Real-world data of anamorelin in advanced gastrointestinal cancer patients with cancer cachexia.

BACKGROUND: Cancer cachexia is characterized by the loss of body weight (BW) and anorexia. Anamorelin (ANAM) is a selective ghrelin receptor agonist with appetite-enhancing anabolic action. The ONO-7643-05 trial demonstrated that ANAM increased lean body mass and improved anorexia in a Japanese population. However, the clinical outcomes of patients on ANAM have not yet been reported. PATIENTS AND METHODS: We investigated the clinical outcomes of patients with unresectable, advanced, or recurrent gastrointestinal cancer (colorectal, gastric, or pancreatic cancer) who were treated with ANAM between April 2017 and August 2022. Cachexia was defined as the presence of anorexia and a loss of ≥ 5% of BW within 6 months. To evaluate the response to ANAM, the patients who had discontinued ANAM within 3 weeks were excluded. Response to ANAM was defined as maintenance of or increase in BW and improved appetite from baseline at every 3-week evaluation. We also collected data on the reasons for the discontinuation of ANAM and the correlation between clinical factors and ANAM response. Safety analysis of ANAM was performed for all patients who received ANAM. RESULTS: Seventy-four patients were included in this study (49 males and 25 females), with a median age of 67.1 years (range, 36-83). The primary tumors were colorectal cancer in 27 (36.5%), gastric cancer in 20 (27.0%), and pancreatic cancer in 27 (36.5%). The Eastern Cooperative Oncology Group performance status was 0 in 10 (13.5%), 1 in 44 (59.5%), and ≥ 2 in 20 (27.0%). The number of previous chemotherapy regimens was 0 in 20 (27.0%), 1 in 22 (29.7%), and ≥ 2 in 32 (43.2%). ANAM was discontinued within 3 weeks in 28 patients for the following reasons: low-grade (grade 1 or 2) adverse events in 15 patients, ileus in three, grade 3 fatigue in one, progressive disease in one, censored follow-up in six, and unknown reasons in three. The proportion of ANAM responders was 63.6% (95% confidence interval, 47.8-77.6%). Among baseline characteristics, age ≥ 75 attenuated the ANAM response (p = 0.03). ANAM responders showed better disease control with chemotherapy than non-responders (75.0% vs. 37.5%, p = 0.02). CONCLUSIONS: ANAM may improve the outcomes of patients with gastrointestinal cancer cachexia in clinical practice.

Impact of relative cisplatin dose to skeletal muscle mass on adverse events in patients with head and neck cancer undergoing chemoradiotherapy.

BACKGROUND: Chemoradiotherapy (CRT) with high-dose cisplatin (CDDP) is the standard treatment for locally advanced head and neck squamous cell carcinoma (HNSCC). Although dosing is based on body surface area (BSA), some patients experience CDDP-related adverse events (AEs). We aimed to evaluate the impact of relative CDDP dose to skeletal muscle mass (SMM) on chemotherapy-associated AEs in patients with HNSCC undergoing CRT with high-dose CDDP. MATERIALS AND METHODS: We retrospectively analyzed data of patients who underwent CRT with high-dose CDDP (80-100 mg/m2, triweekly) between 2010 and 2023. SMM was measured as the cross-sectional muscle area at the third cervical vertebra (C3-SMM) using computed tomography; the skeletal muscle index (SMI) was defined as SMM normalized by squared height. The CDDP index was defined as the prescribed CDDP dose divided by SMI. CDDP-related AEs were assessed during the first cycle using Common Terminology Criteria for Adverse Events v5.0. RESULTS: Overall, 306 patients were identified. The CDDP index cutoff value best associated with grade ≥ 3 AEs was 10.312. Grade ≥ 3 hematological toxicities exhibited stronger association with high CDDP index value than with low CDDP index value (26.9% vs 16.3%, P = .033). Multivariate analysis revealed that high CDDP index value and creatinine clearance < 70 mL/minute were predictive factors for grade ≥ 3 AEs (odds ratio [OR] 2.55, P = .008; OR 3.68, P = .002, respectively). CONCLUSION: The CDDP index based on C3-SMM was an independent predictive factor for grade ≥ 3 CDDP-related AEs. C3-SMM is potentially more useful than BSA for determining the optimal CDDP dose in patients with HNSCC.

