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Radiotherapy plus cetuximab (bioradiotherapy: BRT) is a standard option in the treatment of locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). Published data on its safety and efficacy in real-world settings is limited. Here, we conducted a prospective multi-institutional observational study to evaluate clinical outcomes of BRT in patients with LA-SCCHN.We analyzed real-world data of all patients who underwent BRT from 2013 to 2016. The primary endpoint was 1-year progression-free survival (PFS). Secondary endpoints were 1-year locoregional PFS (LPFS), treatment completion rate (TCR), and adverse events (AEs).A total of 171 patients with a minimum 1-year follow-up were analyzed. Median age was 67 (36-85) years, and 37 patients (21.6%) were aged 75 years or older. 1-year PFS and LPFS were 51.5 and 56.1%, respectively. N stage (p = 0.049) was significantly associated with PFS. TCR was 77.2%. Cetuximab was definitively discontinued in 30 patients (17.5%), in 15 cases due to severe mucositis. N stage, T stage, and comorbidity were significantly associated with TCR. Major AEs of grade 3 or higher were pharyngeal mucositis (48.5%), radiation dermatitis (45.6%), and oral mucositis (40.4%). Pneumonitis was observed in 12 patients (7.0%); 6 cases (3.5%) were grades 3-4 and 2 (1.2%) were grade 5.As a result of the large number of elderly patients in clinical practice, toxicity reduced TCR. BRT-induced pneumonitis, which is sometimes fatal, was found to be more frequent than with chemotherapy plus cetuximab.

To determine the optimal primary tumor dose for cervical cancer treatment using computed tomography (CT)-based image-guided brachytherapy (IGBT).We retrospectively reviewed 171 patients with cervical cancer who underwent both external beam radiation therapy (EBRT) and IGBT between May 2015 and December 2019. Majority of EBRT plan included central shielding technique. CT-based IGBT was performed weekly a median of three times. Magnetic resonance imaging preceded the first and third session of IGBT for target delineation.The median age of the patients was 64 years (range: 30-91 years). The median follow-up time for living patients was 43 months (range: 6-76 months). The 3-year local control rates according to the International Federation of Gynecology and Obstetrics (FIGO, 2008) stages were 89%, 100%, 92%, 89%, 78%, and 100% for stages IB, IIA, IIB, IIIA, IIIB, and IVA, respectively. The median EBRT dose to the central pelvis and parametrium/pelvic wall was 41.4 Gy and 50.4 Gy, respectively. Patients who received a cumulative 2 Gy equivalent dose (EQD2) (α/β = 10 Gy) of high-risk clinical target volume (HR CTV) D90% ≥ 75 Gy achieved a long-term local control rate of 93%, compared with 80% in those who received75 Gy (p = 0.02).This is one of the largest CT-based IGBT series examining the treatment of cervical cancer based on the tumor dose-volume relationship. An HR CTV D90% ≥75 Gy was significantly associated with favorable local control in this study.

The aims of this study are to evaluate the efficacy and safety of first-line treatment with chemotherapy plus cetuximab in real-world patients with recurrent or metastatic squamous cell carcinoma of the head and neck (RM-SCCHN) and to identify prognostic factors for overall survival (OS). This is a prospective observation study involving 20 oncology institutions in Japan. Patients with RM-SCCHN treated with a first-line therapy consisting of cetuximab plus any chemotherapy regimen between December 2013 and February 2017 were enrolled. The primary objective of the study was 1-year OS. Secondary objectives included response rate and adverse events. Of 120 patients recruited, 114 patients were analyzed. Median age was 64 years. Cetuximab in combination with platinum plus 5-FU (EXTREME regimen) was chosen in 86 patients (75.4%). The median OS was 12.4 months. A point estimate of the 1-year survival rate was 51.1%. Overall response rate was 26.3%. Grade 3 or worse adverse events included neutropenia (22.8%), hypokalemia (9.6%), acneiform rash (7.0%), pneumonitis (1.8%), and infusion-related reaction (0.9%). On multivariate analysis, regional lymph node metastasis, absence of intervention by dermatologists, lack of response to therapy, skin metastasis, and non-EXTREME regimen were identified as independent unfavorable prognostic factors for OS. The combination of cetuximab plus chemotherapy was tolerable and efficacious in patients with RM-SCCHN in a real-world setting. Clinical outcomes and prognostic factors extracted from this study provide a reference of the current clinical practice as well as for the future development of novel therapy in RM-SCCHN.

