Trastuzumab deruxtecan in patients with locally advanced or metastatic HER2-positive gastric cancer: a multicenter, open-label, expanded-access study.

BACKGROUND: Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate that consists of an anti-human epidermal growth factor receptor 2 (HER2) antibody bound by a cleavable tetrapeptide-based linker to a cytotoxic topoisomerase I inhibitor. Prior to marketing approval in Japan in September 2020, this expanded-access study was conducted to provide T-DXd to previously treated patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinomas. METHODS: This multicenter, open-label, expanded-access study was conducted between March 25 and September 25, 2020 at 17 Japanese sites. Previously treated patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinomas received T-DXd 6.4 mg/kg via intravenous infusions at 3-week intervals. Serious adverse events (SAEs), all potential cases of interstitial lung disease (ILD)/pneumonitis, all liver-related events potentially meeting Hy's Law criteria, and all cases of overdose were reported on the case report forms. RESULTS: A total of 64 patients were treated with T-DXd. Among the 17 (26.6%) patients with reported SAEs, 10 (15.6%) had SAEs related to T-DXd treatment. Febrile neutropenia was the most common SAE (n = 6). SAEs led to death in six patients; drug-related SAEs (sepsis and febrile neutropenia) led to death in one patient. Drug-related ILD, as determined by the external Adjudication Committee, occurred in three patients (Grade 1, Grade 2, and Grade 3: all n = 1). CONCLUSION: This expanded-access study provided T-DXd to a broader population of Japanese patients prior to marketing approval in Japan, bridging the gap between clinical trials and drug approval. No new safety concerns were identified.

Exploratory analysis of serum HER2 extracellular domain for HER2 positive gastric cancer treated with SOX plus trastuzumab.

BACKGROUND: The aim of this study was to explore the clinical utility of serum HER2 extracellular domain (sHER2 ECD) using data from a clinical trial evaluating trastuzumab combined S-1 plus oxaliplatin (SOX) in HER2 positive gastric cancer. METHODS: sHER2 ECD were prospectively measured at baseline and subsequent treatment courses. Based on each quantile point of baseline sHER2 ECD levels and its early changes, patients were divided into two groups and compared clinical outcomes. RESULTS: 43 patients were enrolled, and 17 patients (39.5%) were positive for baseline sHER2 ECD. Higher baseline sHER2 ECD levels tended to have lower hazard ratios (HRs). When divided into two groups by baseline sHER2 ECD of 19.1 ng/ml, median progression-free survival (PFS) and overall survival (OS) was longer in the higher group (mPFS: 16.8 vs 8.7 months, p = 0.359. mOS: 35.5 vs 20.6 months, p = 0.270), respectively. After initiation of treatment, sHER2 ECD significantly decreased up until the third cycle. Higher reduction rates of sHER2 ECD within 3 cycles also tended to have lower HRs. When divided into two groups by reduction rate of 42.5%, mPFS and mOS was longer in the higher reduced group (mPFS: 17.2 vs 8.7 months, p = 0.095. mOS: 65.0 vs 17.8 months, p = 0.047), respectively. Furthermore, higher reduction rates could surrogate higher objective response rates (ORR) (ORR: 90% vs 63.2% for 29.5%, p = 0.065. 100% vs 70% for 42.5%, p = 0.085), respectively. CONCLUSIONS: Baseline sHER2 ECD levels and its early decline may be useful biomarkers for SOX plus trastuzumab efficacy in HER2 positive gastric cancer.

Preoperative docetaxel, cisplatin, and 5-fluorouracil for resectable locally advanced esophageal and esophagogastric junctional adenocarcinoma.

