed that the vaccination strategy with PCV20 is a dominant option compared to the sequential regimen (PCV15 + PPSV23), resulting in direct cost savings of €85.7 M over 10 years, with a small increase in quality-adjusted life years (QALYs). PCV20 vaccination avoided 2,161 cases of IPD, 19,470 of NBP and 3,396 deaths and according to the PSA, the probability of PCV20 being cost-effective compared to a sequential regimen (PCV15 + PPSV23) was 100%. Conclusions/RecommendationsIn the Spanish adult population older than 60 years, the vaccination strategy with one dose of PCV20 is more effective and less expensive (dominant) than vaccination with a sequential schedule with PCV15 and PPSV23.

A Bilevel Graph Reinforcement Learning Method for Electric Vehicle Fleet Charging Guidance

This letter proposes a bilevel graph reinforcement learning method for electric vehicle (EV) fleet charging guidance, achieving collaborative optimization of the transportation-electrification coupled system. A dual-agent architecture is first constructed, where the upper-level is used for charging and the lower-level is used for routing. The EV traveling and charging behavior is characterized as a graph-structured interaction process. A graph attention network (GAT) is leveraged to extract the topology correlation and feature information. Then the extracted topology embedded with knowledge, as intermediate latent environment states, is fed into the underlying network of deep reinforcement learning (DRL). A DRL-based sequential scheduling pattern is developed to realize the guidance of multiple EVs. Extensive experimental results verify the superiority and adaptability of our proposed methodology.