Survival outcome of esophagectomy and chemoradiotherapy for resectable esophageal squamous cell carcinoma in patients >75 years of age.

BACKGROUND: The gold standard for resectable, locally advanced esophageal squamous cell carcinoma (ESCC) is surgery-based treatment; however, it is unclear whether esophagectomy or chemoradiotherapy is suitable for older patients. This retrospective study aimed to identify the treatment outcomes of surgery-based therapy versus definitive chemoradiotherapy (dCRT) as an initial treatment for older patients with resectable, locally advanced ESCC. METHODS: Data from 434 patients who received radical treatment for resectable, locally advanced ESCC were collected from January 2011 to December 2020. Of the patients >75 years of age, 49 underwent radical esophagectomy and 26 received dCRT. Survival was compared between the surgery and dCRT groups. RESULTS: The mean ages of the surgery and chemoradiotherapy groups were 77.3 and 78.8 years, respectively. Differences in overall survival (OS) between the two groups were not statistically significant (3-year OS: surgery 66.2%, dCRT 55.7%, p = 0.236). Multivariate analysis for OS showed a hazard ratio of 1.229 for dCRT versus surgery (90% confidence interval 0.681-2.217). OS did not differ between the groups in any of the performance statuses. For patients who were able to receive chemotherapy using fluorouracil and cisplatin, OS tended to be better in the surgery group, but the difference was not statistically significant (3-year OS: surgery 68.1%, dCRT 51.8%, p = 0.117). CONCLUSIONS: There was no clear difference in survival outcome between surgery-based therapy and dCRT as an initial treatment for esophageal cancer in older patients. Either treatment may be an option for older patients.

Lenvatinib rechallenge after failure of lenvatinib and sorafenib in metastatic thyroid cancer.

The oral multikinase inhibitors sorafenib and lenvatinib are currently available as first-line treatment for patients with unresectable or metastatic thyroid cancer. However, treatment options for patients who are refractory to these multikinase inhibitors are limited. This study aimed to evaluate the safety and efficacy of rechallenged lenvatinib after failure of both lenvatinib and sorafenib in patients with metastatic thyroid cancer in the real-world clinical practice. We retrospectively reviewed the data of consecutive 16 patients with metastatic thyroid cancer who received lenvatinib as a rechallenge after failure of initial lenvatinib and sorafenib treatment at Shizuoka Cancer Center between 2016 and 2023. Of these, the initial lenvatinib was discontinued in 12 patients owing to progressive disease, in 3 patients owing to adverse events, and in 1 patient owing to both. The overall response rate was 6.7%, and disease control was achieved by rechallenge with lenvatinib in all patients with the target lesions. The median progression free survival after rechallenging with lenvatinib was 15.0 months. No new signs of toxicity were observed after rechallenging with lenvatinib. Our findings suggest that rechallenge with lenvatinib after failure of both lenvatinib and sorafenib showed manageable safety and modest efficacy in patients with metastatic thyroid cancer in clinical practice. The strategy of lenvatinib rechallenge may provide an alternative option for patients with no targetable driver genes or when selective kinase inhibitors are not indicated.

Pemigatinib in previously treated solid tumors with activating FGFR1-FGFR3 alterations: phase 2 FIGHT-207 basket trial.

Fibroblast growth factor receptor (FGFR) alterations drive oncogenesis in multiple tumor types. Here we studied pemigatinib, a selective, potent, oral FGFR1-FGFR3 inhibitor, in the phase 2 FIGHT-207 basket study of FGFR-altered advanced solid tumors. Primary end points were objective response rate (ORR) in cohorts A (fusions/rearrangements, n = 49) and B (activating non-kinase domain mutations, n = 32). Secondary end points were progression-free survival, duration of response and overall survival in cohorts A and B, and safety. Exploratory end points included ORR of cohort C (kinase domain mutations, potentially pathogenic variants of unknown significance, n = 26) and analysis of co-alterations associated with resistance and response. ORRs for cohorts A, B and C were 26.5% (13/49), 9.4% (3/32) and 3.8% (1/26), respectively. Tumors with no approved FGFR inhibitors or those with alterations not previously confirmed to be sensitive to FGFR inhibition had objective responses. In cohorts A and B, the median progression-free survival was 4.5 and 3.7 months, median duration of response was 7.8 and 6.9 months and median overall survival was 17.5 and 11.4 months, respectively. Safety was consistent with previous reports. The most common any-grade treatment-emergent adverse events were hyperphosphatemia (84%) and stomatitis (53%). TP53 co-mutations were associated with lack of response and BAP1 alterations with higher response rates. FGFR1-FGFR3 gatekeeper and molecular brake mutations led to acquired resistance. New therapeutic areas for FGFR inhibition and drug failure mechanisms were identified across tumor types. ClinicalTrials.gov identifier: NCT03822117 .