BACKGROUND: Chemotherapy consisting of 5-fluorouracil, leucovorin, oxaliplatin, and docetaxel is the standard perioperative treatment for resectable esophageal adenocarcinoma and esophagogastric junctional adenocarcinoma (EGJ-AC) in Western countries. Meanwhile, preoperative chemotherapy consisting of docetaxel, cisplatin, and 5-fluorouracil (DCF) has been developed for esophageal squamous cell carcinoma in Japan. However, there are few reports on the safety and efficacy of preoperative DCF for resectable EGJ-AC in the Japanese population. METHODS: Patients with histologically confirmed resectable EGJ-AC who received preoperative DCF (docetaxel 70 mg/m2 and cisplatin 70 mg/m2 on day 1 and continuous infusion of 5-fluorouracil 750 mg/m2/day on days 1-5 every 3 weeks with a maximum of three cycles) between January 2015 and April 2020 were retrospectively evaluated. We assessed the rates of completion of ≥ 2 courses of DCF and R0 resection, histopathological response, progression-free survival (PFS), overall survival (OS), and adverse events. RESULTS: Thirty-two patients were included. Median follow-up was 28.7 (range, 5.2-70.8) months and median age was 63 (range, 42-80) years. Twenty-one patients (66%) had a performance status of 0. The proportions of clinical stage IIA/IIB/III/IVA/IVB disease were 3%/0%/44%/44%/9%, respectively. The treatment completion rate was 84%. A histopathological response of grade 1a/1b/2/3 was obtained in 58%/26%/13%/3% of cases. Median PFS was 40.7 months (95% confidence interval 11.8-NA). Median OS was not reached (80.8% at 3 years). Grade ≥ 3 adverse events were observed in 63% of cases (neutropenia, 44%; febrile neutropenia, 13%). No treatment-related deaths occurred. CONCLUSIONS: Preoperative DCF for resectable EGJ-AC was well tolerated and has promising efficacy.

Pattern of disease progression during third-line or later chemotherapy with nivolumab associated with poor prognosis in advanced gastric cancer: a multicenter retrospective study in Japan.

BACKGROUND: Accelerated tumor growth during immunotherapy in pre-existing measurable lesions, hyperprogressive disease (HPD), has been reported. However, progression of non-measurable lesions and new lesions are frequently observed in patients with advanced gastric cancer (AGC). METHODS: This retrospective study involved AGC patients at 24 Japanese institutions who had measurable lesions and received nivolumab after ≥ 2 lines of chemotherapy. HPD was defined as a ≥ two-fold increase in the tumor growth rate of measurable lesions. The pattern of disease progression was classified according to new lesions in different organs and ascites appeared/increase of ascites. RESULTS: Of 245 patients, 147 (60.0%) showed progressive disease (PD) as the best response and 41 (16.7%) showed HPD during nivolumab monotherapy. There was no significant difference in overall survival (OS) between patients with HPD and those with PD other than HPD (median OS 5.0 vs 4.8 months; hazard ratio [HR] 1.0, 95% confidence interval [CI] 0.6-1.5; p = 1.0). Fifty-three patients developed new lesions in different organs and 58 had appearance/increase of ascites; these patients showed shorter OS than those without each of these features (median OS 3.3 vs 7.1 months, HR 1.8, 95% CI 1.2-2.7, p = 0.0031 for new lesions, and 3.0 vs 7.8 months, HR 2.6, 95% CI 1.8-3.8, p < 0.0001 for ascites). Thirty-one patients who had both features showed the worst prognosis (median OS 2.6 months). CONCLUSIONS: New lesions in different organs and appearance/increase of ascites, rather than the original definition of HPD, are the patterns of disease progression associated with poor prognosis in AGC patients receiving nivolumab whose best response was PD.

Perioperative TAS-118 plus oxaliplatin in patients with locally advanced gastric cancer: APOLLO-11 study.

BACKGROUND: We investigated the feasibility of perioperative chemotherapy with S-1 and leucovorin (TAS-118) plus oxaliplatin in patients with locally advanced gastric cancer. METHODS: Patients with clinical T3-4N1-3M0 gastric cancer received four courses of TAS-118 (40-60 mg/body, orally, twice daily for seven days) plus oxaliplatin (85 mg/m2, intravenously, day one) every two weeks preoperatively followed by gastrectomy with D2 lymphadenectomy, followed by postoperative chemotherapy with either 12 courses of TAS-118 monotherapy (Step 1) or eight courses of TAS-118 plus oxaliplatin (Step 2). The primary endpoints were completion rates of preoperative chemotherapy with TAS-118 plus oxaliplatin and postoperative chemotherapy with TAS-118 monotherapy (Step 1) or TAS-118 plus oxaliplatin (Step 2). RESULTS: Among 45 patients enrolled, the preoperative chemotherapy completion rate was 88.9% (90% CI 78.0-95.5). Major grade ≥ 3 adverse events (AEs) were diarrhoea (17.8%) and neutropenia (8.9%). The R0 resection rate was 95.6% (90% CI 86.7-99.2). Complete pathological response was achieved in 6 patients (13.3%). Dose-limiting toxicity was not observed in 31 patients receiving postoperative chemotherapy (Step 1, n = 11; Step 2, n = 20), and completion rates were 90.9% (95% CI 63.6-99.5) for Step 1 and 80.0% (95% CI 59.9-92.9) for Step 2. No more than 10% of grade ≥ 3 AEs were observed in patients receiving Step 1. Hypokalaemia and neutropenia occurred in 3 and 2 patients, respectively, receiving Step 2. The 3-year recurrence-free and overall survival rates were 66.7% (95% CI 50.9-78.4) and 84.4% (95% CI 70.1-92.3), respectively. CONCLUSIONS: Perioperative chemotherapy with TAS-118 plus oxaliplatin with D2 gastrectomy is feasible.