Anticancer drug delivery by small molecules offers a number of advantages over conventional macromolecular drug delivery systems. We previously developed phenylcyclopropylamine (PCPA)-drug conjugates (PDCs) as small-molecule-based drug delivery vehicles for targeting lysine-specific demethylase 1 (LSD1)-overexpressing cancers. In this study, we applied this PDC strategy to the HDAC-inhibitory anticancer agent vorinostat. Among three synthesized PCPA or arylcyclopropylamine (ACPA)-vorinostat conjugates

Our observational study aimed to verify the safety of our original titanium fiducial markers in gynecological cancer by using a simple insertion method. We prospectively evaluated the safety in patients with gynecological cancer who had undergone our insertion procedure of the titanium markers. The decision to implant a titanium marker was at the discretion of each radiation oncologist. The fiducial markers were manufactured by severing ligating clips for surgery into 3–6 mm pieces and were sterilized thereafter. We inserted an 18-gauge injection needle containing the marker before the marker was extruded by a 22-gauge Cattelan needle or shape memory alloy wire into the tumor or tissues close to the tumor. Severe complications within 3 months after implantation were scored according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events version 4.0. Between August 2016 and December 2018, we enrolled 46 patients. Of 46, 44 underwent implantation. The median age was 58.5 years. The most common primary site was the cervix. Two patients experienced detachment of the markers after implantation. No Grade 3 or higher level of complications was observed. Our simple insertion technique for original titanium fiducial markers was well-tolerated.

Objective To compare patient preferences and acute adverse events of hypofractionated (HF) and conventionally fractionated (CF) whole-breast irradiation (WBI) after breast-conserving surgery in our institution. Methods We conducted a patient preference study comparing CF-WBI (50 Gy/25 fractions) and HF-WBI (41.6 Gy/16 fractions) after breast-conserving surgery. Eligible patients selected either type of fractionation following an explanation from the radiation oncologist. In this report, we analyzed the selection rate and acute toxicities. Results Between June 2009 and December 2013, 348 patients (349 breasts) were identified as eligible for the study. Among them, 259 patients (260 breasts [74.5%]) selected CF-WBI and 89 patients (89 breasts [25.5%]) selected HF-WBI. Factors significantly associated with the selection of HF-WBI were older age (P = 0.028) and no adjuvant chemotherapy (P = 0.041). Regarding acute adverse events, Grade 2 (G2) or higher radiation dermatitis was less frequently observed in HF-WBI than in CF-WBI (13.8% vs. 29.4%; P = 0.004). In addition, G2 or higher breast pain was only observed in the CF-WBI group (6.9%; P = 0.012). There were no significant differences in the presence of fatigue, wound pain or radiation pneumonitis of G2 or higher between the groups. Conclusions In this study, in which patients themselves selected the irradiation method, more patients tended to select CF-WBI. The frequency of G2 or higher dermatitis and breast pain was significantly lower in the HF-WBI group than in the CF-WBI group. Our results support the evidence for recommending HF-WBI after breast-conserving surgery while presenting aspects of patient preferences.

Prodrug approaches are useful for enhancing the efficacies and reducing the side effects of anticancer drugs. Previously, we proposed a prodrug strategy for targeting cancers overexpressing lysine-specific demethylase 1 (LSD1), namely, conjugates of trans-2-phenylcyclopropylamine (PCPA, an LSD1 inhibitor) and anticancer drugs. In this study, we applied this prodrug strategy to the anticancer agent 5-fluorouracil (5-FU). In vitro assays showed that the PCPA-5-FU conjugate (1) released 5-FU upon the inhibition of LSD1. Furthermore, the conjugate (1) exerted an antiproliferative effect on colon cancer HCT116 cells. Thus, the PCPA-5-FU conjugate (1) was able to function as a prodrug of 5-FU, activated by LSD1 inhibition, and provided a useful new lead structure for further development.

