Transarterial Radioembolization for Unresectable Hepatocellular Carcinoma: Real-Life Efficacy and Safety Analysis of Korean Patients

Transarterial radioembolization (TARE) has become widely used in the treatment of HCC, one of the most common causes of cancer mortality worldwide. Here we investigated the long-term clinical outcomes of patients with hepatocellular carcinoma (HCC) treated with TARE in a multi-medical center in Korea. A total of 149 patients treated with TARE from 2008–2014 were recruited. The pre-treatment HCC stage was classified according to the BCLC stage, of which C and D were defined as advanced HCC. Advanced HCC stage and Child–Turcotte–Pugh (CTP) score A were identified in 62 (42%) and 134 (90%) patients, respectively. Portal vein thrombosis (PVT) was identified in 58 patients (38.9%). The median time to progression (TTP) was 14 months, and the median overall survival (OS) and progression-free survival (PFS) were 18.6 and 8.9 months, respectively. The overall tumor response was 47%, and the disease control rate was 78%. OS and PFS differed significantly according to the presence of liver cirrhosis, extrahepatic metastasis, tumor response and curative treatment after TARE (all, p < 0.05). Multiple tumors and major PVT were other independent factors related to OS, while the des-gamma carboxy protein level predicted PFS (all, p < 0.05). Tumor size was an independent predictor of tumor response. TTP, OS and PFS all differed among BCLC stages. The serious adverse effect after TARE was clinically not significant. Therefore, TARE is safe and effective in treating early to advanced HCCs.

Transanal endoscopic microsurgery in the treatment of patients with benign neoplasms and early rectal cancer

Introduction. Transanal endoscopic microsurgery (tem) is a method that allows the specialists to clearly visualize a tumor and bimanually remove the tumor using a set of special instruments. For a number of patients with a good tumor response to chemoradiation therapy (crt), tem is used as an advanced biopsy technique for tumor verification. The purpose of the study was to analyze the results of tem performed at a. Tsyb mrrc. Material and methods. Between 2015 and 2020, 64 patients (men – 42.2 % and women – 57.8 %) underwent tem. Forty patients had rectal cancer and 25 patients had benign rectal tumors. The indication for tem in patients with rectal cancer was the evidence of tis-t1 tumor by postoperative examination findings (mri and endosonography). Eleven patients with stage ii–iii rectal cancer received chemoradiation therapy. The indication for performing tem after rt in patients with rectal cancer was a good tumor response (mri trg1- 2). For statistical processing, commercial biomedical packages prism 3.1 and instat (graphpad software, inc., san diego, usa) were used. The significance of the differences between the indicators was assessed using the pearson χ2 test. Differences were considered significant if the p value was less than 0.05. Results. The median duration of surgery was 110 minutes (30–385). The volume of blood loss did not exceed 40 ml. Postoperative complications were observed in 15 cases (23.4 %). Grade 3 complications according to the clavien-dindo classification were observed in 5 (7.8 %) cases. Postoperative complications occurred more frequently in patients after crt (10.7 and 18.2 %; p=0.603), however, the differences were not statistically significant. At a median follow-up of 18 months (7–30), local relapses developed in 6 out of 26 (23 %) patients who underwent surgery alone. There were no signs of local recurrence in patients with adenocarcinomas after neoadjuvant chemotherapy and rectal adenomas. When comparing patients with the depth of tumor invasion tis-t1sm2 and t1sm3-t2, local relapses occurred in 1 of 21 (4.7 %) and 5 of 12 (41.6 %) cases, respectively (p=0.015). Conclusion. The analysis of the results of tem interventions in patients with rectal neoplasms allows us to conclude that this method of treatment is a priority for patients with benign rectal neoplasms and early rectal cancer. The method can also be used after rt or crt in patients with tumor invasion ≥t1sm3, provided a complete or almost complete tumor response to the treatment.

