Albumin-Lymphocyte-Globulin-C-Reactive Protein Index as a Novel Prognostic Biomarker for Hepatocellular Carcinoma After Hepatectomy.

INTRODUCTION: This study evaluated the performance of the albumin-lymphocyte-globulin-C-reactive protein (CRP) (ALGC) index as a novel prognostic biomarker for hepatocellular carcinoma (HCC) after hepatectomy. METHODS: Patients (n=178) who underwent hepatectomy for HCC (July 2010 - December 2021) were analyzed. The ALGC index was calculated as [(albumin × lymphocyte) / (CRP × globulin × 104)]. Patients were divided into a low ALGC group (<1.82; n=81) and a high ALGC group (≥1.82; n=97). The association of the ALGC index with survival was assessed by univariate and multivariate analyses. RESULTS: The median overall survival (OS) was 100 (range: 1-149) months with 1-, 3-, and 5-year OS rates of 91.6%, 81.2%, and 64.2%, respectively. In univariate analysis, ALGC index (<1.82), alpha-fetoprotein (≥25 ng/mL), tumor size (≥3.5 cm), microvascular invasion, and multiple tumors were associated with shorter OS. ALGC index (<1.82) (hazard ratio [95% confidence interval]) (2.48 [1.407-4.513]; P=0.001) and multiple tumors (1.92 [1.070-3.356]; P=0.029) were independent predictors of OS in multivariate analysis. CONCLUSION: ALGC index is a novel prognostic biomarker for HCC after hepatectomy. It may assist in treatment stratification and better management of patients with HCC.

Incidence of Metachronous Remnant Gastric Cancer after Proximal Gastrectomy with the Double-flap Technique (rD-FLAP-rGC Study): A Multicenter, Retrospective Study.

BACKGROUND: Although proximal gastrectomy (PG) with the double-flap technique (DFT) is a function-preserving surgery that prevents esophagogastric reflux, there is a risk of developing metachronous remnant gastric cancer (MRGC). Moreover, details of MRGC and appropriate postoperative follow-up after PG with DFT are unclear. METHODS: We reviewed the medical records of 471 patients who underwent PG with DFT for cancer in a preceding, multicenter, retrospective study (rD-FLAP Study). We investigated the incidence of MRGC, frequency of follow-up endoscopy, and eradication of Helicobacter pylori (H. pylori) infection. RESULTS: MRGC was diagnosed in 42 (8.9%) of the 471 patients, and 56 lesions of MRGC were observed. The cumulative 5- and 10-year incidence rates were 5.7 and 11.4%, respectively. There was no clinicopathological difference at the time of primary PG between patients with and without MRGC. Curative resection for MRGC was performed for 49 (88%) lesions. All patients with a 1-year, follow-up, endoscopy interval were diagnosed with early-stage MRGC, and none of them died due to MRGC. Overall and disease-specific survival rates did not significantly differ between patients with and without MRGC. The incidence rate of MRGC in the eradicated group after PG was 10.8% and that in the uneradicated group was 19.6%, which was significantly higher than that in patients without H. pylori infection at primary PG (7.6%) (p = 0.049). CONCLUSIONS: The incidence rate of MRGC after PG with DFT was 8.9%. Early detection of MRGC with annual endoscopy provides survival benefits. Eradicating H. pylori infection can reduce the incidence of MRGC.

Daily irradiation versus irradiation at two- to three-day intervals in stereotactic radiotherapy for patients with 1-5 brain metastases: study protocol for a multicenter open-label randomized phase II trial.

BACKGROUND: Radiobiological daily changes within tumors are considered to be quite different between stereotactic radiotherapy (SRT) (e.g., 50 Gy in 4 fractions) and conventional radiotherapy (e.g., 60 Gy in 30 fractions). We aim to assess the optimal interval of irradiation in SRT and compare outcomes of daily irradiation with irradiation at two- to three-day intervals in SRT for patients with one to five brain metastases (BM). METHODS: This study is conducted as a multicenter open-label randomized phase II trial. Patients aged 20 or older with one to five BM, less than 3.0 cm diameter, and Karnofsky Performance Status ≥70 are eligible. A total of 70 eligible patients will be enrolled. After stratifying by the number of BMs (1, 2 vs. 3-5) and diameter of the largest tumor (< 2 cm vs. ≥ 2 cm), we randomly assigned patients (1:1) to receive daily irradiation (Arm 1), or irradiation at two- to three-day intervals (Arm 2). Both arms are performed with total dose of 27-30 Gy in 3 fractions. The primary endpoint is an intracranial local control rate, defined as intracranial local control at initially treated sites. We use a randomized phase II screening design with a two-sided α of 0∙20. The phase II trial is positive with p < 0.20. All analyses are intention to treat. This study is registered with the UMIN-clinical trials registry, number UMIN000048728. DISCUSSION: This study will provide an assessment of the impact of SRT interval on local control, survival, and toxicity for patients with 1-5 BM. The trial is ongoing and is recruiting now. TRIAL REGISTRATION: UMIN000048728. Date of registration: August 23, 2022. https://center6.umin.ac.jp/cgi-bin/ctr/ctr_view_reg.cgi?recptno=R000055515 .