In treatment of locally advanced squamous cell carcinoma of the head and neck (SCCHN), the use of docetaxel, cisplatin, and 5-fluorouracil (TPF) followed by high-dose cisplatin chemoradiotherapy (CRT) carries concerns over toxicity. We evaluated the feasibility of TPF as induction chemotherapy (IC) to Japanese patients and the tolerability of CRT with fractionated administration of cisplatin after IC. Patients with unresectable stage III, IV SCCHN received IC followed by CRT. IC consisted of three 3-week cycles of docetaxel 70–75 mg/m2 on day 1, cisplatin 70–75 mg/m2 on day 1, and 5-fluorouracil 750 mg/m2 on days 1–5. Patients subsequently received IMRT concomitant with fractionated administration of cisplatin (20 mg/m2) on days 1–4, repeated every 3 weeks. The primary endpoint was completion of the three cycles of IC. Forty-eight patients were enrolled. The IC treatment completion rate was 85%. Grade 3–4 toxicities of TPF were neutropenia (79%) and febrile neutropenia (15%). Thirty-eight patients (79%) achieved a response after IC. Forty patients subsequently underwent CRT. Thirty-three patients (83%) completed the planned cycles of fractionated administration of cisplatin, but seven (18%) did not. Grade 3–4 toxicities during CRT were neutropenia (23%), mucositis (53%), and dysphagia (33%). With a median follow-up of 36.1 months, 3-year overall survival was 65%. TPF IC is feasible and CRT with fractionated administration of cisplatin after IC is tolerable. IC followed by CRT appears to be a useful and safe sequential treatment. (Trial registration no. UMIN000024686).

A phase II study of adaptive two-step intensity-modulated radiotherapy (IMRT) with chemotherapy for nasopharyngeal cancer (NPC) (JCOG1015) was conducted to evaluate the efficacy and safety. Patients aged 20–75 years with stages II–IVB NPC were enrolled. As adaptive two-step IMRT, computed tomography planning was performed twice before IMRT for the initial plan of 46 Gy/23 fractions and during treatment for the boost plan of 24 Gy/12 fractions with a total dose of 70 Gy. Chemotherapy (cisplatin 80 mg/m2/3-weeks × 3 courses) was administered concurrently with IMRT, followed by adjuvant chemotherapy (cisplatin at 70 mg/m2 with 5-FU 700 at mg/m2 for 5 days/4 weeks × 3 courses). Between 2011 and 2014, 75 patients were enrolled from 12 institutions. The 3-year overall survival (OS) for the 75 patients was 88%, and the upper and lower limits of the 95% CI of 78%–94% were higher than the expected 3-year OS of 75% for the target population adjusted by the actual proportion of stage II:III:IV = 21%:44%:35%. The 3-year progression-free survival (PFS) and loco-regional PFS were 71% [59–80%] and 77% [66–85%], respectively. Although no grade 4–5 late toxicities were observed, 15 patients (20%) developed grade 3 late toxicities. Grade 2 xerostomia was noted in 26%, 12%, and 9% at 1, 2, and 3 years after starting IMRT, respectively. Adaptive two-step IMRT for NPC demonstrated an excellent 3-year OS with acceptable toxicities. This method may be one treatment option for locally advanced NPC.