Dynamics of surgical smoke in the operating room during spinal surgery: Comparison of particulate matter 2.5-air concentration between the electric scalpel with and without a smoke evacuation pencil: A cross-sectional study.

BACKGROUND: Surgical smoke is a vaporous by-product generated during tissue incision and cauterization with an electric scalpel. This smoke contains tissue- and blood/vascular-derived substances, bacteria, viruses, and chemical substances. Among them, it contains many fine particles called particulate matter (PM) 2.5, which are harmful and hazardous to the human body. We aimed to investigate the occurrence of PM2.5 in surgical smoke produced during spinal surgery and to evaluate the efficacy of an electric scalpel with a smoke evacuation pencil. METHODS: In this retrospective observational study, 89 patients who underwent spinal surgery between June 2019 and May 2021 were included. A dust monitor was installed in the operating room to measure the PM2.5 air concentration during the surgery. During each surgery, the total amount of PM2.5, the maximum PM2.5 air concentration, the exposure time to PM2.5, and the average value of PM2.5 air concentration from the start to the end of the surgery were calculated. RESULTS: We found that in 29 of the 89 cases (32.6%), the air concentration of PM2.5 increased to a level that could cause health damage during the surgery. Twelve cases (13.4%) reached the level that could cause serious health damage, and 8 cases (9%) reached an emergency warning level. The total amount and the maximum and average levels of PM2.5 were significantly suppressed in the surgery with a smoke evacuation pencil group than in the surgery without a smoke evacuation pencil group. CONCLUSION: We detected hazardous levels of PM2.5 in the air during spinal surgery, highlighting the importance of considering smoke control or reduction during spinal surgery. We recommend using an electric scalpel with a smoke evacuation pencil for regulating PM2.5 levels in the operating room.

Randomized trial of granulocyte colony-stimulating factor for spinal cord injury.

Attenuation of the secondary injury of spinal cord injury (SCI) can suppress the spread of spinal cord tissue damage, possibly resulting in spinal cord sparing that can improve functional prognoses. Granulocyte colony-stimulating factor (G-CSF) is a haematological cytokine commonly used to treat neutropenia. Previous reports have shown that G-CSF promotes functional recovery in rodent models of SCI. Based on preclinical results, we conducted early phase clinical trials, showing safety/feasibility and suggestive efficacy. These lines of evidence demonstrate that G-CSF might have therapeutic benefits for acute SCI in humans. To confirm this efficacy and to obtain strong evidence for pharmaceutical approval of G-CSF therapy for SCI, we conducted a phase 3 clinical trial designed as a prospective, randomized, double-blinded and placebo-controlled comparative trial. The current trial included cervical SCI [severity of American Spinal Injury Association (ASIA) Impairment Scale (AIS) B or C] within 48 h after injury. Patients are randomly assigned to G-CSF and placebo groups. The G-CSF group was administered 400 µg/m2/day × 5 days of G-CSF in normal saline via intravenous infusion for five consecutive days. The placebo group was similarly administered a placebo. Allocation was concealed between blinded evaluators of efficacy/safety and those for laboratory data, as G-CSF markedly increases white blood cell counts that can reveal patient treatment. Efficacy and safety were evaluated by blinded observer. Our primary end point was changes in ASIA motor scores from baseline to 3 months after drug administration. Each group includes 44 patients (88 total patients). Our protocol was approved by the Pharmaceuticals and Medical Device Agency in Japan and this trial is funded by the Center for Clinical Trials, Japan Medical Association. There was no significant difference in the primary end point between the G-CSF and the placebo control groups. In contrast, one of the secondary end points showed that the ASIA motor score 6 months (P = 0.062) and 1 year (P = 0.073) after drug administration tend to be higher in the G-CSF group compared with the placebo control group. Moreover, in patients aged over 65 years old, motor recovery 6 months after drug administration showed a strong trend towards a better recovery in the G-CSF treated group (P = 0.056) compared with the control group. The present trial failed to show a significant effect of G-CSF in primary end point although the subanalyses of the present trial suggested potential G-CSF benefits for specific population.

