Background
Hyperprogressive disease (HPD) during treatment with anti-programmed death-1/programmed death-ligand 1 monoclonal antibodies has anecdotally been reported in some types of cancers, but is ...not well-characterized in patients with advanced gastric cancer (AGC).
Methods
Total 62 AGC patients treated with nivolumab in a single institution from September 2017 to April 2018 were enrolled in this study. Tumor responses were assessed according to Response Evaluation Criteria in Solid Tumors version 1.1, and HPD was defined as ≥ two fold increase in tumor growth rate. Clinicopathological and molecular characteristics associated with HPD were also investigated.
Results
Thirteen of 62 patients (21%) developed HPD after nivolumab treatment. Overall survival (OS) and progression-free survival (PFS) were significantly shorter in patients with HPD than in patients without HPD (median OS: 2.3 months vs. not reached,
P
< 0.001; median PFS: 0.7 months vs. 2.4 months,
P
< 0.001). Liver metastases (77% vs. 41%), Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 1 or 2 (77% vs. 29%), and a large sum of target lesion diameters at baseline (median 104.2 mm vs. 44.9 mm) were significantly associated with HPD. Absolute neutrophil count (ANC) and C-reactive protein (CRP) level significantly increased in the first 4 weeks in only patients with HPD.
Conclusions
HPD was observed in AGC patients treated with nivolumab and correlated with some clinicopathological characteristics. Elevations in ANC and CRP levels upon treatment might indicate HPD.
Purpose
Whether indocyanine green fluorescence angiography (ICG-FA) during rectal surgery is effective in reducing anastomotic leakage remains unclear. This study aimed to investigate the effect of ...intraoperative ICG-FA on anastomotic leakage after sphincter-sparing surgery for malignant rectal tumors.
Methods
This was a retrospective, single-center cohort study conducted on 852 consecutive patients who underwent laparoscopic sphincter-sparing surgery from January 2007 to June 2017 at our institution. The incidence of anastomotic leakage was compared between patients who underwent ICG-FA to determine the proximal resection margin and those in whom this technique was not performed, using logistic regression analysis, including propensity score.
Results
A total of eight patients were excluded (one patient with previous low anterior resection and seven patients who underwent simultaneous resection for other primary cancers), resulting in 844 patients being analyzed. Before propensity score matching, 141 patients (16.7%) who underwent ICG-FA were compared with 703 patients (83.3%) in whom ICG-FA was not performed. The incidence of anastomotic leakage was 2.8% (4/141) in the ICG-FA group and 12.4% (87/703) in the control group (
p
= 0.001). After propensity score matching (
n
= 420), the patient characteristics between the two groups were well balanced, and the incidence of anastomotic leakage was 2.8% (4/141) in the ICG-FA group and 13.6% (38/279) in the control group (
p
= 0.001). Logistic regression analyses using propensity score showed that patients who underwent ICG-FA had significantly lower odds of anastomotic leakage.
Conclusion
Intraoperative ICG-FA is a promising method to reduce anastomotic leakage after laparoscopic rectal surgery.
Abstract
Objectives
Salvage endoscopic resection is recommended when the local recurrence at primary site after chemoradiotherapy for esophageal squamous cell carcinoma is localized and superficial. ...This retrospective study aimed to comparatively analyse the short-term outcomes and local control of salvage endoscopic submucosal dissection versus salvage endoscopic mucosal resection for local recurrence after chemoradiotherapy or radiotherapy.
Methods
A total of 96 patients who underwent initial salvage endoscopic resection for cT1N0M0 local recurrence after chemoradiotherapy or radiotherapy for esophageal squamous cell carcinoma between December 1998 and August 2019 patients were assigned to either the salvage endoscopic submucosal dissection (40 patients; 40 lesions) or salvage endoscopic mucosal resection (56 patients; 56 lesions) group. We evaluated the en bloc and R0 resection rates, severe adverse events and local failure rate after salvage endoscopic resection. Multivariate analysis was conducted to identify risk factors of local failure after salvage endoscopic resection.
Results
The en bloc resection rate was significantly higher in the salvage endoscopic submucosal dissection group than in the salvage endoscopic mucosal resection group (95% versus 63%; P < 0.001). There were no differences in R0 resection rate between the two groups (73% versus 52%, P = 0.057). One patient (3%) in the salvage endoscopic submucosal dissection group had perforation. The 3-year cumulative local failure rate of salvage endoscopic mucosal resection was significantly higher than that of salvage endoscopic submucosal dissection (27% versus 5%, P = 0.032). In multivariate analysis, salvage endoscopic mucosal resection (hazard ratio: 2.7, P = 0.044) was the only independent risk factor of local failure after salvage endoscopic resection.
Conclusions
Salvage endoscopic submucosal dissection is the effective treatment for local recurrence based on the short-term outcomes and local efficacy.
Salvage endoscopic submucosal dissection is the effective treatment for local recurrence after chemoradiotherapy for esophageal cancer compared with salvage endoscopic resection.