Toll-like receptors (TLRs) are a family of pattern-recognition receptors that recognize pathogen-associated molecular patterns. TLR7 stimulation in pDCs (plasmacytoid dendritic cell) induces type I interferon, which results in innate immune activation. We previously showed that intravenously injectable DSP-0509 activated anti-tumor immunity in combination with immune checkpoint inhibitors. In this study, we present that DSP-0509 can enhance anti-tumor activity of radiation therapy (RT). RT is generally known to induce not only anti-tumor effector T cells through immunogenic cell death, but also cause immune suppression. We assessed the modulatory activity of DSP-0509 on immune suppressive cells. In CD8+ T cell suppression assay in which CD8+ T cells were cocultured with mMDSC (monocytic myeloid-derived suppressor cell, CD11b+Gr-1low), DSP-0509 restored the proliferation of CD8+ T cell suppressed by mMDSC. In Treg differentiation assay, in which Treg (CD4+CD25+Foxp3+) was differentiated from naïve CD4+ T cell in the presence of TGF-β, DSP-0509 suppressed the Treg differentiation. Treg function was assessed in coculture system, in which proliferation of CTV-labeled (CellTrace™ Violet) CD4+ T cell was suppressed by Treg. DSP-0509 restored the proliferation of CD4+ T cell. As a next step, to confirm a combination effect with RT, DSR-0509 (5 mg/kg, weekly) was administered with RT (5 Gy x 5 consecutive day). The combination administration extended the survival of CT26-bearing mice. The ratio of effector memory T cell (CD8+CD62L-CD127+) in CD8+ T cell was increased after administration of combination of DSP-0509 with RT. ELISpot assay using splenocytes collected from CT26-bearing mice after the administration of combination of DSP-0509 with RT was conducted. As a result, the number of IFNγ secreting cytotoxic T lymphocytes (CTLs) that responded to gp70 peptide was increased in combination of DSP-0509 with RT. When CT26 cells were re-challenged to the mice that completely rejected tumor after combination of DSP-0509 with RT, no tumor growth was observed in all mice. Anti-CD8 antibody treatment prior to re-challenge of CT26 cells cancelled this memory effect. qPCR analysis using mRNA isolated from treated tumor was conducted. RT monotherapy increased the expression of Cd8b1, but addition of DSP-0509 further enhanced the expression of Gzmb and Il12b in tumor. We showed two novel effects of DSP-0509 in this study, 1) modulation of immune suppressive cells and 2) extension of the survival of tumor-bearing mice in combination with RT, which would be explained by the additive CTL activation and memory T cell induction. Taken together, these results supported the hypothesis that combination of DSP-0509 with RT may enhance the anti-tumor immune activity by modulating CTL activity as well as immune suppressive cells. Citation Format: Yosuke Ota, Yasuhiro Nagai, Masashi Goto, Jun Oishi, Setsuko Yamamoto. Modulation of immune suppressive cells by toll-like 7 agonist DSP-0509 which leads to potentiate anti-tumor activity of radiotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 523.

We are developing an art-appreciation system that can teach viewers about pictures through active appreciation. This system can convey information about pictures by enabling a viewer to “talk” to an artist or people portrayed in the pictures using a voice recognition system. Furthermore, the system responds to the movement and location of the user, and it generates a sensation such that the user feels he/she is interacting with the pictures and thus actively appreciating them. Here, we quantitatively evaluate this system two ways. We measure electrodermal activity to determine whether the user is interested in a picture when interacting with it using the voice recognition system. We also conducted a questionnaire-based user evaluation with schoolchildren. In this paper, we summarize the current system and the describe two evaluation results, which show that the system has good potential for use in general museums.

This paper describes the relationship between visual attention and eye blink frequency. In an experiment, we prompted the activation of a subject’s visual attention and examined the influence of visual attention (as measured using electrodermal activity (EDA), which is meaningfully correlated with visual attention) on the subject’s eye blink frequency. Experimental results show that engagement of visual attention decreased eye blink frequency and that when visual attention was not activated, eye blink frequency increased. Knowledge of this relationship provides a technique using EDA to objectively determining a subject’s visual attention status.

Background: Induction chemotherapy (IC) is a treatment option for locally advanced squamous cell carcinoma of the head and neck (LA SCCHN). However, treatment with docetaxel, cisplatin, and 5-FU (TPF) followed by cisplatin and radiotherapy is controversial because of toxicity concerns. The aim of this phase II study was to assess the feasibility of docetaxel, cisplatin, and cetuximab (TPEx) followed by cetuximab and concurrent radiotherapy for LA SCCHN. Patients and Methods: We enrolled patients with histological evidence of squamous cell carcinoma of the oropharynx, hypopharynx, or larynx without distant metastases. IC comprised cisplatin (75 mg/m2) and docetaxel (75 mg/m2) on day 1, repeated every 3 weeks for up to three courses. Cetuximab was initiated at 400 mg/m2, followed by 250 mg/m2 doses weekly until the end of radiotherapy. Radiotherapy (70 Gy/35 fr/7 w) was initiated after the last docetaxel administration. The primary endpoint was the rate of treatment completion. Results: We enrolled 54 patients (median age, 58 years) between August 2013 and October 2015. Our patients were 49 males and 5 females with hypopharyngeal (n = 28), oropharyngeal (n = 19), or laryngeal (n = 7) cancers, and 48 of them had stage IV disease. The overall response rate was 72.2% with a median follow-up of 36.1 months and a 3-year overall survival of 90.7%. The treatment completion rate was 76%; 50 patients (93%) received ≥2 courses of IC, and 41 (76%) completed radiotherapy. The frequencies of grade ≥3 febrile neutropenia or allergy/infusion reactions were 39% and 11%, respectively. There was one treatment-related death. Conclusions: IC with TPEx followed by cetuximab with concurrent radiotherapy showed acceptable compliance for the treatment of LA SCCHN. However, high frequency of febrile neutropenia remains a challenge and further improvement in the management of TPEx is necessary. Trial Registration: UMIN000009928