Topical corticosteroid therapy for facial acneiform eruption due to EGFR inhibitors in metastatic colorectal cancer patients: a randomized controlled trial comparing starting with a very strong or a weak topical corticosteroid (FAEISS study, NCCH1512, colorectal part).

BACKGROUND: Although pre-emptive therapy with oral tetracycline, moisturizer, sunscreen, and topical corticosteroid is useful for preventing acneiform eruption (AfE) due to epidermal growth factor receptor (EGFR) inhibitors, no studies have examined the efficacy of topical corticosteroids themselves, or investigated the optimal potency of corticosteroid for treating facial AfE (FAfE). PATIENTS AND METHODS: Screened patients with RAS wild-type colorectal cancer started pre-emptive therapy with oral minocycline and moisturizer on initiation of cetuximab or panitumumab therapy. Patients who developed grade 1 or 2 FAfE were randomly allocated to two groups: a ranking-down (RD) group that started with a very strong corticosteroid and serially ranked down every 2 weeks unless FAfE exacerbated; and a ranking-up (RU) group that started with a weak corticosteroid and serially ranked up at exacerbation. FAfE grade, patient quality of life, and adverse events (AEs) with topical corticosteroid were evaluated every 2 weeks. The primary endpoint was the total number of times grade 2 or higher FAfE was identified in the central review of the 8-week treatment period. RESULTS: No significant differences in total numbers of grade 2 or higher FAfE or in AEs caused by topical corticosteroids were observed between groups during the 8 weeks. Incidence of grade 2 or higher FAfE tended to be lower in the RD group during the first 2 weeks. CONCLUSION: Considering the long-term care of FAfE, the RU regimen appears suitable and should be considered the standard treatment for FAfE due to EGFR inhibitor therapy. TRIAL REGISTRATION: UMIN Clinical Trials Registry (UMIN000024113).

REVIVE study: a prospective observational study in chemotherapy after nivolumab therapy for advanced gastric cancer.

Nivolumab is an increasingly used standard care treatment for heavily pretreated patients with advanced gastric cancer, with increasing clinical use in Japan. Data from retrospective studies on various tumors have shown the objective response rate to cytotoxic chemotherapy potentially improves after an exposure to immune checkpoint inhibitors. Based on these data, we conducted the multicenter observational REVIVE study to evaluate the efficacy and safety of cytotoxic chemotherapy in nivolumab-refractory or nivolumab-intolerant patients with advanced gastric cancer. Patients who are refractory or intolerant to nivolumab and scheduled to receive irinotecan monotherapy, oxaliplatin combination treatment or oral trifluridine/tipiracil hydrochloride therapy will be included. The primary end point is overall survival of nivolumab-pretreated patients with advanced gastric cancer after the cytotoxic chemotherapy. Clinical trial registration: UMIN000032182 (umin.ac.jp).

Indication for drainage for a hematogenous iliopsoas abscess: Analysis of patients initially treated without drainage.

BACKGROUND: This study aimed to determine the indications for drainage in extended haematogenous iliopsoas abscesses (IPAs), which include both primary and vertebral osteomyelitis-related IPAs. METHODS: Sixty-three IPA patients who were initially treated with only antibiotics and no drainage were enrolled. The success (S) group included patients who were cured without drainage, while the failure (F) group included those who required open or percutaneous drainage or died. RESULTS: Compared with patients in the S group, patients in the F group (n = 15) had a higher incidence of end-stage renal disease on hemodialysis, compromised immunity, vertebral osteomyelitis of the cervicothoracic spine, other musculoskeletal infections, and multilocular abscesses. The IPAs in the F group had larger transverse and longitudinal diameters. In receiver operating characteristic curve analyses for the diameter of IPAs, the most valuable cut-off points predicting the F group were a longitudinal diameter of 5.0 cm (sensitivity, 1.0; specificity, 0.67) and a transverse diameter of 2.3 cm (sensitivity, 0.73; specificity, 0.73). A combination of both diameter cut-offs had high specificity (sensitivity, 0.73; specificity, 0.90). CONCLUSIONS: Drainage should be applied in case of a larger abscess with transverse diameter ≥ 2.3 cm and longitudinal diameter ≥ 5.0 cm. Conversely, IPAs with longitudinal diameter <5 cm do not require drainage. Haemodialysis, compromised immunity, vertebral osteomyelitis of the cervicothoracic spine, and musculoskeletal infections are risk factors of conservative treatment failure.