Radiation-induced xerostomia and cariogenic dietary habits.

PURPOSE: Despite the availability of various prevention methods, dental caries continue to be diagnosed in patients receiving head and neck radiotherapy (RT). Since conventional approaches do not evaluate posttreatment alterations in dietary behaviors, we aimed to assess the influence of radiation-induced xerostomia on post-RT cariogenic dietary habits in patients. METHODS: Fifty-seven patients completed the Xerostomia Questionnaire (XQ) and answered questions regarding daily cariogenic food and beverage (CFB) intake, daily tooth brushing, fluoride application, and subjective total taste acuity (STTA). They also underwent evaluations to determine the Simplified Oral Hygiene Index (OHI-S) score, Saxon test score, number of decayed-missing-filled teeth (DMFT), and proportion of DMFT to the test teeth (DMFT rate). Clinical records were searched for information regarding RT modalities, including the median of the mean dose to the parotid glands, days after the completion of RT, submandibular gland resection, whole-neck irradiation, and the DMFT value and rate before RT. The patients were divided into low and high XQ score groups based on the median XQ score of 47.5 for the two sample tests. Univariable and multivariable regression analyses were used to identify independent factors for frequent CFB intake. RESULTS: Higher XQ scores were associated with a significantly greater frequency of CFB intake (p = 0.028*). Regression analysis also identified a higher XQ score (p = 0.017*) as an independent risk factor for frequent CFB intake. CONCLUSION: Radiation-induced xerostomia increased the frequency of CFB intake.

Metallaantiaromaticity of 10-Platinacorrole Complexes.

The aromaticity of cyclic π-conjugated organometallic compounds is known as metallaaromaticity. π-Conjugated metallacycles, such as metallabenzenes and metallapentalenes, have been investigated in order to understand the involvement of the d electrons from the metal center in the π-conjugated systems of the organic ligands. Here, we report the synthesis of Pd(II) 10-platinacorrole complexes with cyclooctadiene (COD) and norbornadiene (NBD) ligands. While the Pd(II) 10-platinacorrole COD complex adopts a distorted structure without showing appreciable antiaromaticity, the corresponding NBD complex exhibits a distinct antiaromatic character due to its highly planar conformation. Detailed density functional theory (DFT) calculations revealed that two d orbitals are involved in macrocyclic π-conjugation. We furthermore demonstrated that Craig-Möbius antiaromaticity is not present in the studied system. The synthesis of 10-platinacorroles enables a systematic comparison of the antiaromaticity and aromaticity of closely related porphyrin analogues, providing a better understanding of π-conjugation that involves d orbitals.

Novel approach of prophylactic radiation to reduce toxicities comparing 2-step40 with 56-Gy simultaneous integrated boost intensity-modulated radiation therapy for locally advanced squamous cell carcinoma of the head and neck, an intergroup phase III trial (JCOG1912, NEW BRIDGE).