Targeting cancer with small molecule prodrugs should help overcome problems associated with conventional cancer-targeting methods. Herein, we focused on lysine-specific demethylase 1 (LSD1) to trigger the controlled release of anticancer drugs in cancer cells, where LSD1 is highly expressed. Conjugates of the LSD1 inhibitor trans-2-phenylcyclopropylamine (PCPA) were used as novel prodrugs to selectively release anticancer drugs by LSD1 inhibition. As PCPA-drug conjugate (PDC) prototypes, we designed PCPA-tamoxifen conjugates 1 a and 1 b, which released 4-hydroxytamoxifen in the presence of LSD1 in vitro. Furthermore, 1 a and 1 b inhibited the growth of breast cancer cells by the simultaneous inhibition of LSD1 and the estrogen receptor without exhibiting cytotoxicity toward normal cells. These results demonstrate that PDCs provide a useful prodrug method that may facilitate the selective release of drugs in cancer cells.

We describe the structure-activity relationship of various arylcyclopropylamines (ACPAs), which are potent LSD1 inhibitors. More than 45 ACPAs were synthesized rapidly by an unconventional method that we have recently developed, consisting of a C-H borylation and cross-coupling sequence starting from cyclopropylamine. We also generated NCD38 derivatives, which are known as LSD1 selective inhibitors, and discovered a more effective inhibitor compared to the original NCD38.

Lysine-specific demethylase 1 (LSD1) mainly removes methyl groups of mono- or di-methylated lysine residues at the fourth position of histone H3 to epigenetically regulate the expression of genes associated with several diseases, such as cancer. Therefore, LSD1 inactivators are expected to be used as therapeutic agents. In this study, to identify novel peptide-based LSD1 inactivators, we focused on the X-ray structure of LSD1 complexed with a H3 peptide-based suicide substrate. It has been proposed that a methylated histone substrate forms three consecutive γ-turn structures in the active pocket of LSD1. Based on this, we designed and synthesized novel histone H3 peptide-based LSD1 inactivators 2a–c by incorporating various α,α-disubstituted amino acids with γ-turn-inducing structures. Among synthetic peptides 2a–c, peptide 2b incorporating two 1-aminocyclohexanecarboxylic acids at both sides of a lysine residue bearing a trans-2-phenylcyclopropylamine (PCPA) moiety, which is a pharmacophore for LSD1 inactivation, was the most potent and selective LSD1 inactivator. These findings are useful for the further development of histone H3 peptide-based LSD1 inactivators.

Lysine-specific demethylase 1 (LSD1) is one of the flavin-dependent oxidases and is involved in many cellular processes by controlling the methylation of histone H3. Recently, it has been reported that LSD1 is associated with several diseases such as cancer, metabolic disorders, and psychiatric diseases. Thus, LSD1 is an attractive molecular target for the treatment of these diseases, and its inhibitors are predicted as therapeutic agents. Although a variety of LSD1 inhibitors have been reported to date, many of them show insufficient activities and selectivity toward LSD1. Meanwhile, we identified several LSD1-selective inhibitors using target-guided synthesis strategies based on our original ideas. Our LSD1 inhibitors show not only potent LSD1-selective inhibitory activities, but also unique bioactivities both in vitro and in vivo. This account highlights our drug design concepts for and identification of LSD1-selective inhibitors.

Lysine-specific demethylase 1 (LSD1), the first histone demethylase to be identified, catalyzes specifically the demethylation of the mono- and dimethyl groups of histone H3 lysine 4, and its dysregulation is thought to contribute to the development of cancer. We have recently reported that NCL1 (4) is the first cell-active LSD1-selective inhibitor. To find LSD1 inhibitors that show higher potency than NCL1 (4), we designed and synthesized an N-alkylated analogue of NCL1 (5), and evaluated its biological activity. In enzyme assays, compound 5 was six times more potent than 4, and compound 5 exhibited cell growth inhibition in cervical cancer HeLa cell line and neuroblastoma SH-SY5Y cell line. Compound 5 should be useful as a lead structure for anticancer drugs.