Survival Outcomes of Resected BRAF V600E Mutant Colorectal Liver Metastases: A Multicenter Retrospective Cohort Study in Japan.

BACKGROUND: Although the prognosis for patients with resected BRAF mutant colorectal liver metastases (CRLM) is poor, the survival impact of the BRAF V600E mutation in such cases remains unclear. METHODS: A multicenter retrospective cohort study was performed to investigate the survival outcomes of patients who underwent initial hepatectomy for histologically confirmed BRAF V600E mutant CRLM between January 2005 and December 2017. RESULTS: Thirty-three patients from 6 institutions were included in this study. During the median duration of the post-hepatectomy follow-up period of 49.2 months, 31 patients (93.9%) developed recurrence after a median period of 5.3 months and the 1-year recurrence-free survival (RFS) rate was 24.2%. Only two patients underwent repeated surgery for recurrence. The other 29 patients had unresectable recurrent lesions, and 27 of them received systemic chemotherapy. The median overall survival (OS) period was 31.1 months and the 5-year OS rate was 18.2%. The factors for a poor RFS prognosis were an elevated serum CA19-9 level (≥ 37 IU/ml) at hepatectomy (HR: 2.139, 95% CI: 1.009-4.534, P = 0.047) and R1 resection (HR: 5.827, 95% CI: 1.585-21.42, P = 0.008), and that for OS was R1 resection only (HR: 4.129, 95% CI: 1.104-15.45, P = 0.035). CONCLUSIONS: Since the early onset unresectable recurrence rate was very high, systemic chemotherapy should be considered for resectable BRAF V600E mutant CRLM. A novel perioperative treatment strategy is needed to improve the survival of such patients.

Retrospective comparison of nab-paclitaxel plus ramucirumab and paclitaxel plus ramucirumab as second-line treatment for advanced gastric cancer focusing on peritoneal metastasis.

Background Ramucirumab (RAM) plus solvent-based (sb)-paclitaxel (PTX) is the standard second-line chemotherapy for advanced gastric cancer (AGC). The subset analysis of the ABSOLUTE trial, which confirmed non-inferiority of weekly nanoparticle albumin-bound (nab)-PTX to weekly sb-PTX, suggested that nab-PTX might have better efficacy than sb-PTX in patients with peritoneal metastasis. We retrospectively evaluated the efficacy and safety of RAM plus sb-PTX and nab-PTX in patients with peritoneal metastasis of AGC. Methods AGC patients who received RAM plus sb-PTX or nab-PTX as second-line chemotherapy from June 2015 to February 2019 were included in the study. Overall survival (OS), progression-free survival (PFS), response rate, and safety were assessed. Results A total of 128 patients were included in this study (93 in the RAM plus sb-PTX group and 35 in the RAM plus nab-PTX group). PFS was 4.1 months in the RAM plus sb-PTX group and 4.6 months in the RAM plus nab-PTX group (HR 0.90; 95%CI 0.58-1.41, p = 0.643). OS was 8.9 months in the RAM plus sb-PTX group and 11.4 months in the RAM plus nab-PTX group (HR 0.95; 95%CI 0.56-1.62, p = 0.847). A total of 62 and 31 patients had peritoneal metastasis in the RAM plus sb-PTX and the RAM plus nab-PTX groups, respectively. RAM plus nab-PTX showed a slightly longer survival compared to RAM plus sb-PTX in patients with peritoneal metastasis (PFS 5.8 vs 3.5 months, HR 0.66; 95% CI 0.40-1.10, p = 0.109). Conclusion This study suggests that RAM plus nab-PTX might be a more effective treatment for peritoneal metastasis of AGC.

Identification of serum microRNAs predicting the response of esophageal squamous-cell carcinoma to nivolumab.