Proton beam therapy (PBT) is a potential new alternative to treatment with photon radiotherapy that may reduce the risk of late toxicity and secondary cancer, especially for pediatric tumors. The ...goal of this study was to evaluate the long‐term benefits of PBT in cancer survivors. A retrospective observational study of pediatric patients who received PBT was performed at four institutions in Japan. Of 343 patients, 62 were followed up for 5 or more years. These patients included 40 males and 22 females, and had a median age of 10 years (range: 0–19 years) at the time of treatment. The irradiation dose ranged from 10.8 to 81.2 GyE (median: 50.4 GyE). The median follow‐up period was 8.1 years (5.0–31.2 years). The 5‐, 10‐ and 20‐year rates for grade 2 or higher late toxicities were 18%, 35% and 45%, respectively, and those for grade 3 or higher late toxicities were 6%, 17% and 17% respectively. Univariate analysis showed that the irradiated site (head and neck, brain) was significantly associated with late toxicities. No malignant secondary tumors occurred within the irradiated field. The 10‐ and 20‐year cumulative rates for all secondary tumors, malignant secondary tumors, and malignant nonhematologic secondary tumors were 8% and 16%, 5% and 13%, and 3% and 11%, respectively. Our data indicate that PBT has the potential to reduce the risk of late mortality and secondary malignancy. Longer follow‐up is needed to confirm the benefits of PBT for pediatric tumors.
A retrospective observational study of pediatric patients who received PBT was performed at four institutions in Japan. Of 343 patients, 62 were followed up for 5 or more years. The 5‐, 10‐ and 20‐year rates for grade 2 or higher late toxicities were 8%, 35% and 45%, respectively, and those for grade 3 or higher late toxicities were 6%, 17% and 17% respectively. The irradiated site (head and neck, brain) was significantly associated with late toxicities. No malignant secondary tumors occurred within the irradiated field. The 10‐ and 20‐year cumulative rates for all malignant secondary tumors were 5% and 13%, respectively. Our data indicate that PBT can reduce the risk of late mortality and secondary malignancy.
To evaluate the safety and efficacy of hypofractionated whole breast irradiation for Asian women after breast-conserving surgery. This is an updated report with 5-year follow-up.
Asian women who had ...invasive breast cancer with clinical tumor size ≤3 cm, pN0-1c and negative inked margins were enrolled. Hypofractionated whole breast irradiation of 42.56 Gy/16 fractions was delivered, and boost irradiation of 10.64 Gy/4 fractions was added when the surgical margin was ≤5 mm. The primary endpoint was the proportion of grade ≥ 2 late adverse reactions within 3 years. Secondary endpoints included early adverse events, overall survival, disease-free survival, ipsilateral breast relapse-free survival, late adverse reactions and cosmetic outcome. Toxicities were evaluated using CTCAE ver3.0. Cosmetic outcomes were assessed using a 4-point scale and CTCAE ver3.0 for hyper/hypopigmentation, breast nipple/areolar deformity and breast volume/deformity.
Between February 2010 and August 2012, 312 patients were enrolled, and 306 received hypofractionated whole breast irradiation. Median follow-up was 70.5 (range 7.6-88.9) months. The proportion of grade ≥ 2 late adverse reactions within 3 years was 4.3% (90% confidence interval 2.5-6.7%). Grade 2 early adverse events occurred in 38 (12.4%); none had grade 3/4. Five-year overall survival, disease-free survival and ipsilateral breast relapse-free survival were 98.7, 95.4 and 98.0%, respectively. Of the 304 evaluable patients, 29 (9.5%; 95% confidence interval 6.5-13.4%) had grade 2/3 late adverse reactions; none had grade 4/5. At 5 years, 70/289 (24.2%) showed any worsening of breast cosmetic changes.
Hypofractionated whole breast irradiation is considered a standard treatment for Asian women with margin-negative invasive breast cancer after breast-conserving surgery.
The diagnosis of gastrointestinal stromal tumor (GIST) using conventional endoscopy is difficult because submucosal tumor (SMT) lesions like GIST are covered by a mucosal layer. Near-infrared ...hyperspectral imaging (NIR-HSI) can obtain optical information from deep inside tissues. However, far less progress has been made in the development of techniques for distinguishing deep lesions like GIST. This study aimed to investigate whether NIR-HSI is suitable for distinguishing deep SMT lesions. In this study, 12 gastric GIST lesions were surgically resected and imaged with an NIR hyperspectral camera from the aspect of the mucosal surface. Thus, the images were obtained ex-vivo. The site of the GIST was defined by a pathologist using the NIR image to prepare training data for normal and GIST regions. A machine learning algorithm, support vector machine, was then used to predict normal and GIST regions. Results were displayed using color-coded regions. Although 7 specimens had a mucosal layer (thickness 0.4-2.5 mm) covering the GIST lesion, NIR-HSI analysis by machine learning showed normal and GIST regions as color-coded areas. The specificity, sensitivity, and accuracy of the results were 73.0%, 91.3%, and 86.1%, respectively. The study suggests that NIR-HSI analysis may potentially help distinguish deep lesions.