Lysine-specific demethylase 1 (LSD1) is an attractive molecular target for cancer therapy. We have previously reported potent LSD1-selective inhibitors (i.e., NCD18, NCD38, and their analogs) consisting of trans-2-phenylcyclopropylamine (PCPA) or trans-2-arylcyclopropylamine (ACPA) and a lysine moiety that could form a γ-turn structure in the active site of LSD1. Herein we report the design, synthesis and evaluation of γ-turn mimetic compounds for further improvement of LSD1 inhibitory activity and anticancer activity. Among a series of γ-turn mimetic compounds synthesized by a Mitsunobu-reaction-based amination strategy, we identified 1n as a potent and selective LSD1 inhibitor. Compound 1n induced cell cycle arrest and apoptosis through histone methylation in human lung cancer cells. The γ-turn mimetics approach should offer new insights into drug design for LSD1-selective inhibitors.

Lysine-specific demethylase 1 (LSD1) is a flavin-dependent enzyme that removes methyl groups from mono- or dimethylated lysine residues at the fourth position of histone H3. We have previously reported several histone H3 peptides containing an LSD1 inactivator motif at Lys-4. In this study, histone H3 peptides having a trans-2-phenylcyclopropylamine (PCPA), a 2,5-dihydro-1H-pyrrole, and a 1,2,3,6-tetrahydropyridine moiety at Lys-4 were prepared along with related compounds possessing a shorter side chain at the fourth position. Enzymatic assays showed that PCPA peptides containing a longer side chain, which can react with FAD in the active site, are potent LSD1-selective inhibitors.

Objective: To investigate the optimal treatment method and risk factor of neck node metastasis from unknown primary tumors (NUP) treated by radiotherapy. Methods: Retrospective case study based on a multi-institutional survey was conducted by the Japanese Radiation Oncology Study Group. Patients pathologically diagnosed as having NUP from 1998 to 2007 were identified. Univariate and multivariate analyses of overall survival (OS), progression free survival (PFS), neck progression free survival (NPFS) and mucosal progression free survival (MPFS) were evaluated. Results: In total, 130 patients with median age of 65 years were included. Nodal stages N1, N2a, N2b and N2c were observed for 10, 26, 43, 12 and 39 patients, respectively. All the patients received radiotherapy (RT) with neck dissection in 60 and with chemotherapy in 67 cases. The median doses to the metastatic nodes, prophylactic neck and prophylactic mucosal sites were 60.0, 50.4 and 50.4 Gy, respectively. The median follow-up period for surviving patients was 42 months. Among 12 patients, occult primary tumors in the neck region developed after radiotherapy. The 5-year OS, PFS, NPFS and MPFS were 58.1%, 42.4%, 47.3% and 54.9%, respectively. Univariate analysis showed that lower N stage (N1?2b), non-bulky node (, Japanese Journal of Clinical Oncology, 47(9), pp.856-862; 2017

Introduction:We aimed to develop a more accurate model for predicting severe radiation pneumonitis (RP) after concurrent chemoradiotherapy for non–small-cell lung cancer.Methods:We retrospectively analyzed data from 122 patients with locally advanced non–small-cell lung cancer treated with concurrent chemoradiotherapy. Several dose-volume histogram metrics including absolute lung volume spared from a 5 Gy dose (VS5) were analyzed for an association with RP above NCI-CTC grade 3 (RP ≥ G3). Clinical factors including pulmonary fibrosis score (PFS) and pulmonary emphysema score on baseline chest computed tomography (CT) were also analyzed.Results:Fourteen patients (11.4%) developed RP greater than or equal to G3. On univariate analysis, all dose-volume histogram metrics, sex, and PFS on baseline CT were significantly (p < 0.05) associated with occurrence of RP greater than or equal to G3. Multivariate analysis revealed that V20 greater than or equal to 26%, VS5 less than 1500 cc, age greater than or equal to 68 years, and PFS on baseline CT greater than or equal to 2 were significant risk factors. Thus, we defined a new predictive risk score (PRS) that combines these factors. The cumulative incidence of RP greater than or equal to G3 at 12 months were 0%, 7.8%, 26.6%, and 71.4% when the PRS was 0, 3–5, 6–8, and 9–14, respectively (p < 0.001). This PRS was superior at predicting RP than both V20 and VS5 combined, or V20 alone by receiver operating characteristic analysis (area under the curve, 0.888 versus 0.779 versus 0.678).Conclusions:V20, VS5, age, and PFS on baseline CT are independent and significant risk factors for occurrence of severe RP. Combining these factors may improve the predictability of severe RP.