BACKGROUND: Nivolumab, a programmed cell death protein 1 (PD-1) inhibitor, showed promising activity for the treatment of advanced esophageal squamous-cell carcinoma in a phase II study (ONO-4538-07; JapicCTI-No.142422). We explored serum microRNA (miRNA) candidate predictive markers of the response to nivolumab. METHODS: In the phase II study, 19 patients received nivolumab (3 mg/kg IV Q2W) at National Cancer Center Hospital. The expression of 2565 serum miRNAs before and during treatment was analyzed using a 3D-Gene Human miRNA Oligo Chip (Toray Industries, Inc.). Immune-related response evaluation criteria used to evaluate response and miRNA expression were compared between responders and non-responders. The top 20 miRNAs by accuracy in receiver operating characteristic curve analysis were identified by leave-one-out cross-validation, and those with the area under curve values > 0.8, cross-validated accuracy > 0.8, and a 0.5 difference in the average log2 expression level between responders and non-responders were further analyzed. RESULTS: Of the 19 patients, five responded to nivolumab. We identified miRNAs related to the response to nivolumab, including one detected in the serum before treatment (miR-1233-5p; AUC = 0.895) and three present after treatment (miR-6885-5p, miR-4698 and miR-128-2-5p; AUC = 0.93, 0.97 and 0.93, respectively). CONCLUSIONS: Candidate miRNAs capable of predicting the response to nivolumab were identified in the serum of patients with advanced esophageal squamous-cell carcinoma in ONO-4538-07.

Safety and efficacy of cell-free and concentrated ascites reinfusion therapy (CART) in gastrointestinal cancer patients with massive ascites treated with systemic chemotherapy.

PURPOSE: Gastrointestinal cancer is frequently associated with malignant ascites, resulting in poor prognosis. While cell-free and concentrated ascites reinfusion therapy (CART) improves ascites-related symptoms, its clinical impact in combination with systemic chemotherapy is unclear. The purpose of this study was to evaluate the safety and efficacy of CART in gastrointestinal cancer patients with massive ascites treated with chemotherapy. METHODS: We retrospectively reviewed the medical records of gastrointestinal cancer patients with massive ascites who received CART and chemotherapy at our hospital between July 2015 and September 2017. RESULTS: A total of 30 patients received CART and chemotherapy: gastric cancer (n = 21) and colorectal cancer (n = 9). The initial CART improved performance status in 20% of the patients, and the mean serum albumin and creatinine was significantly improved. Median time to treatment failure and overall survival of chemotherapy following CART were 2.1 and 3.5 months in gastric cancer patients and 5.8 and 5.8 months in colorectal cancer patients, respectively. The frequency of paracentesis was decreased after introduction of CART followed by chemotherapy in 83% of gastric cancer and in all colorectal cancer patients who had received paracentesis before the initial CART. There were no grade 3/4 adverse events during the CART procedure. Grade 3/4 hematotoxic and non-hematotoxic adverse events of chemotherapy following CART were 30% and less than 10%, respectively. CONCLUSIONS: The combination of CART followed by chemotherapy is safe and could be a treatment option for gastrointestinal cancer patients with massive ascites.

Comparison of involved field radiotherapy and elective nodal irradiation in combination with concurrent chemotherapy for T1bN0M0 esophageal cancer.

BACKGROUND: The optimal radiation field of chemoradiation therapy (CRT) for stage I esophageal squamous cell carcinoma (ESCC) is unknown. This retrospective study compared efficacy and safety of two CRT modalities, involved field irradiation (IFI) and elective nodal irradiation (ENI), when treating patients with clinical stage I (T1bN0M0) ESCC. METHODS: Patients had received 60 Gy CRT concurrently with 5-FU and cisplatin between January 2000 and December 2012. The clinical target volume of IFI was limited to the primary tumor plus a 2-cm craniocaudal margin; that of ENI covered the primary tumor plus the field of regional lymph nodes. RESULTS: One hundred and ninety-five patients were selected (IFI group, 78; ENI group, 117). The 5-year overall, cause-specific and progression-free survival rates were 90.5%, 91.6% and 77.6% in the IFI group, and 72.5%, 88.3%, 57.9% in the ENI group, respectively. Of recurrent patients (n = 16 in the IF and n = 33 in the ENI groups) after achieving complete remission, 12 (75%) in the IFI group received definitive salvage therapy, 11 (33%) patients did in the ENI group. More patients died of diseases other than esophageal cancer in the ENI group (n = 29, 25%) than in the IFI group (n = 3, 3.8%). Multivariate analysis identified ENI (HR 3.63 [1.78-7.38], p < 0.001), age ≥ 70 (HR 2.65 [1.53-4.58], p < 0.001) and PS = 1 (HR 2.36 [1.33-4.18], p = 0.003) as poor prognostic factors for OS. CONCLUSIONS: IF irradiation would be better than ENI for the patients with stage I ESCC who received definitive chemoradiotherapy.