Radiotherapy (RT) combined with immune checkpoint inhibitors has recently produced outstanding results and is expected to be adaptable for various cancers. However, the precise molecular mechanism by ...which immune reactions are induced by fractionated RT is still controversial. We aimed to investigate the mechanism of the immune response regarding multifractionated, long‐term radiation, which is most often combined with immunotherapy. Two human esophageal cancer cell lines, KYSE‐450 and OE‐21, were irradiated by fractionated irradiation (FIR) daily at a dose of 3 Gy in 5 d/wk for 2 weeks. Western blot analysis and RNA sequencing identified type I interferon (IFN) and the stimulator of IFN genes (STING) pathway as candidates that regulate immune response by FIR. We inhibited STING, IFNAR1, STAT1, and IFN regulatory factor 1 (IRF1) and investigated the effects on the immune response in cancer cells and the invasion of surrounding immune cells. We herein revealed type I IFN‐dependent immune reactions and the positive feedback of STING, IRF1, and phosphorylated STAT1 induced by FIR. Knocking out STING, IFNAR1, STAT1, and IRF1 resulted in a poorer immunological response than that in WT cells. The STING‐KO KYSE‐450 cell line showed significantly less invasion of PBMCs than the WT cell line under FIR. In the analysis of STING‐KO cells and migrated PBMCs, we confirmed the occurrence of STING‐dependent immune activation under FIR. In conclusion, we identified that the STING‐IFNAR1‐STAT1‐IRF1 axis regulates immune reactions in cancer cells triggered by FIR and that the STING pathway also contributes to immune cell invasion of cancer cells.
We elucidated that the fractionated irradiation‐induced immune response is regulated by the STING‐IFNAR1‐STAT1‐IRF1 pathway, which includes positive feedback, and that this mechanism acts not only on cancer cells but also on surrounding PBMCs.
We conducted a retrospective, nationwide multicenter study to evaluate the clinical outcomes of proton beam therapy for bone sarcomas of the skull base and spine in Japan. Eligibility criteria ...included: (i) histologically proven bone sarcomas of the skull base or spine; (ii) no metastases; (iii) ≥20 years of age; and (iv) no prior treatment with radiotherapy. Of the 103 patients treated between January 2004 and January 2012, we retrospectively analyzed data from 96 patients who were followed‐up for >6 months or had died within 6 months. Seventy‐two patients (75.0%) had chordoma, 20 patients (20.8%) had chondrosarcoma, and four patients (7.2%) had osteosarcoma. The most frequent tumor locations included the skull base in 68 patients (70.8%) and the sacral spine in 13 patients (13.5%). Patients received a median total dose of 70.0 Gy (relative biological effectiveness). The median follow‐up was 52.6 (range, 6.3–131.9) months. The 5‐year overall survival, progression‐free survival, and local control rates were 75.3%, 49.6%, and 71.1%, respectively. Performance status was a significant factor for overall survival and progression‐free survival, whilst sex was a significant factor for local control. Acute Grade 3 and late toxicities of ≥Grade 3 were observed in nine patients (9.4%) each (late Grade 4 toxicities n = 3 patients; 3.1%). No treatment‐related deaths occurred. Proton beam therapy is safe and effective for the treatment of bone sarcomas of the skull base and spine in Japan. However, larger prospective studies with a longer follow‐up are warranted.
This study is the first to demonstrate the safety and efficacy of proton beam therapy for bone sarcomas of the skull base and spine on a nationwide multicenter basis in Japan. Univariate and multivariate analyses revealed that performance status is a significant factor for overall survival and progression‐free survival, and sex is a significant factor for local control.
ABSTRACT
Proton beam therapy (PBT) combined with chemotherapy, such as cis-diamminedichloroplatinum (II) (CDDP) and 5-fluorouracil (5-FU), has been employed as an alternative approach to improve ...clinical outcomes. PBT has been reported to be effective against esophageal cancer. However, apart from 5-FU and CDDP, almost no other drug has been tested in combined chemotherapy with PBT. Therefore, we investigated the effects of a poly (ADP-ribose) polymerase inhibitor on enhancing proton beam effects using esophageal cancer cell lines that exhibit resistance to radiation and CDDP. Esophageal squamous cell carcinoma cell lines OE-21 and KYSE-450 were exposed to the drugs for 1 h prior to irradiation. The cell survival curve was obtained using a clonogenic assay and the sensitizing effect ratio (SER) was calculated. The clonogenic assay was used to compare the effect of multi-fractioned irradiation between 8 Gy/1 fraction (fr) and 8 Gy/4 fr. γH2AX, Rad51, BRCA1, BRCA2 and 53BP1 foci were detected via immunofluorescence. Olaparib exhibited an SER of 1.5–1.7 on PBT. The same sensitizing effect was exhibited in multi-fractioned irradiation, and the combined use increased the expression of double-strand breaks and homologous recombination-related genes in an additive manner. Such additive effects were not observed on non-homologous end joining-related genes. We demonstrated that olaparib has a high sensitizing effect on PBT in platinum- and radiation-resistant esophageal cancer cells. Our results suggest a potential clinical application of olaparib-proton irradiation (PT) against platinum- and radiation-resistant esophageal cancer.
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