Efficacy and Safety of Trans-Arterial Yttrium-90 Radioembolization in Patients with Unresectable Liver-Dominant Metastatic or Primary Hepatic Soft Tissue Sarcomas

Patients with liver-dominant metastatic or primary hepatic soft tissue sarcomas (STS) have poor prognosis. Surgery can prolong survival, but most patients are not surgical candidates, and treatment response is limited with systemic chemotherapy. Liver-directed therapies have been increasingly employed in this setting, and Yttrium-90 trans-arterial radioembolization (TARE) is an understudied yet promising treatment option. This is a retrospective analysis of 35 patients with metastatic or primary hepatic STS who underwent TARE at a single institution between 2006 and 2020. The primary outcomes that were measured were overall survival (OS), liver progression-free survival (LPFS), and radiologic tumor response. Clinical and biochemical toxicities were assessed 3 months after the procedure. Median OS was 20 months (95% CI: 13.9–26.1 months), while median LPFS was 9 months (95% CI: 6.2–11.8 months). The objective response rate was 56.7%, and the disease control rate was 80.0% by mRECIST at 3 months. The following correlated with better OS post-TARE: liver disease control (DC) at 6 months (median OS: 40 vs. 17 months, p = 0.007); LPFS ≥ 9 months (median OS: 50 vs. 8 months, p < 0.0001); ECOG status 0–1 vs. 2 (median OS: 22 vs. 6 months, p = 0.042); CTP class A vs. B (median OS: 22 vs. 6 months, p = 0.018); and TACE post-progression (median OS: 99 vs. 16 months, p = 0.003). The absence of metastases at diagnosis was correlated with higher median LPFS (7 vs. 1 months, p = 0.036). Two grade 4 (5.7%) and ten grade 3 (28.6%) laboratory toxicities were identified at 3 months. There was one case of radioembolization-induced liver disease and two cases of radiation-induced peptic ulcer disease. We concluded that TARE could be an effective and safe treatment option for patients with metastatic or primary hepatic STS with good tumor response rates, low incidence of severe toxicity, and longer survival in patients with liver disease control post-TARE.

Maximizing response to intratumoral immunotherapy in mice by tuning local retention

Direct injection of therapies into tumors has emerged as an administration route capable of achieving high local drug exposure and strong anti-tumor response. A diverse array of immune agonists ranging in size and target are under development as local immunotherapies. However, due to the relatively recent adoption of intratumoral administration, the pharmacokinetics of locally-injected biologics remains poorly defined, limiting rational design of tumor-localized immunotherapies. Here we define a pharmacokinetic framework for biologics injected intratumorally that can predict tumor exposure and effectiveness. We find empirically and computationally that extending the tumor exposure of locally-injected interleukin-2 by increasing molecular size and/or improving matrix-targeting affinity improves therapeutic efficacy in mice. By tracking the distribution of intratumorally-injected proteins using positron emission tomography, we observe size-dependent enhancement in tumor exposure occurs by slowing the rate of diffusive escape from the tumor and by increasing partitioning to an apparent viscous region of the tumor. In elucidating how molecular weight and matrix binding interplay to determine tumor exposure, our model can aid in the design of intratumoral therapies to exert maximal therapeutic effect.

Adenosine 2A receptor and TIM3 suppress cytolytic killing of tumor cells via cytoskeletal polarization

Tumors generate an immune-suppressive environment that prevents effective killing of tumor cells by CD8+ cytotoxic T cells (CTL). It remains largely unclear upon which cell type and at which stage of the anti-tumor response mediators of suppression act. We have combined an in vivo tumor model with a matching in vitro reconstruction of the tumor microenvironment based on tumor spheroids to identify suppressors of anti-tumor immunity that directly act on interaction between CTL and tumor cells and to determine mechanisms of action. An adenosine 2A receptor antagonist, as enhanced by blockade of TIM3, slowed tumor growth in vivo. Engagement of the adenosine 2A receptor and TIM3 reduced tumor cell killing in spheroids, impaired CTL cytoskeletal polarization ex vivo and in vitro and inhibited CTL infiltration into tumors and spheroids. With this role in CTL killing, blocking A2AR and TIM3 may complement therapies that enhance T cell priming, e.g. anti-PD-1 and anti-CTLA-4.