BACKGROUND: Chemoradiotherapy (CRT) with concurrent cisplatin is the standard of care as a nonsurgical definitive treatment for patients with locally advanced squamous cell carcinoma of the head and neck (LA-SCCHN). However, CRT is associated with increased severe late adverse events, including swallowing dysfunction, xerostomia, ototoxicity, and hypothyroidism. Few strategies aimed at less invasive CRT without compromising treatment outcomes have been successful. The purpose of this study is to confirm the non-inferiority of reduced dose prophylactic radiation with 40 Gy compared to standard dose prophylactic radiation with 56 Gy in terms of the time to treatment failure (TTF) among patients with clinical stage III-IVB LA-SCCHN. METHODS: This study is a multicenter, two-arm, open-label, randomized phase III trial. Patients with LA-SCCHN excluding p16 positive oropharynx cancer are randomized to the standard arm or experimental arm. A total dose of 70 Gy for tumors with concurrent cisplatin at 100 mg/m2 are administered in both arms. For prophylactic field, patients in the standard arm receive a total dose of 56 Gy in 35 fractions for 7 weeks using simultaneous integrated boost (SIB56) and those in the experimental arm receive 40 Gy in 20 fractions using two-step methods for 4 weeks (2-step40). A total of 400 patients will be enrolled from 52 Japanese institutions within 5 years. The primary endpoint is TTF, and the secondary endpoints are overall survival, complete response rate, progression-free survival, locoregional relapse-free survival, acute and late adverse events, quality of life score, and swallowing function score. DISCUSSION: If the experimental arm is non-inferior to the standard arm in terms of TTF and superior on the safety endpoints, the 2-step40 procedure is the more useful treatment than SIB56 for definitive CRT. TRIAL REGISTRATION: This trial has been registered in the Japan Registry of Clinical Trials as jRCTs031210100 ( https://jrct.niph.go.jp/latest-detail/jRCTs031210100 ). Date of Registration: May 2021.

Multidisciplinary tumor board for head and neck cancer from the perspective of medical oncologists-optimizing its effectiveness.

Head and neck cancer (HNC) treatment is becoming increasingly multidisciplinary, and patient characteristics vary. Therefore, a multidisciplinary tumor board (MTB) is essential in clinical practice. This review provides insights into the benefits and tips for improving head and neck MTB from the perspective of medical oncologists. The MTB is a platform to discuss the optimal application of the standard of care to each case, reach a consensus, and establish a recommendation to support patients' decision-making. A productive and educational MTB also provides an opportunity to share information on ongoing clinical trials with physicians. Case presentations should be systematic to discuss all new and challenging cases before, during, and after the treatment. Human resource development, particularly of head and neck medical oncologists, is crucial. The type of multidisciplinary network between medical staff and the extent of patient intervention differs among MTB teams. Subsequently, a virtual MTB can establish a medical network between institutions that will contribute to the equalization and centralization of head and neck oncologic care.

Bevacizumab, Irinotecan, and Biweekly Trifluridine/Tipiracil for Metastatic Colorectal Cancer: MODURATE, a Phase Ib Study.

BACKGROUND: In this phase Ib study MODURATE, we optimized the dosing schedule and tested the efficacy and safety of trifluridine/tipiracil, irinotecan, and bevacizumab in patients with metastatic colorectal cancer with fluoropyrimidine and oxaliplatin treatment failure. METHODS: We included a dose escalation (3 + 3 design) and an expansion cohort. Patients were administered trifluridine/tipiracil (25-35 mg/m2 twice daily, days 1-5), irinotecan (150-180 mg/m2, day 1), and bevacizumab (5 mg/kg, day 1) every 2 weeks. The recommended phase II dose (RP2D) in the dose escalation cohort was administered to at least 15 patients in both cohorts combined. RESULTS: Twenty-eight patients were enrolled. Five dose-limiting toxicities were observed. RP2D was defined as trifluridine/tipiracil 35 mg/m2, irinotecan 150 mg/m2, and bevacizumab 5 mg/kg. Of 16 patients who received RP2D, 86% (14/16) experienced grade ≥3 neutropenia without febrile neutropenia. Dose reduction, delay, and discontinuation occurred in 94%, 94%, and 6% of patients, respectively. Three patients (19%) showed partial response and 5 had stable disease for >4 months, with a median progression-free and overall survival of 7.1 and 21.7 months, respectively. CONCLUSION: Biweekly trifluridine/tipiracil, irinotecan, and bevacizumab administration may have moderate antitumor activity with high risk of severe myelotoxicity in previously treated patients with metastatic colorectal cancer [UMIN Clinical Trials Registry (UMIN000019828) and Japan Registry of Clinical Trials (jRCTs041180028)].

Real-world experience of tropomyosin receptor kinase inhibition with entrectinib in ETV6-NTRK3 positive metastatic salivary secretory carcinoma: A case series.

