Current status of the cost burden of first-line systemic treatment for patients with advanced hepatocellular carcinoma in Japan, 2021-22.

BACKGROUND: Although recent advances in systemic therapies for hepatocellular carcinoma (HCC) have led to prolonged patient survival, the high costs of the drugs place a heavy burden on both patients and society. The objectives of this study were to examine the treatment regimens used as first-line systemic treatment for patients with advanced HCC in Japan and to estimate the treatment costs per regimen. METHODS: For this study, we aggregated the data of patients who had received first-line systemic treatment for advanced HCC between July 2021 and June 2022. The treatment cost per month of each regimen was estimated based on standard usage, assuming an average weight of 60 kg for male patients. The data were categorized by the treatment regimen, and the treatments were categorized based on the cost into very high-cost (≥1 000 000 Japanese yen [JPY]/month), high-cost (≥500 000 JPY/month) and other (<500 000 JPY/month) treatments. RESULTS: Of the total of 552 patients from 24 institutions whose data were analyzed in this study, 439 (79.5%) received atezolizumab plus bevacizumab, 98 (17.8%) received lenvatinib and 15 (2.7%) received sorafenib as the first-line treatment. The treatment cost per month for each of the above regimens was as follows: atezolizumab plus bevacizumab, 1 176 284 JPY; lenvatinib, 362 295 JPY and sorafenib, 571 644 JPY. In total, 82.2% of patients received high-cost regimens, and the majority of these patients received a very high-cost regimen of atezolizumab plus bevacizumab. CONCLUSIONS: Advances in systemic therapies for HCC have led to prolonged patient survival. However, the treatment costs are also increasing, imposing a burden on both the patients and society.

Effect of systemic inflammatory response on induction chemotherapy followed by chemoradiotherapy for locally advanced pancreatic cancer: an exploratory subgroup analysis on systemic inflammatory response in JCOG1106.

OBJECTIVE: JCOG1106, a randomized phase II trial conducted to compare chemoradiotherapy (S-1 concurrent radiotherapy) with (Arm B) or without (Arm A) induction chemotherapy using gemcitabine in patients with locally advanced pancreatic cancer, showed a more favorable long-term survival in Arm A. This study was aimed at exploring whether some subgroups classified by the systemic inflammatory response might derive greater benefit from either treatment. METHODS: All subjects eligible for JCOG1106 were included in this analysis (n = 51/49 in Arm A/B). This exploratory subgroup analysis was performed by Cox regression analysis to investigate the impact of the systemic inflammatory response, as assessed based on the serum C-reactive protein, serum albumin (albumin), Glasgow Prognostic Score and derived neutrophil-lymphocyte ratio, at the baseline on overall survival. P values <0.1 for the interaction were regarded as denoting significant association. RESULTS: Glasgow prognostic score showed significant treatment interactions for overall survival. Hazard ratios of Arm B to Arm A were 1.35 (95% confidence interval, 0.82-2.23) in the Glasgow Prognostic Score 0 (C-reactive protein ≤10 mg/L and albumin ≥35 g/L) (n = 44/34 in Arm A/B) and 0.59 (95% confidence interval, 0.24-1.50) in the Glasgow Prognostic Score 1/2 (C-reactive protein >10 mg/L and/or albumin <35 g/L) (n = 7/15) (P-interaction = 0.06). C-reactive protein alone and albumin alone also showed significant treatment interactions for overall survival. CONCLUSIONS: Survival benefits of induction chemotherapy in chemoradiotherapy for locally advanced pancreatic cancer were observed in patients with elevated Glasgow Prognostic Score, high C-reactive protein and low albumin. These results suggest that systemic inflammatory response might be considered to apply induction chemotherapy preceding chemoradiotherapy.

Analysis of Circulating DNA to Assess Prognoses for Metastatic Colorectal Cancer Patients Treated with Regorafenib Dose-Escalation Therapy: A Retrospective, Exploratory Analysis of the RECC Trial.

