Supplementary Data from Preoperative Chemoradiotherapy plus Nivolumab before Surgery in Patients with Microsatellite Stable and Microsatellite Instability–High Locally Advanced Rectal Cancer
<div>AbstractPurpose:<p>Preoperative chemoradiotherapy (CRT) and surgical resection are the standard treatment for locally advanced rectal cancer (LARC). Combining immune checkpoint inhibitors with radiation suggests a promising approach for enhancing efficacy. We investigated the efficacy of CRT followed by nivolumab and surgery in patients with LARC.</p>Patients and Methods:<p>In phase I, we investigated the feasibility of sequentially combined CRT, 5 cycles of nivolumab, and radical surgery. In phase II, patients with microsatellite stable (MSS) and microsatellite instability-high (MSI-H) LARC were evaluated.</p>Results:<p>Three patients in phase I received full courses of CRT and nivolumab without dose modification; the schedule was recommended for phase II. A pathologic complete response (pCR) was centrally confirmed in 30% [11/37; 90% confidence interval (CI), 18%–44%] and 60% (3/5) of the MSS and exploratory MSI-H cohorts, respectively. While immune-related severe adverse events were observed in 3 patients, no treatment-related deaths were observed. In 38 patients with MSS who underwent surgery, pCR rates of 75% (6/8) and 17% (5/30; <i>P</i> = 0.004, Fisher exact test) were observed in those with programmed cell death ligand 1 (PD-L1) tumor proportion score ≥1% and <1%, respectively; IHC staining was performed using pre-CRT samples. In 24 patients with MSS, pre-CRT samples were analyzed by flow cytometry; pCR rates of 78% (7/9) and 13% (2/15; <i>P</i> = 0.003, Fisher exact test) were observed for CD8<sup>+</sup> T cell/effector regulatory T cell (CD8/eTreg) ratios of ≥2.5 and <2.5, respectively, in tumor-infiltrating lymphocytes.</p>Conclusions:<p>CRT followed by consolidation nivolumab could increase pCR. PD-L1 expression and an elevated CD8/eTreg ratio were positive predictors in patients with MSS LARC.</p></div>
High-Altitude Platform Station (HAPS) has recently been attracting much attention as a new mobile communication platform for ultra-wide coverage areas and disaster-resilient networks since it can provide communication services from an altitude of approximately 20 km via a balloon, an Unmanned Aerial Vehicle (UAV) or other aircraft. In order to design efficient cell configurations for HAPS-based services, we need radio wave propagation models that consider various factors of vegetation, terrain, urban-suburban areas, and building entry loss. This paper focuses on propagation loss at high-elevation angles in urban and suburban areas. Recommendation ITU-R (International Telecommunication Union Radio communication sector) P.2108-1 describes the clutter loss model, which is the propagation loss caused by features such as buildings. The applicable frequency for ITU-R P.2108-1 is above 10 GHz; however, this model has no parameters for urban structure. Therefore, it needs to consider a correction for an urban structure to precisely evaluate clutter loss. We propose a new model that corrects Recommendation ITU-R P.2108 using shielding building heights as the urban structure. Since this new model was created based on measurements from 0.7 GHz to 5.7 GHz, the applicable frequencies are from 0.7 GHz to 5.7 GHz. Therefore, it is necessary to confirm whether the model applies to frequencies above 5.7 GHz. This paper compares the results of new propagation measurements at 29.3 GHz using a helicopter with the predicted results of the proposed model. The results show that the proposed model is applicable above 5.7 GHz.