BACKGROUND: The efficacy of entrectinib, a potent inhibitor of tropomyosin receptor kinases, c-ros oncogene 1, and anaplastic lymphoma kinase has been demonstrated in neurotrophic receptor tyrosine kinase fusion-positive pediatric and adult solid tumors. However, real-world data on entrectinib therapy for salivary gland malignancies are limited. METHODS: We describe a multicenter case series of four consecutive patients with ETV6-NTRK3 fusion-positive metastatic salivary secretory carcinoma (SSC) treated with entrectinib. RESULTS: All patients had a prior history of systemic therapy with cytotoxic chemotherapy or immune checkpoint inhibitors. All patients achieved durable radiographic complete response. Adverse events included weight gain, dizziness, increase in creatine kinase level, and withdrawal pain, but were manageable by the interruption and dose reduction of entrectinib. CONCLUSION: Durable complete response was achieved with entrectinib in patients with ETV6-NTRK3 fusion-positive metastatic SSC. The clinical benefit of entrectinib supports the importance of routine screening for NTRK gene fusion in patients with SSC.

Asymmetric Friedel-Crafts-Type Reaction of 2-Vinylindoles to N-Boc Imines Using a Chiral Imidazolidine-Containing NCN-Pincer Pd Catalyst.

A chiral imidazolidine-containing NCN-pincer Pd-OTf complex (NCN-Pd cat) promoted the asymmetric nucleophilic addition of unprotected 2-vinylindoles to N-Boc imines in a Friedel-Crafts-type manner. The chiral (2-vinyl-1H-indol-3-yl)methanamine products become nice platforms for constructing multiple ring systems.

Biomarker analysis for patients with pancreatic cancer treated with nanoliposomal irinotecan plus 5-fluorouracil/leucovorin.

BACKGROUND: Nanoliposomal irinotecan plus fluorouracil/leucovorin (5-FU/LV) is a standard second-line therapy for patients with pancreatic cancer. Identification of biomarkers is important to determine appropriate treatment strategies. We investigated the clinical practice outcomes and biomarkers associated with the nanoliposomal irinotecan plus 5-FU/LV regimen. METHODS: We retrospectively reviewed the data of patients treated with nanoliposomal irinotecan plus 5-FU/LV as a second or subsequent treatment after gemcitabine-based therapy between June 2020 and March 2021 at Shizuoka Cancer Center. RESULTS: We analyzed 55 consecutive patients who met the selection criteria. At a median of 9.4 months, median progression-free survival (PFS) and median overall survival (OS) were 2.3 and 6.6 months, respectively. Multivariate analysis showed that Glasgow prognostic score (GPS) was significantly associated with PFS (hazard ratio [HR] 2.16; 95% confidence interval [CI] 1.09-4.30; P = 0.028) and OS (0 vs. 1 or 2: HR 2.46; 95% CI 1.15-5.25; P = 0.029). The OS was significantly longer in patients with CA19-9 response than in those without CA19-9 response (12.6 vs. 5.6 months; HR 0.24; 95% CI 0.08-0.75; P = 0.014). CONCLUSIONS: Nanoliposomal irinotecan was efficacious and tolerable in clinical practice. GPS and CA19-9 response were good candidates as predictive biomarkers, whereas GPS was a good candidate prognostic biomarker for the nanoliposomal irinotecan plus 5-FU/LV regimen.

Genetic medicine in companion diagnostics of germline BRCA testing of Japanese pancreatic cancer patients.

In 2021, Japan's national health insurance made germline BRCA (g.BRCA) testing available to unresectable pancreatic cancer (PC) patients as a companion diagnostic (CD) of the PARP inhibitor. This study investigated the incidence of the g.BRCA variant (g.BRCAv.) and the status of the genetic medicine associated with its testing. A total of 110 PC patients underwent the testing, five of whom (4.5%) had a deleterious g.BRCA2v. (all truncations) but no g.BRCA1v. The turnaround time (TAT) to the doctors was 13 days, and to the patients, 17 days. A higher incidence of a BRCA-related family history and a shorter TAT were seen in the g.BRCAv. patients, but they were insignificant (p = 0.085 and p = 0.059, respectively). Genetic counseling was not performed for three g.BRCA2v. patients because two of them had no accessible relatives and one died of the cancer before the genetic report was completed. Two families underwent generic counseling and testing based on the patient's genetic data. g.BRCAv. is recognized in a small fraction of PC cases, and the following genetic counseling is done more for the relatives than for the patients. TAT was constant and did not affect much on the genetic counseling, but the earlier testing is expected for patients with a deadly cancer.