INTRODUCTION: Regorafenib is a multi-kinase inhibitor approved for patients with metastatic colorectal cancer (mCRC) who were previously treated with standard therapies. A few reports showed the impact of KRAS mutation on therapeutic efficacy of regorafenib. Only one study reported poor prognoses for patients treated with regorafenib who had large amounts of circulating cell-free DNA (cfDNA). In the present study, we evaluated the impact of KRAS mutations in tissue or plasma and amounts of cfDNA on prognoses of mCRC patients treated with regorafenib. METHOD: This is a biomarker investigation of the RECC study, which evaluated efficacy of regorafenib dose-escalation therapy. Plasma samples were obtained just before initiation of treatment with regorafenib. KRAS mutations were evaluated using tissue and plasma samples. cfDNA was extracted from plasma samples and quantified. RESULTS: Forty-five patients were enrolled in this biomarker study. Median progression-free survival (PFS) and overall survival (OS) of patients without KRAS mutations in tissues were 1.9 months (95% confidence interval [CI] 1.7-2.0) and 8.9 months (95% CI: 6.5-11.2), and those of patients with KRAS mutations were 1.4 months (95% CI: 1.3-1.5) and 6.8 months (95% CI: 5.0-8.5). Median PFS and OS of patients with plasma KRAS mutations were 1.9 months (95% CI: 1.8-1.9) and 7.0 months (95% CI: 5.3-8.7), respectively. Median PFS and OS of patients without plasma KRAS mutations were 1.7 months (95% CI: 1.1-2.3) and 8.9 months (95% CI: 6.7-11.2), respectively. Prior to administration of regorafenib, KRAS mutations were detected in 6 of 16 (37.5%) patients who had no tissue KRAS mutations. Median OS of patients with high cfDNA concentration (>median) was significantly poorer than that of patients with low cfDNA. CONCLUSION: KRAS mutations in the tissue or plasma have no impact on efficacy of regorafenib. KRAS emerging mutations were observed in quite a few patients. Large amounts of cfDNA may indicate poorer prognoses for patients receiving late-line regorafenib chemotherapy.

Impact of chronological age on efficacy and safety of fluoropyrimidine plus bevacizumab in older non-frail patients with metastatic colorectal cancer: a combined analysis of individual data from two phase II studies of patients aged >75 years.

OBJECTIVE: Many clinical trials for older patients with metastatic colorectal cancer have been conducted, and fluoropyrimidine and bevacizumab are standard treatments. However, the relationship between age and the efficacy and safety of this treatment is unclear in older metastatic colorectal cancer patients. METHODS: Individual data from two phase II studies on older (≥75 years), non-frail patients with metastatic colorectal cancer treated with uracil-tegafur/leucovorin or S-1 combined with bevacizumab were collected. Patient characteristics were evaluated with multiple regression analyses for survival outcomes, using the Cox proportional hazard model and linear regression analyses for the worst grade of adverse events. RESULTS: We enrolled 102 patients with a median age of 80 years (range, 75-88 years). Of the 70 patients who died, seven (10%) died of causes unrelated to disease or treatment. The study treatment was discontinued due to adverse events in 19 patients (18.6%), with 63% aged ≥85 years. The adverse event that most commonly resulted in treatment discontinuation was grade 2 fatigue (21%). Chronological age was not associated with progression-free survival (Hazard ratio, 1.03; P = 0.40) or overall survival (Hazard ratio, 1.02; P = 0.65). Age was weakly associated with non-hematologic adverse events (regression coefficient [R], 0.27; P = 0.007), especially fatigue (R, 0.23; P = 0.02) and nausea (R, 0.19; P = 0.06), but not with hematologic (R, 0.05; P = 0.43) or bevacizumab-related (R, -0.06; P = 0.56) adverse events. CONCLUSIONS: The efficacy of fluoropyrimidine plus bevacizumab was age-independent in patients with metastatic colorectal cancer aged ≥75 years, and attention should be paid to non-hematologic adverse events as age increases.

Biweekly TAS-102 and bevacizumab as third-line chemotherapy for advanced or recurrent colorectal cancer: a phase II, multicenter, clinical trial (TAS-CC4 study).