Impact of peripheral neuropathy induced by platinum in first-line chemotherapy on second-line chemotherapy with paclitaxel for advanced gastric cancer.

BACKGROUND: Fluoropyrimidine plus platinum, followed by paclitaxel (PTX) plus ramucirumab is a recommended treatment strategy for advanced gastric cancer (AGC). We investigated how peripheral neuropathy (PN), induced by platinum in first-line chemotherapy, affected the tolerability of second-line chemotherapy with PTX (2nd-PTX). METHODS: The subjects were AGC patients who received second-line chemotherapy with PTX (2nd-PTX) after the failure of platinum-based chemotherapy between March 2015 and June 2018. We retrospectively reviewed PN severity, and dose reduction and/or discontinuation due to PN during 2nd-PTX, and compared the cumulative incidence of grade 2 PN between the two groups according to first-line chemotherapy containing oxaliplatin (L-OHP) or cisplatin (CDDP). RESULTS: The L-OHP and CDDP groups consisted of 50 patients each. PN severity before 2nd-PTX was grade 1/2 in 46/12% of patients in the L-OHP group, and 100/0% in the CDDP group. The worst grades of chemotherapy-induced PN during 2nd-PTX were grades 1/2/3 in 40/34/14% of patients in the L-OHP group, and 36/18/0% in the CDDP group. Median time to grade 2 PN after starting second-PTX was 2.5 months in the L-OHP group and 8.6 months in the CDDP group (hazard ratio 3.34, p = 0.002). The frequencies of a PN-related dose reduction and/or discontinuation of PTX were 18% in the L-OHP group and 8% in the CDDP group (p = 0.234). CONCLUSIONS: The severity of PN and tolerability of 2nd-PTX may be affected by first-line chemotherapy with L-OHP or CDDP for AGC.

Flexibility of the thoracic curve and three-dimensional thoracic kyphosis can predict pulmonary function in nonoperatively treated adult patients with adolescent idiopathic scoliosis.

BACKGROUND: Although several radiographic predictors for pulmonary function in adolescent patients have been reported, those in adult patients remain unclear. Therefore, we aimed to investigate the associations between spinal deformity and pulmonary function in nonoperatively treated adult patients with adolescent idiopathic scoliosis (AIS). METHODS: Of 319 patients treated nonoperatively for AIS, 90 (average age, 40.0 ± 6.5 years) underwent both full-length standing radiographs and pulmonary function test. Standard two-dimensional (2-D) radiographic measurements were performed. Three-dimensional thoracic kyphosis (3-D TK) was calculated from 2-D standing radiograph data using a validated formula: 3-D TK (°) = 18.1 + 0.81 × (2-D TK) + 0.54 × (Cobb angle of thoracic curve). 3-D TK was defined as the sum of segmental kyphosis between T5 and T12, which eliminates the overestimation of TK in 2-D measurements due to rotational deformity. Bivariable correlation analysis, followed by a stepwise multiple linear regression analysis, was performed. RESULTS: The average Cobb angle of the thoracic curve at the time of survey was 49.4° ± 14.6° with flexibility of 37.5% ± 18.2%. Thoracic curve magnitude, flexibility, apical vertebral rotation and translation, and 3-D TK were significantly correlated with percent-predicted forced vital capacity (%FVC) and expiratory volume in 1 s (%FEV1.0). Stepwise multiple regression analysis showed that curve flexibility and 3-D TK were significant, independent predictors of %FVC (R2 = 0.358) and %FEV1.0 (R2 = 0.335), curve flexibility having a greater impact (standardized coefficient > 0.45) than 3-D TK (<0.32). CONCLUSIONS: Our results indicate that nonoperatively treated patients with AIS should be recommended to maintain flexibility of the thoracic curve to prevent future pulmonary impairment. Moreover, 3-D TK is another independent predictor of pulmonary function, which suggests that segmental sagittal alignment is a component of deformity correction to focus on.

Three-dimensional morphological analysis of cervical foraminal stenosis using dynamic flexion-extension computed tomography images.