Background Some studies have demonstrated that concurrent chemo-radiotherapy is an effective salvage treatment for isolated para-aortic lymph node (PALN) recurrence. However, no studies have compared multi-treatment modalities, such as radiation therapy (RT), concurrent chemoradiotherapy (CCRT), surgery, chemotherapy, and best supportive care (BSC), across a sufficient number of patients with PALN recurrence. We thus aimed to evaluate the clinical outcomes of multi-treatment modalities for isolated PALN recurrence in uterine cervical cancer. Methods Records of 50 patients who were first diagnosed with isolated PALN recurrence after definitive cervical cancer treatment from 2002 to 2016 at our institution were reviewed retrospectively. The initial definitive cervical cancer therapies included RT alone, CCRT, or surgery with or without post-operative RT. The median follow-up time was 33 months. The median age at recurrence diagnosis was 57 years (range, 26–84 years). The median duration between the end of initial treatment and recurrence was 10 months (range, 1–91 months). The median maximum metastatic lesion size was 17 mm (range, 8–60 mm). Twenty-four patients had one or two PALN metastases, while 26 had 3 or more. Eighteen patients were treated for recurrence with RT alone, seven with CCRT, three with surgery, 17 with chemotherapy, and five with BSC. Potential prognostic factors included histopathology, initial FIGO stage, initial treatment, age at recurrence, tumor markers (serum SCC-Ag and CEA) at recurrence, time to recurrence, maximum size of the metastatic lesion, number of metastases, and the recurrence treatment method. Results The 3-year overall survival (OS) rates of all patients were 47.0%. The 3-year OS rate of patients who underwent CCRT for recurrence was 85.7%; surgery, 66.7%; chemotherapy, 48.8%; RT, 41.3%; and BSC, 0% (p = 0.014). Univariate analysis revealed that only the recurrence treatment method was significantly associated with OS. The 3-year local control rate (LCR) and progression free survival (PFS) rate for CCRT were 100 and 71.4%; for surgery, 100 and 66.7%; for chemotherapy, 33.6 and 13.7%; and for RT, 55.5 and 14.1%, respectively (LCR: p = 0.028, PFS: p = 0.059). The number of metastatic lesions, SCC-Ag levels and recurrence treatment method were significantly associated with LCR. Age at recurrence, SCC-Ag levels, and number of metastatic lesions were significantly associated with PFS. Conclusions Although our patient cohort size was small, our results suggest that CCRT may be effective in preventing local disease recurrence in the PALN and may improve OS.

Background While immune checkpoint inhibitors (ICIs) have been shown to be effective for non-small cell lung cancer (NSCLC), their monotherapeutic response rate (RR) is roughly 20%. It has been noted that local radiation therapy (RT) might potentially activate off-target antitumor effect, which is so called “abscopal effect” induced by immune-mediated mechanism. We evaluated whether palliative-RT induced abscopal effect, resulting in improvement of Nivolumab (Nivo) effectiveness. Methods Pretreated advanced NSCLC patients (pts) who were indicated for Nivo and scheduled for palliative-RT were started on RT within 10 days of administration of Nivo 3 mg/kg q2 weeks until attached document was revised to 240 mg/body q2 weeks. The primary endpoint was RR of non-irradiated tumor lesions. Results Twenty-eight pts were enrolled from May 2016 to January 2019. The study was terminated before completion of targeted initial sample size (n = 35), because of poor accrual. The median age was 67 years (range: 53-89). 15 pts were male. 21 pts had adenocarcinoma histology, 2 pts squamous histology, and 6 pts driver oncogene alterations. 25 pts were PS0/1, and 3 pts PS2. 14 pts were treated as 2nd-line, 2 pts as 3rd-line, and 12 pts as 4th-line or later. The median number of treatment cycles was 4 (range: 1-6). Median radiation dose was 30 Gy (range: 25-40), and 16 pts were irradiated on the bone, 5 pts on the adrenal grand, and 2 pts on the primary lesion. The objective RR of non-irradiated tumor lesions was 14.3% (95% CI: 1.3–27.2). Partial response (PR) was observed in 3 pts treated as 2nd-line (3/14, 21.4%), and 1 pt as 3rd-line (1/2, 50%). No PR was observed in pts treated as 4th-line or later (0/12, 0%). The median PFS was 2.7 months (95% CI: 1.0–3.5). No severe and specific adverse events (AEs) of Nivo in combination with RT were observed compared to historical data of Nivo monotherapy. Conclusions Although the sample size was small, cleared abscopal effect by palliative-RT was not observed in Nivo treatment. However, some pts well responded to Nivo with palliative-RT during early-lines of treatment (2nd/3rd-line). Further investigations in the early-lines are warranted to evaluate a substantial synergistic effect of RT with ICIs. Clinical trial identification UMIN000023646. Legal entity responsible for the study HANSHIN Oncology Group. Funding ONO Pharmaceutical Company. Disclosure A. Hata: Speaker Bureau / Expert testimony, Research grant / Funding (institution): Boehringer Ingelheim; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Eli Lilly; Speaker Bureau / Expert testimony, Research grant / Funding (institution): AstraZeneca; Speaker Bureau / Expert testimony: Chugai; Research grant / Funding (institution): MSD. M. Satouchi: Speaker Bureau / Expert testimony, Research grant / Funding (institution): AstraZeneca; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Boehringer Ingelheim; Speaker Bureau / Expert testimony, Research grant / Funding (institution): BMS; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Chugai; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Eli Lilly; Speaker Bureau / Expert testimony, Research grant / Funding (institution): MSD; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Novartis; Speaker Bureau / Expert testimony, Research grant / Funding (institution): ONO; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Takeda; Speaker Bureau / Expert testimony: Taiho. D. Harada: Honoraria (self): ONO; Honoraria (self): BMS. All other authors have declared no conflicts of interest.