BACKGROUND: TAS-102 improves overall survival (OS) of patients with refractory colorectal cancer (CRC), resulting in median progression-free survival (PFS) of 2.0 months (RECOURSE trial). Subsequently, a combination of TAS-102 and bevacizumab was shown to extend median PFS by 3.7 months. However, approximately half of these patients experience grade 3/4 neutropenia. In this study, we evaluated whether biweekly TAS-102 and bevacizumab therapy has efficacy equal to that of conventional TAS-102 and bevacizumab therapy and whether it reduces adverse hematological effects. METHODS: This phase II, investigator-initiated, open-label, single-arm, multicenter study was conducted in Japan. Eligible patients had previously received first- and second-line chemotherapy for metastatic CRC. TAS-102 (35 mg/m2) was given twice daily on days 1-5 and days 15-19 in a 4-week cycle, and bevacizumab (5 mg/kg) was administered by intravenous infusion for 30 min every 2 weeks. The primary end point was progression-free survival (PFS), and secondary end points were time-to-treatment failure (TTF), response rate (RR), OS, and safety. RESULTS: 44 patients with metastatic colorectal cancer were enrolled in this study. Median PFS was 4.6 months (95% confidence interval [95% CI] 3.6-5.3) and median OS was 10.5 months (95% CI 9.6-11.4). A partial response was observed in 2 patients (4.5%, 95% CI 0.4-16.0%). The most common adverse event above grade 3 was neutropenia (7 patients, 15.9%, 95% CI 7.6-29.7%). CONCLUSIONS: Biweekly TAS-102 and bevacizumab therapy as third-line chemotherapy appears as effective as conventional TAS-102 and bevacizumab therapy, and this approach reduces adverse hematological effects.

Efficacy and safety of regorafenib dose-escalation therapy for Japanese patients with refractory metastatic colorectal cancer (RECC study).

BACKGROUND: Regorafenib significantly improves overall survival in previously treated metastatic colorectal cancer patients. However, various toxicities, such as hand-foot skin reaction (HFSR), fatigue, and liver dysfunction have limited the use of regorafenib. These toxicities appear soon after treatment initiation. The ReDOS study demonstrated the effectiveness of a weekly dose-escalation therapy of regorafenib starting with a lower daily dose; however, its usefulness in Asian subjects is unknown. We conducted a phase II study to evaluate the safety and survival benefit of regorafenib dose-escalation therapy for Japanese patients. METHODS: Patients with sufficient organ function, who had previously received more than two lines of chemotherapy were included. Regorafenib was started at 80 mg/day and escalated to 120 mg/day in Week 2 and 160 mg/day in Week 3, if no severe drug-related toxicities were observed. The primary endpoint was cancer progression-free survival (PFS). Tumor response and progression were assessed radiologically every 8 weeks. This study was registered in the University Hospital Medical Information Network (UMIN#UMIN000028933). RESULTS: 57 patients were enrolled and all started regorafenib at 80 mg/day. 32 patients (56.1%) were subsequently escalated to 120 mg/day and 19 (33.3%) to 160 mg/day. Only 8 patients (14.0%) discontinued treatment because of adverse events. Median PFS was 1.9 months. Median overall survival was 8.9 months, the response rate was 0%, and the disease control rate was 31.6%. The most frequent adverse event greater than grade 3 was hypertension (19.3%), followed by HFSR (14.0%). CONCLUSIONS: Regorafenib dose-escalation therapy is well tolerated with PFS-like regorafenib standard therapy.

Combination of TAS-102 and bevacizumab as third-line treatment for metastatic colorectal cancer: TAS-CC3 study.

BACKGROUND: TAS-102 improved the overall survival of metastatic colorectal cancer (CRC) patients with a median progression-free survival (PFS) in the RECOURSE trial. Subsequently, the combination of TAS-102 and bevacizumab was shown to extend the median PFS (C-TASK FORCE study). However, the study included patients who received second- and third-line treatment. Our study exclusively examined patients receiving this combination as a third-line treatment to investigate the clinical impact beyond cytotoxic doublets. METHODS: This investigator-initiated, open-label, single-arm, multi-centered phase II study was conducted in Japan. Eligible CRC patients were refractory or intolerant to fluoropyrimidine, irinotecan, and oxaliplatin in first- and second-line therapy. TAS-102 (35 mg/m2) was given orally twice daily on days 1-5 and 8-12 in a 4-week cycle, and bevacizumab (5 mg/kg) was administered by intravenous infusion every 2 weeks. The primary endpoint was PFS and the secondary endpoints were time-to-treatment failure, response rate, overall survival (OS), and safety. RESULTS: Between June 2016 and August 2017, 32 patients were enrolled. All patients previously received bevacizumab. The median PFS was 4.5 months; the median overall survival was 9.3 months. Partial response was observed in two patients. The most common adverse events above grade 3 were neutropenia followed by thrombocytopenia. There were no non-hematological adverse events above grade 3 and no treatment-related deaths occurred. CONCLUSIONS: This study met its primary endpoint of PFS, which is comparable to the results of the C-TASK FORCE study. The TAS-102 and bevacizumab combination has the potential to be a therapeutic option for third-line treatment of metastatic CRC.