First-line pembrolizumab ± chemotherapy for recurrent/metastatic head and neck cancer: Japanese subgroup of KEYNOTE-048.

BACKGROUND: Here, we report the results of the Japanese subgroup of the phase 3 KEYNOTE-048 study of pembrolizumab alone, pembrolizumab plus platinum and 5-fluorouracil (pembrolizumab-chemotherapy), or cetuximab plus platinum and 5-fluorouracil (EXTREME) in previously untreated recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). METHODS: Primary end points were overall survival (OS) and progression-free survival (PFS). Efficacy was evaluated in patients with PD-L1 combined positive score (CPS) ≥ 20 and ≥ 1 and the total Japanese subgroup (n = 67). RESULTS: At data cutoff (25 February 2019), pembrolizumab led to longer OS versus EXTREME in the PD-L1 CPS ≥ 20 subgroup (median, 28.2 vs. 13.3 months; HR, 0.29 [95% CI 0.09-0.89]) and to similar OS in the total Japanese (23.4 vs. 13.6 months; HR, 0.51 [95% CI 0.25-1.05]) and CPS ≥ 1 subgroups (22.6 vs. 15.8 months; HR, 0.66 [95% CI 0.31-1.41]). Pembrolizumab-chemotherapy led to similar OS versus EXTREME in the PD-L1 CPS ≥ 20 (median, 18.1 vs. 15.8 months; HR, 0.72 [95% CI 0.23-2.19]), CPS ≥ 1 (12.6 vs. 15.8 months; HR, 1.19 [95% CI 0.55-2.58]), and total Japanese subgroups (12.6 vs. 13.3 months; unadjusted HR, 1.10 [95% CI 0.55-2.22]). Median PFS was similar for pembrolizumab and pembrolizumab-chemotherapy versus EXTREME in all subgroups. Grades 3-5 treatment-related adverse events occurred in 5 (22%), 19 (76%), and 17 (89%) patients receiving pembrolizumab, pembrolizumab-chemotherapy, and EXTREME, respectively. One patient receiving pembrolizumab-chemotherapy died because of treatment-related pneumonitis. CONCLUSION: These results support the use of first-line pembrolizumab and pembrolizumab-chemotherapy for Japanese patients with R/M HNSCC. Clinical trial registry ClinicalTrials.gov, NCT02358031.

Prognostic impact of the number of metastatic lymph nodes after surgery in locally advanced hypopharyngeal cancer.

BACKGROUND: Postoperative chemoradiotherapy (CRT) is a standard therapy for patients with high-risk factors for head and neck squamous cell carcinoma, including positive margin and extra-nodal extension (ENE). However, the prognostic impact of the number of pathological metastatic lymph nodes (pLNs) in hypopharyngeal carcinoma (HPC) is unclear. Thus, this study aimed to investigate postoperative prognostic factors for locally advanced hypopharyngeal squamous cell carcinoma (LA-HPSCC) with a focus on the number of pLNs. METHODS: We retrospectively analyzed medical records of 99 consecutive patients with LA-HPSCC who underwent total pharyngo-laryngo-esophagectomy (TPLE) and bilateral neck dissection (ND) between December 2002 and May 2019. RESULTS: The median follow-up time for all censored patients was 63.2 months. The median overall survival (OS) was 101.0 months (95% confidence interval [CI] 48.1-134.9). patients had pLNs ≥ 3. Forty-six (45.5%) patients were diagnosed with ENE. Twenty (20.2%) patients received postoperative CRT. The multivariate analysis revealed that pLNs ≥ 3 (median OS: 163.2 vs. 31.8 months, hazard ratio [HR] 2.39, 95% CI 1.16-4.94, p < 0.01) and ENE (median OS: 161.0 vs. 26.3 months, HR 4.60, 95% CI 2.26-9.36, p < 0.01) were significantly associated with poor prognosis and that postoperative CRT (HR 0.34, 95% CI 0.16-0.72, p < 0.01) was significantly associated with better prognosis. The cumulative incidence of distant metastasis was higher in patients with pLNs ≥ 3 than in those with pLNs < 3 (p < 0.01). CONCLUSION: pLNs ≥ 3 and ENE were significant poor prognostic factors for patients with LA-HPSCC who underwent TPLE and bilateral ND.