Prediction of biomarkers and therapeutic combinations for anti-PD-1 immunotherapy using the global gene network association

Owing to a lack of response to the anti-PD1 therapy for most cancer patients, we develop a network approach to infer genes, pathways, and potential therapeutic combinations that are associated with tumor response to anti-PD1. Here, our prediction identifies genes and pathways known to be associated with anti-PD1, and is further validated by 6 CRISPR gene sets associated with tumor resistance to cytotoxic T cells and targets of the 36 compounds that have been tested in clinical trials for combination treatments with anti-PD1. Integration of our top prediction and TCGA data identifies hundreds of genes whose expression and genetic alterations that could affect response to anti-PD1 in each TCGA cancer type, and the comparison of these genes across cancer types reveals that the tumor immunoregulation associated with response to anti-PD1 would be tissue-specific. In addition, the integration identifies the gene signature to calculate the MHC I association immunoscore (MIAS) that shows a good correlation with patient response to anti-PD1 for 411 melanoma samples complied from 6 cohorts. Furthermore, mapping drug target data to the top genes in our association prediction identifies inhibitors that could potentially enhance tumor response to anti-PD1, such as inhibitors of the encoded proteins of CDK4, GSK3B, and PTK2.

Hyperfractionated Treatment with 177Lu-Octreotate Increases Tumor Response in Human Small-Intestine Neuroendocrine GOT1 Tumor Model

Radionuclide treatment of patients with neuroendocrine tumors has advanced in the last decades with favorable results using 177Lu-octreotate. However, the gap between the high cure rate in animal studies vs. patient studies indicates a potential to increase the curation of patients. The aim of this study was to investigate the tumor response for different fractionation schemes with 177Lu-octreotate. BALB/c mice bearing a human small-intestine neuroendocrine GOT1 tumor were either mock treated with saline or injected intravenously with a total of 30–120 MBq of 177Lu-octreotate: 1 × 30, 2 × 15, 1 × 60, 2 × 30, 1 × 120, 2 × 60, or 3 × 40 MBq. The tumor volume was measured twice per week until the end of the experiment. The mean tumor volume for mice that received 2 × 15 = 30 and 1 × 30 MBq 177Lu-octreotate was reduced by 61% and 52%, respectively. The mean tumor volume was reduced by 91% and 44% for mice that received 2 × 30 = 60 and 1 × 60 MBq 177Lu-octreotate, respectively. After 120 MBq 177Lu-octreotate, given as 1–3 fractions, the mean tumor volume was reduced by 91–97%. Multiple fractions resulted in delayed regrowth and prolonged overall survival by 20–25% for the 120 MBq groups and by 45% for lower total activities, relative to one fraction. The results indicate that fractionation and hyperfractionation of 177Lu-octreotate are beneficial for tumor reduction and prolongs the time to regrowth.

Circulating T-Cell Repertoires Correlate With the Tumor Response in Patients With Breast Cancer Receiving Neoadjuvant Chemotherapy

PURPOSE Neoadjuvant chemotherapy (NAC) has been widely used in patients with breast cancer to minish tumor burden and increase resection rate of cancer. T-cell repertoire has been believed to be able to monitor antitumor immune responses. This study aimed to explore the dynamic change of T-cell repertoire and its clinical value in evaluating the tumor response in patients with breast cancer receiving NAC. MATERIALS AND METHODS Ninety-four patients who underwent NAC before surgery were recruited, and peripheral blood samples were collected at multiple time points during NAC. High-throughput T-cell receptor (TCR)-β sequencing was used to characterize the T-cell repertoire of every sample and analyzed the changes in circulating T-cell repertoire during NAC. RESULTS We found that the diversity of TCR repertoires was associated with age and clinical stage of the patients with breast cancer. The distribution of Vβ and Jβ genes in TCR repertoires was skewed in patients with human epidermal growth factor receptor 2–positive (HER2+) breast cancer. Vβ20.1 and Vβ30 expression levels before NAC correlate with tumor response after all cycles of NAC in HER2– and HER2+ patients, respectively. Some CDR3 motifs that correlated with clinical response in either HER2+ or HER2– patients were identified. Besides, TCR repertoire evolved during NAC and the diversity of TCR repertoire decreased more after two cycles of NAC in patients with good tumor response after all cycles of NAC ( P = .0061). CONCLUSION Our results demonstrated that TCR repertoire correlated with the characteristics of the tumor, such as the expression status of HER2. Moreover, some characteristics of TCR repertoires that correlated with clinical response were identified and they might provide useful information to tailor therapeutic regimens at the early cycle of NAC.