The relationship between peripheral neuropathy and efficacy in second-line chemotherapy for unresectable advanced gastric cancer: a prospective observational multicenter study protocol (IVY).

BACKGROUND: Paclitaxel is used in second-line conventional chemotherapies to manage patients with unresectable advanced gastric cancer (GC). Paclitaxel-induced peripheral neuropathy is a known adverse event leading to treatment discontinuation. Additionally, oxaliplatin which causes irreversible peripheral neuropathy is now commonly used in first-line chemotherapy for advanced GC in Japan. Thus, examining the incidence of peripheral neuropathy with paclitaxel after oxaliplatin is necessary to improve the quality of life and outcomes of patients with advanced GC in the second-line treatment setting. METHODS: This prospective observational multicenter study, (which we named IVY study), will evaluate the degree of chemotherapy-induced peripheral neuropathy (CIPN) and the efficacy of second-line chemotherapy for unresectable advanced GC. A patient neurotoxicity questionnaire (PNQ) and the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx) will be used to assess CIPN during the second-line treatment. The key eligibility criteria are as follows: 1) unresectable or recurrent GC histologically confirmed to be primary adenocarcinoma of the stomach, 2) age over 20 years, 3) Eastern Cooperative Oncology Group performance status score of 0-2, 4) written informed consent following full study information is provided to the patient, 5) progression or intolerance for first-line chemotherapy comprising fluorinated pyrimidine and platinum anticancer drugs (cisplatin or oxaliplatin) for advanced GC. 6) presence of evaluable lesions as confirmed using a computed tomography (CT) or magnetic resonance imaging. A total of 200 patients is considered to be appropriate for inclusion in this study. DISCUSSION: The results of this study will provide some information on CIPN with the sequential usage of oxaliplatin as first-line chemotherapy to paclitaxel as second-line chemotherapy in clinical practice. TRIAL REGISTRATION: This trial is registered in the University Hospital Medical Information Network's Clinical Trials Registry with the registration number UMIN000033376 (Registered 11 July 2018).

Dramatic response of FOLFIRINOX regimen in a collision pancreatic adenocarcinoma patient with a germline BRCA2 mutation: a case report.

Germline BRCA1 and BRCA2 mutations are the most common gene mutations in familial pancreatic adenocarcinoma. Several reports have demonstrated the utility of platinum-based chemotherapy for treating cancer patients who harbour a BRCA mutation. Here we discuss a 47-year-old Japanese female with no relevant past history who presented with epigastralgia and fever in September 2016. A computed tomography scan revealed a low-density, low-enhanced tumour 15 mm in diameter in the head of the pancreas. The pathological diagnosis was a ductal pancreatic carcinoma. A 6 mm low-enhanced metastatic tumour was also detected in segment 4 of the liver. Because she had early onset of the disease and a family history-her mother died of pancreatic adenocarcinoma at age 48-we considered a diagnosis of familial pancreatic adenocarcinoma. She received modified FOLFIRINOX. Two months after starting chemotherapy, she was diagnosed with an invasive ductal carcinoma in the right breast. FOLFIRINOX was continued for 8 cycles (4 months); the primary pancreatic adenocarcinoma shrank and the liver metastatic foci disappeared, but the size of the breast tumour increased. Total right breast excision and sentinel lymph node dissection were performed. FOLFIRINOX was continued and after 12 cycles (6 months), both her pancreatic adenocarcinoma and liver metastasis were no longer visible using imaging. Pancreatoduodenectomy was performed and the primary tumour had shrunk to 2.5 mm. Genetic testing revealed a germline BRCA2 mutation. The FOLFIRINOX regimen showed dramatic effects on the collision pancreatic but not on the breast cancer.

PTEN mRNA expression is less pronounced in left- than right-sided colon cancer: a retrospective observational study.