Immunological and Genetic Characterization of Patients With Head and Neck Cancer who Developed Recurrence.

BACKGROUND/AIM: The recurrence rate of head and neck squamous cell carcinoma (HNSCC) remains high; thus the control of recurrence is a clinical problem to be challenged. To clarify the precise mechanism, specific immunological biomarkers responsible for recurrence were investigated. PATIENTS AND METHODS: The expression levels of immune response-associated and Shizuoka Cancer Center 820 cancer-associated genes, and genetic mutations from whole-exome sequencing were compared between HNSCC patients who developed recurrence (n=8) and HNSCC patients who did not develop recurrence (n=19) using a volcano plot analysis. Cytokine and epithelial-mesenchymal transition marker genes were analyzed using quantitative PCR. Tumor-infiltrating lymphocytes, immune checkpoint molecules, and human papilloma virus status were investigated using immunohistochemistry (IHC). RESULTS: Twenty-seven evaluable patients with HNSCCs received radiation therapy after surgery. Recurrence was identified in 8 patients. TP53 mutations tended to be higher in patients who developed recurrence than in those who did not develop recurrence (75% vs. 31.6%). Gene expression profiling showed the down-regulation of T cell activation genes (ICOS, CD69 and CD83) and the upregulation of the ERBB4, EGFR, VEGF, HIF1A, TGFB1, TWIST1, IL-8, and PAX7 genes, which suggested the activation of the TP53 mutation-TGF-ß1-PAX7 pathway and epithelial-mesenchymal transition. Additionally, IHC indicated a tendency toward a reduction in T cell accumulation and an increase in M2-type macrophage infiltration in tumors that recurred. CONCLUSION: A TP53 mutation-mediated immune-suppressive state in the tumor microenvironment and TGF-ß1-PAX7-mediated EMT might contribute to the promotion of recurrence in patients with HNSCC after postoperative radiotherapy.

Real-world clinical outcomes in Japanese patients with locally advanced squamous cell carcinoma of the head and neck treated with radiotherapy plus cetuximab: a prospective observational study (JROSG12-2).

BACKGROUND: 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. METHODS: 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). RESULTS: 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. CONCLUSION: 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.

Effectiveness and safety of gemcitabine plus nab-paclitaxel in elderly patients with advanced pancreatic cancer: a single-center retrospective cohort study.

PURPOSE: This study aimed to evaluate the effectiveness and safety of gemcitabine (GEM) plus nab-paclitaxel (GnP) in patients aged ≥ 75 years with advanced pancreatic cancer and compare it with monotherapy (GEM or S-1). METHODS: We retrospectively reviewed the data of consecutive patients with advanced pancreatic cancer aged ≥ 75 years who received either GnP or monotherapy (GEM or S-1) between January 2014 and May 2020. The primary efficacy outcome was overall survival (OS). RESULTS: A total of 96 patients were included in this study; 51 were treated with GnP and 45 with monotherapy (31 with GEM and 14 with S-1). The median OS and progression-free survival were 10.8 and 6.7 months in the GnP group and 10.7 and 4.3 months in the monotherapy group, respectively. The treatment effect on OS was consistently favorable in the GnP group across most subgroups, particularly in patients with locally advanced cancer, modified Glasgow prognostic score of 0 or 1, and neutrophil/lymphocyte ratio < 3.1. The disease control rates were 76% and 48% in the GnP and monotherapy groups, respectively, and grade 3 or 4 neutropenia occurred in 23 (45%) and 11 (24%) patients of the GnP and monotherapy groups, respectively. CONCLUSIONS: This study demonstrated that GnP was not superior to monotherapy with regard to OS. However, multivariate analysis showed that GnP treatment positively affected the OS and could be considered as a treatment option, even for elderly patients.