Abstract Introduction: Multi-parametric assessment, including heart sounds in addition to conventional parameters, may enhance the efficacy of noninvasive telemonitoring for heart failure (HF). We sought to assess the feasibility of self-telemonitoring with multiple devices including a handheld heart sound recorder and its association with clinical events in patients with HF. Methods Ambulatory HF patients recorded their own heart sounds, mono-lead electrocardiograms, oxygen saturation, body weight, and vital signs using multiple devices every morning for six months. Results In the 77 patients enrolled (63 ± 13 years old, 84% male), daily measurements were feasible with a self-measurement rate of > 70% of days in 75% of patients. Younger age and higher Minnesota Living with Heart Failure Questionnaire scores were independently associated with lower adherence (P = 0.001 and 0.017, respectively). A usability questionnaire showed that 87% of patients felt self-telemonitoring was helpful, and 96% could use the devices without routine cohabitant support. Six patients experienced 10 HF events of re-hospitalization and/or unplanned hospital visits due to HF. In patients who experienced HF events, a significant increase in heart rate and diastolic blood pressure and a decrease in the time interval from Q wave onset to the second heart sound were observed 7 days before the events compared with those without HF events. Conclusions Self-telemonitoring with multiple devices including a handheld heart sound recorder was feasible even in elderly patients with HF. This intervention may confer a sense of relief to patients and enable monitoring of physiological parameters that could be valuable in detecting the deterioration of HF.
Background: Depletion of CD4+ immunosuppressive cells using an anti-CD4 monoclonal antibody (mAb) results in a strong antitumor effect by expanding a broad variety of tumor-reactive CD8+ T cells in mice. However, the impact of CD4+ cell depletion on the immune response in cancer patients is not known. Here, we analyzed changes in the T cell receptor (TCR) repertoire of blood and tumor biopsy samples following depletion of CD4+ cells by IT1208, a defucosylated humanized anti-CD4 mAb, in a first-in-human clinical trial.Methods: Patients with advanced gastrointestinal tumors were treated with 0.1 or 1.0 mg/kg IT1208. The count and immunophenotype of peripheral blood T cells were analyzed by flow cytometry. Libraries for TCR sequencing were prepared from purified blood CD4+ and CD8+ T cells, and unfractionated tumor biopsies, collected before and after IT1208 treatment. TCR sequencing was performed using Ion Proton and Ion S5 sequencers, then changes in the repertoire, and temporal and inter-organ overlap after IT1208 treatment, were analyzed.Results: Among 11 patients enrolled in the trial, one achieved a durable partial response and two achieved stable disease lasting at least 3 months. The blood CD4+ T cell count decreased rapidly after IT1208 treatment and remained low during the observation period. In contrast, the blood CD8+ T cell count increased from day 29 after treatment compared to baseline in most patients, resulting in a remarkably decreased CD4/8 ratio. Immunohistological analysis showed a decrease of CD4+ T cells in the tumor after IT1208 treatment. In the TCR repertoire analysis, a decrease in similarity and increase in clonality were observed in blood CD4+ and CD8+ T cells after IT1208 treatment, particularly in patients receiving 1.0 mg/kg IT1208. These changes persisted to at least day 60 after treatment in some cases. Temporal tracking of the blood TCR repertoire revealed that the number of expanded CD4+ T cell clones increased in a dose-dependent manner. In addition, the number of contracted CD8+ T cell clones showed a strong correlation with the increased CD8+ T cell count and CD45RAhi CCR7- effector population among CD8+ T cells in the blood. We also analyzed blood-tumor overlapping CD8+ T cell clones to investigate changes in potential tumor-associated clones. The frequency of overlapping CD8+ T cell clones in the blood tended to increase after treatment. Interestingly, an increased frequency of these overlapping clones in the blood was associated with maximum shrinkage in the tumor diameter.Conclusion: IT1208 treatment depleted CD4+ T cells from the blood and tumor. This depletion promoted the replacement of CD4+ and CD8+ T cell repertoire systemically. The IT1208 treatment-induced increase of tumor-associated CD8+ T cell clones may be associated with its anti-tumor effect in cancer patients.Citation Format: Hiroyasu Aoki, SATOSHI UEHA, Shigeyuki Shichino, Haru Ogiwara, Kohei Shitara, Tetsuya Nakatsura, Toshihiro Suzuki, Manami Shimomura, Toshiaki Yoshikawa, Kayoko Shoda, Shigehisa Kitano, Makiko Yamashita, Takayuki Nakayama, Akihiro Sato, Sakiko Kuroda, Masashi Wakabayashi, Shogo Nomura, Shoji Yokochi, Satoru Ito, Toshihiko Doi, Kouji Matsushima. Anti-CD4 monoclonal antibody immunotherapy exerts an antitumor effect by replacing the T cell receptor repertoire in patients with gastrointestinal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-019.
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