BACKGROUND: Several recent studies have reported that patients with metastatic colorectal cancer (CRC) whose primary tumor is located in left side of the colon have more favorable responses to anti-epidermal growth factor receptor (EGFR) antibody therapy than those with right-sided tumors. However, the mechanism for this phenomenon is unknown. METHODS: Fifty-two cases of primary CRC with liver metastases were analyzed in this retrospective study. The mRNA levels of 19 signal transduction genes in both primary tumor and liver metastases were measured by real-time reverse transcription polymerase chain reaction. The purposes of this study were (1) to determine the correspondence between signal transduction gene expressions in primary tumors and corresponding liver metastases, and (2) to determine whether expression levels of these genes differ by primary tumor location. RESULTS: mRNA expression levels of 14 of 19 signal transduction genes, including PTEN, ERBB2, MET, HGF, AREG, and EREG, showed significant correlations between the primary tumor and corresponding liver metastases. When the mRNA levels of the primary tumors were compared by tumor location, only PTEN mRNA expression differed significantly between left and right-sided CRC (median PTEN expression: left 1.00 vs. right 1.68; p = 0.017). When rectal cancers were separated from left-sided colon cancers, PTEN mRNA levels increased progressively from rectum to right-sided colon (median; rectum 0.84, left colon 1.23, right colon 1.68, p = 0.013). PTEN mRNA expression in liver metastases also differed significantly according to primary tumor location (median; left 0.92 vs. right 1.27, p = 0.048). There was no difference in overall survival between patients with high versus low levels of PTEN mRNA (p = 0.59). CONCLUSIONS: Our data suggest that the PIK3/AKT/mTOR pathway is more active in left- than right-sided CRC, which provides a possible explanation for the fact that efficacy of anti-EGFR therapy differs by location of primary tumor.

ERCC1 mRNA expression as a postoperative prognostic marker in extrahepatic bile duct cancer.

BACKGROUND: No reliable biomarker for biliary tract cancer has yet been identified because of the varying composition of the cancer type, differences in tumor location, a mixture of curative and non-curative operations, and differences in operative methods. METHODS: Fifty extrahepatic bile duct cancer patients, pathologically diagnosed with papillary or tubular adenocarcinoma who underwent a pancreatoduodenectomy with R0 resection, were included in the study. Messenger RNA (mRNA) expression levels were measured from formalin-fixed, paraffin-embedded samples by real-time reverse-transcription polymerase chain reaction. RESULTS: The preliminary analysis selected ten patients who have survived more than 5 years (LS group) and ten who had a relapse within 2 years (SS group). mRNA expression of seven target genes was examined, but only excision repair cross-complementing 1 (ERCC1) mRNA levels showed a significant difference between the LS and SS groups (median ERCC1: LS 26.5 vs. SS 9.7; p = 0.0073). The median survival time of patients with high ERCC1 levels was significantly longer than in patients with low ERCC1 levels (p = 0.0105). Thirty more patients with identical backgrounds were added to the study, and ERCC1 mRNA levels were measured in all 50 patients. Those with high ERCC1 mRNA levels had a significantly greater overall survival (OS) time compared with those with low ERCC1 levels (MST: 174 vs. 86 M; p = 0.048). Multivariate analysis found that an absence of lymph node metastases and high ERCC1 expression were significantly associated with improved OS. CONCLUSION: ERCC1 mRNA expression appears to be a useful prognostic biomarker for extrahepatic bile duct cancer with R0 resection.

Enhancement of 5-fluorouracil-induced cytotoxicity by leucovorin in 5-fluorouracil-resistant gastric cancer cells with upregulated expression of thymidylate synthase.