Toll-like receptors (TLRs) are a family of pattern-recognition receptors (PRR) that recognize pathogen-associated molecular patterns (PAMPs). TLR7 is mainly expressed in plasmacytoid dendritic cells (pDCs) and recognizes virus derived single-stranded RNA (ssRNA). TLR7 stimulation in pDCs induces type I interferon secretion, which results in innate immune activation. In this preclinical study, the characteristic changes in the tumor microenvironment (TME) after the combination treatment of DSP-0509 with immune checkpoint inhibitors (ICIs) in DSP-0509-responsive and -resistant tumors were assessed. Mutation rates of microsatellite loci were measured by 3130 xl Genetic Analyzer. Anti-tumor activity was evaluated in syngeneic mouse models along with flow cytometric analysis of tumor infiltrating lymphocytes (TILs). Gene expression profiles in tumor tissues were measured by qPCR arrays. Mutation rates of 5 microsatellite loci and basal levels of CD8+T cell infiltration were examined in tumor tissues derived from 10 syngeneic tumor-bearing mouse models. Intravenous administration of DSP-0509 significantly suppressed tumor growth in some tumor-bearing mouse models with high mutation rates and CD8+T cell infiltration including the CT26 (P Citation Format: Yosuke Ota, Takeshi Otsubo, Masashi Goto, Yasushi Matsuki. Enhanced anti-tumor activity through a combination of intravenous injectable TLR7 agonist, DSP-0509 and immune checkpoint inhibitors [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 4078.

The purpose of this study is to determine the incidence, clinical characteristics and risk factors of postradiation pelvic insufficiency fracture (PIF) in women with uterine cervical cancer. We reviewed the medical records of 126 patients who received definitive radiotherapy (RT) for uterine cervical cancer between 2003 and 2009 at our institution. Among them, 99 patients who underwent at least one computed tomography (CT) or magnetic resonance imaging of the pelvis during their follow-up at more than 6 months were included in this analysis. The relationship between the incidence of PIF and several patient- and treatment-related factors was analyzed. The median follow-up period was 21 months. Of the 126 patients, 33 (with a total of 50 lesions) were diagnosed with PIF. The 2-year cumulative incidence was 32%. Univariate analysis showed that age ≥70 years (P= 0.0010), postmenopausal state (P = 0.0013), and lower CT density of bone and bone marrow (P= 0.020) significantly related to PIF. In a multivariate analysis, of the 59 patients whose CT densities were evaluable, lower CT density was the only significant factor associated with PIF (P = 0.0026). In conclusion, postradiation PIFs were detected in a considerable number of patients after definitive RT for cervical cancer. Predisposing factors were older age, postmenopausal state, and decreased density of bone and bone marrow on CT.