BACKGROUND: Morphological features of foraminal stenosis in cervical spondylotic radiculopathy and the adequate extent of facet resection in posterior cervical foraminotomy remain uncertain. Herein, we evaluated quantitatively foraminal widths in cervical spondylotic radiculopathy on dynamic flexion-extension computed tomography using a novel three-dimensional analysis method and determined the extent of facet resection in posterior cervical foraminotomy. METHODS: Seventeen patients undergoing posterior cervical foraminotomy for cervical spondylotic radiculopathy were evaluated. A neuroforamen three-dimensional model was built from preoperative images of flexion-extension computed tomography myelography, and an ordinary cervical spine coordinate system and an original neuroforaminal coordinate system, were established. In the neuroforaminal coordinate system, minimum areas perpendicular to the long axis by the slices from inlet to outlet of neuroforamen and narrowest foraminal width in a slice of minimum area were measured. The location of the narrowest region from inlet of the foramen was calculated. Ratios of minimum and sufficient facet resection were obtained from the location of the narrowest region in the neuroforaminal coordinate system. RESULTS: The narrowest foraminal widths (flexion/extension) in the cervical spine coordinate system and the neuroforaminal coordinate system were 2.9/2.3 and 2.6/1.9 mm, respectively. The mean values of the location of the narrowest region (flexion/extension) were 0.27/0.22 and 0.50/0.45 mm, respectively, and the narrowest region in the neuroforaminal coordinate system was located on the outer side than in the cervical spine coordinate system (p < 0.001). The ratios of minimum and sufficient facet resection were 23 ± 8% and 32 ± 9%, respectively. CONCLUSIONS: The narrowest regions both in flexion and extension are located at the middle of the foramen based on the neuroforaminal coordinate system. Ordinary evaluation of axial computed tomography images likely underestimates the extent of facet resection, whereas certain extent of facet resection does not exceed 50% in cases with single-level cervical spondylotic radiculopathy. STUDY DESIGN: A retrospective case control study.

CA19-9 and apolipoprotein-A2 isoforms as detection markers for pancreatic cancer: a prospective evaluation.

Recently, we identified unique processing patterns of apolipoprotein A2 (ApoA2) in patients with pancreatic cancer. Our study provides a first prospective evaluation of an ApoA2 isoform ("ApoA2-ATQ/AT"), alone and in combination with carbohydrate antigen 19-9 (CA19-9), as an early detection biomarker for pancreatic cancer. We performed ELISA measurements of CA19-9 and ApoA2-ATQ/AT in 156 patients with pancreatic cancer and 217 matched controls within the European EPIC cohort, using plasma samples collected up to 60 months prior to diagnosis. The detection discrimination statistics were calculated for risk scores by strata of lag-time. For CA19-9, in univariate marker analyses, C-statistics to distinguish future pancreatic cancer patients from cancer-free individuals were 0.80 for plasma taken ≤6 months before diagnosis, and 0.71 for >6-18 months; for ApoA2-ATQ/AT, C-statistics were 0.62, and 0.65, respectively. Joint models based on ApoA2-ATQ/AT plus CA19-9 significantly improved discrimination within >6-18 months (C = 0.74 vs. 0.71 for CA19-9 alone, p = 0.022) and ≤ 18 months (C = 0.75 vs. 0.74, p = 0.022). At 98% specificity, and for lag times of ≤6, >6-18 or ≤ 18 months, sensitivities were 57%, 36% and 43% for CA19-9 combined with ApoA2-ATQ/AT, respectively, vs. 50%, 29% and 36% for CA19-9 alone. Compared to CA19-9 alone, the combination of CA19-9 and ApoA2-ATQ/AT may improve detection of pancreatic cancer up to 18 months prior to diagnosis under usual care, and may provide a useful first measure for pancreatic cancer detection prior to imaging.

Live single cell mass spectrometry reveals cancer-specific metabolic profiles of circulating tumor cells.

Recently, there has been increased attention on the analysis of circulating tumor cells (CTCs), also known as liquid biopsy, owing to its potential benefits in cancer diagnosis and treatment. Circulating tumor cells are released from primary tumor lesions into the blood stream and eventually metastasize to distant body organs. However, a major hurdle with CTC analysis is their natural scarcity. Existing methods lack sensitivity, specificity, or reproducibility required in CTC characterization and detection. Here, we report untargeted molecular profiling of single CTCs obtained from gastric cancer and colorectal cancer patients, using live single cell mass spectrometry integrated with microfluidics-based cell enrichment techniques. Using this approach, we showed the difference in the metabolomic profile between CTCs originating from different cancer groups. Moreover, potential biomarkers were putatively annotated to be specific to each cancer type.