BACKGROUND: Elucidation of the mechanisms by which gastric cancer cells acquire resistance to 5-fluorouracil (5FU) may provide important clues to the development of effective chemotherapy for 5FU-resistant gastric cancer METHODS: Four 5FU-resistant cell lines (MKN45/5FU, MKN74/5FU, NCI-N87/5FU, and KATOIII/5FU) were established by continuous exposure of the cells to progressively increasing concentrations of 5FU for about 1 year. Then, mRNA expression levels of four genes associated with 5FU metabolism, i.e., thymidylate synthase (TS), dihydropyrimidine dehydrogenase, thymidine phosphorylase, and orotate phosphoribosyltransferase, were quantitatively evaluated by real-time reverse transcriptase-polymerase chain reaction. In addition, TS protein expression was measured by Western blot analysis. RESULTS: As compared with the parent cell lines, the 5FU-resistant cell lines showed 3.8- to 11.6-fold higher resistance to 5FU, as well as 1.9- to 3.5-fold higher TS mRNA expression and 1.6- to 7.1-fold higher TS protein expression. In contrast, the expressions of other genes did not differ significantly among the cell lines. The cytotoxicity of 5FU was enhanced 2.3- to 2.8 fold by leucovorin (LV) against three of the four 5FU-resistant cell lines. CONCLUSIONS: Collectively, LV enhanced the cytotoxicity of 5FU not only against the parent gastric cancer cell lines, but also against the 5FU-resistant cell lines, even those with elevated TS expression levels. These results suggest that clinical studies of a combination of 5FU and LV are warranted in patients who have recurrent gastric cancer after 5FU-based therapy.

Degraded DNA may induce discordance of KRAS status between primary colorectal cancer and corresponding liver metastases.

BACKGROUND: KRAS mutation is widely accepted as a strong, negative predictive marker for anti-epidermal growth factor receptor antibodies, including cetuximab and panitumumab. Previous reports demonstrated approximately 100 % concordance of KRAS status between primary colorectal cancer and liver metastases; however, mismatched KRAS status still occurs. METHODS: KRAS status was evaluated in 105 pairs of formalin-fixed primary colorectal cancer and corresponding liver metastases specimens by direct sequencing. DNA quality of patients displaying mismatched KRAS status between primary tumors and metastases was assessed using a Bioanalyzer. RESULTS: KRAS status was successfully analyzed in 90/105 patients (85.7 %). The concordance rate between primary tumors and metastases was 88.2 % in synchronous metastases (n = 76) and 100 % in metachronous metastases (n = 14). Discordance in KRAS status was observed in nine patients. Independent method validation revealed only five samples showed the same KRAS status between the two methods. DNA quality assessment by a Bioanalyzer revealed that the median length of DNA samples in the peak concentration of the mismatched group was significantly shorter than those in the control group (153.5 vs 276.5 bp, P = 0.0059). In addition, the median value of the percentage of degraded DNA (0-200 bp) in each sample in the mismatched group was significantly higher than the control group (35.5 vs 22 %, P = 0.020). These data suggest that the discordant results for these nine patients (18 samples) were due to low quality DNA, which may obscure polymerase chain reaction analysis, affecting sequencing reliability. CONCLUSION: Quality control and assurance of KRAS genotyping is critical, and standardization of the methodology is warranted.

Long-term Results of a Phase II Study of Neoadjuvant SOX for Advanced Gastric Cancer.

BACKGROUND/AIM: This study aimed to evaluate the long-term survival outcomes from our previous study: a phase II study of neoadjuvant chemotherapy with S-1 plus oxaliplatin for cT4 or N2-3 advanced gastric cancer. PATIENTS AND METHODS: The patients with clinical T4 and/or N2 or more lymph nodes received two cycles (3 weeks per cycle) of neoadjuvant chemotherapy with S-1 plus oxaliplatin (oxaliplatin at 130 mg/m2 on day 1 and S-1 at 80-120 mg/day on days 1 to 14), followed by gastrectomy with D2 lymphadenectomy. The final preplanned analysis of long-term outcomes, including overall and relapse-free survival, was performed. This trial has been completed and registered with the University Hospital Medical Information Network Clinical Trials Registry under number UMIN 000024656. RESULTS: Between May 2016 and March 2019, 30 patients were enrolled. All patients completed the protocol. After a median follow-up of 50 months for surviving patients, the 3-year overall and recurrence-free survival rates were 80.0% and 76.7%, respectively, at the last follow-up in March 2023, whereas the 5-year overall and recurrence-free survival rates were 72.7% and 73.0%, respectively. CONCLUSION: The administration of two cycles of neoadjuvant chemotherapy with S-1 plus oxaliplatin, followed by D2 gastrectomy, was associated with relatively good long-term oncologic outcomes for patients with high-risk gastric cancer.

A Case of Pathologically Complete Response After Nivolumab Combined with Chemotherapy in a Gastric Cancer Patient with Virchow's Lymph Node Metastasis.

Gastric cancer with Virchow's lymph node metastasis (LNM) is not indicated for initial curative surgery. Although there have been some case reports of curative resections after pre-operative treatment, including immune checkpoint inhibitors (ICIs), there is no consensus regarding the optimal timing of surgery. We describe a rare case of initially unresectable gastric cancer treated preoperatively with nivolumab combined chemotherapy, which achieved a pathologically complete response. An 82-year-old man was referred for gastric cancer treatment. Contrast-enhanced computed tomography revealed stomach wall thickening and swollen left supraclavicular LN. This gastric cancer was assessed as unresectable due to the presence of Virchow's LNM; therefore, chemotherapy and ICI using S-1 plus oxaliplatin plus nivolumab were administered. After three courses of treatment, the primary tumor and Virchow's LN showed a marked reduction in size. The patient underwent Virchow's LNM resection as a preliminary step to determine indications for curative surgery. A pathological examination revealed no viable cancer cells were found inside the resected LN. The patient underwent distal gastrectomy. Pathological examination revealed complete degeneration of the primary tumor and regional LN without residual carcinoma. The patient did not receive adjuvant chemotherapy and survived with no evidence of recurrence for one year after the initial treatment.

Characteristic cerebrospinal fluid findings in immune checkpoint inhibitor-related peripheral neuropathy: A case report.

Although immune checkpoint inhibitors (ICIs) are widely used to treat unresectable malignant tumors, they can cause undesirable side effects called immune-related adverse events, including neurological toxicities. Here, we describe a case of ICI-related peripheral neuropathy (irPN) with characteristic cerebrospinal fluid (CSF) findings. In addition to pleocytosis and increased protein levels, the present case showed increased levels of CSF soluble interleukin-2 receptor (sIL-2R), IL-6, and IL-10, suggesting activated T cell-related autoimmunity. We believe that CSF cytokines and sIL-2R could be novel biomarkers of irPN.

Amphiregulin and Epiregulin mRNA expression in primary colorectal cancer and corresponding liver metastases.

BACKGROUND: Amphiregulin (AREG) and Epiregulin (EREG), ligands of EGFR, are reported to be predictive biomarkers of colorectal cancer patients treated with Cetuximab, an anti-EGFR antibody. The purpose of this study is to determine the correlation of AREG and EREG expression between primary colorectal cancer and corresponding liver metastases. METHODS: One hundred twenty colorectal cancer patients with liver metastases (100 with synchronous metastases, 20 with metachronous) were evaluated. No patients had ever received anti-EGFR antibody agents. AREG and EREG mRNA expression from both the primary tumor and liver metastases were measured using real-time RT-PCR. KRAS codon 12, 13 mutation status was analyzed by direct sequencing. RESULTS: Modest, but significant, correlations were observed between primary tumor and corresponding liver metastases in both AREG mRNA expression (Rs = 0.54, p < 0.0001) and EREG mRNA expression (Rs = 0.58, p < 0.0001). AREG and EREG mRNA expression was strongly correlated in both the primary tumor (Rs = 0.81, p < 0.0001) and the liver metastases (Rs = 0.87, p < 0.0001). No significant survival difference was observed between low and high AREG or EREG patients when all 120 patients were analyzed. However, when divided by KRAS status, KRAS wild-type patients with low EREG mRNA levels in the primary site showed significantly better overall survival rates than those with high levels (p = 0.018). In multivariate analysis, low EREG expression was significantly associated with better overall survival (p = 0.006). CONCLUSIONS: AREG and EREG expression showed a modest correlation between primary tumor and liver metastases. As EREG mRNA expression was associated with decreased survival, it is appeared to be a useful prognostic marker in KRAS wild-type patients who never received anti-EGFR therapy.

A Trial Protocol of Precision Medicine for Patients with RAS Wild Metastatic Colorectal Cancer Using Liquid Biopsy (RAS-liquid Study): A Prospective, Multicenter Observational Study.

BACKGROUND: Anti-epidermal growth factor receptor (EGFR) therapy has been identified to prolong the survival of metastatic colorectal cancer (mCRC) patients without RAS mutations. However, its efficacy is not always consistent for these patients. Genomic profiles of primary tumors and metastases are not always concordant; thus, chemotherapeutic agents can alter the tumor molecular profile. This molecular heterogeneity may explain resistance to anti-EGFR therapy. Liquid biopsy using circulating tumor DNA (ctDNA) is a novel, non-invasive diagnostic tool that can accommodate this molecular heterogeneity, providing a comprehensive, real-time view of the molecular landscape. In this study, we evaluated the predictive value of genomic mutations in ctDNA for primary and acquired resistance to anti-EGFR therapy. METHODS/DESIGN: This study is a prospective, multicenter, observational study of mCRC patients with wild-type tissue RAS treated with cytotoxic agents and anti-EGFR antibodies as first-line therapy. Genomic mutations, including RAS, BRAF, PIK3CA, and EGFR in ctDNA, are assessed via Droplet Digital PCR before starting chemotherapy and every 3 months thereafter until disease progression. The target sample size is estimated to be 100. The primary endpoint is the response rate in patients without RAS mutation in their blood sample before starting chemotherapy. DISCUSSION: This study will clarify the predictive value of baseline RAS mutation in ctDNA for responses to anti-EGFR therapy; the frequency of emerging RAS, BRAF, PIK3CA, and EGFR mutations in ctDNA; and the association with secondary resistance to anti-EGFR therapy in first-line therapy for wild-type tissue RAS mCRC patients.

Gene expression of the mismatch repair gene MSH2 in primary colorectal cancer.

Microsatellite instability (MSI) is caused by defective mismatch repair (MMR) and is one of the very few molecular markers with proven clinical importance in colorectal cancer with respect to heredity, prognosis, and treatment effect. The gene expression of the MMR gene MSH2 may be a quantitative marker for the level of MMR and a potential molecular marker with clinical relevance. The aim was to investigate the gene expression of MSH2 in primary operable colorectal cancer in correlation with MSI, protein expression, and promoter hypermethylation. In a cohort of 210 patients, the primary tumor and lymphnode metastases were analyzed with immunohistochemistry, methylation and MSI analyses, and quantitative polymerase chain reaction (PCR). The median gene expression of MSH2 was 1.00 (range 0.16-11.2, quartiles 0.70-1.51) and there was good agreement between the gene expression in primary tumor and lymph node metastasis (Spearman's rho = 0.57, p < 0.001, n = 73). The validity of gene expression analysis was made probable by a significant correlation to protein expression (p = 0.005). MSI was most often caused by deficient MLH1 and was not correlated to MSH2 expression. Hypermethylation of the MSH2 gene promoter was only detected in 14 samples and only at a low level with no correlation to gene expression. MSH2 gene expression was not a prognostic factor for overall survival in univariate or multivariate analysis. The gene expression of MSH2 is a potential quantitative marker ready for further clinical validation.

Phase II study of neoadjuvant chemotherapy with S-1 plus oxaliplatin for gastric cancer clinical T4 or N2-3.

In Japan, the standard treatment for stage II or III gastric cancer is D2 gastrectomy followed by administration of S-1 for one year. However, patients with stage III disease have unsatisfactory survival rates. The purpose of this study was to evaluate the efficacy and safety of neoadjuvant chemotherapy consisting of S-1 and oxaliplatin for advanced gastric cancer. Patients with cT4 or cN2-3 gastric cancer were scheduled to receive two courses of chemotherapy (130 mg/m2 oxaliplatin on Day 1, 80 mg/m2 S-1 per day twice daily for 14 days) followed by surgery. The primary endpoint was the R0 resection rate. The secondary endpoints were rates of completion of protocol treatment, pathological response, and adverse events; and 3-year overall survival, 5-year overall survival, and 5-year recurrence-free survival. Between May 2016 and March 2019, 30 patients were enrolled in the study, all of whom completed the protocol treatment. The R0 resection rate (primary endpoint) was 93.3% (95% confidence interval: 77.9-99.2). The pathological response rate was 63.3%. Grade 3-4 toxicities included anemia (3.3%), anorexia (6.7%), and fatigue (3.3%). Relative dose intensities were 91.2% and 94.2% for S-1 and oxaliplatin, respectively. Neoadjuvant S-1 and oxaliplatin is highly effective, achieving an acceptable R0 resection rate with relatively few severe toxicities and good compliance.Trial registration: Registry name: A prospective intervention study on the availability of preoperative SOX therapy for T4 or N2-3 gastric cancer. Trial ID: UMIN: UMIN000024656. https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R00002836.