Antibody responses induced by the BNT162b2 mRNA COVID-19 vaccine in healthcare workers in a single community hospital in Japan.

INTRODUCTION: The effectiveness of several vaccines against coronavirus disease (COVID-19) has been reported in the real-world setting. However, it is still unknown how long antibodies persist following vaccination and whether or not the persistence of antibodies has a protective effect against COVID-19. METHODS: Healthcare workers who had received two doses of the BNT162b2 mRNA COVID-19 vaccine were enrolled, and a single-center study was conducted at the National Hospital Organization Hakodate National Hospital. Serum samples from all participants were collected 13-21 weeks (median: 20 weeks) after the second dose of vaccination. The antibody titers were measured using an electrochemiluminescence immunoassay (Elecsys® Anti-SARS-CoV-2 S). Data on characteristics of the participants were gathered from patient records and interview sheets. RESULTS: A total of 401 participants, among whom 70.1% were women and the median age was 42 years, were evaluated in this study. None of the participants had a definite COVID-19 history, and all participants who received complete vaccination showed positive antibody titers. The antibody titer was observed to be higher in participants with younger age (p < 0.001) and those who were females (p = 0.028). Despite the higher risk of infection than that of the general public, no vaccinated staff developed breakthrough infections. CONCLUSIONS: This study demonstrates the significant contribution of the BNT162b2 vaccine in the acquisition of anti-SARS-CoV-2S antibodies; therefore, the general population should benefit from these two vaccine doses, which are expected to be protective for at least five months.

[Laparoscopic Surgery for Gastric Gastrointestinal Stromal Tumors].

Gastric gastrointestinal stromal tumors(GISTs)are rarely accompanied by lymph node metastasis; therefore, laparoscopic partial gastrectomy is feasible for managing GISTs. Between 2005 and 2022, 60 patients underwent open or laparoscopic surgery for preoperatively suspected or histopathologically confirmed GISTs. Tumors were detected in the upper, mid, and lower stomach in 38, 18, and 4 patients, respectively. Intraluminal tumors or those with a mixed tumor growth pattern were identified in 42 patients, whereas tumors with an extraluminal growth pattern were noted in 18 patients. Open and laparoscopic surgery was performed in 28 and 32 patients, respectively. The adaptation for laparoscopic surgery was less than 5 cm in size. The laparoscopic approaches were as follows: conventional wedge resection in 19 patients, transillumination and serosal dissection method in 3, laparoscopic and endoscopic cooperative surgery in 8, and gastrectomy in 2 patients. Compared with the open surgery group, the laparoscopic surgery group presented a significant reduction in operation time, estimated blood loss, tumor size, and length of postoperative hospitalization. Based on the modified-Fletcher clinicopathological risk classification, 49, 6, and 5 patients were categorized into the low- or very low-, mid-, and high-risk groups, respectively. Recurrence was only observed in the open surgery group. The 10-year survival rates were 100% in both groups. The 5-year recurrence-free survival rates were 100 and 87% in the laparoscopic and open surgery groups, respectively. The aforementioned laparoscopic approaches were associated with favorable surgical outcomes.

A combined prediction model for biliary tract cancer using the prognostic nutritional index and pathological findings: a single-center retrospective study.

BACKGROUND: The prognostic nutritional index, a marker of nutritional status and systemic inflammation, is a known biomarker for various cancers. However, few studies have evaluated the predictive value of the prognostic nutritional index in patients with biliary tract cancer. Therefore, we investigated the prognostic significance of the prognostic nutritional index, and developed a risk-stratification system to identify prognostic factors in patients with biliary tract cancer. METHODS: Between July 2010 and March 2021, 117 patients with biliary tract cancer were recruited to this single-center, retrospective study. The relationship between clinicopathological variables, including the prognostic nutritional index, and overall survival was analyzed using univariate and multivariate analyses. A P < 0.05 was considered statistically significant. RESULTS: The median age was 75 (range 38-92) years. Thirty patients had intrahepatic cholangiocarcinoma; 29, gallbladder carcinoma; 27, distal cholangiocarcinoma; 17, ampullary carcinoma; and 13, perihilar cholangiocarcinoma. Curative (R0) resection was achieved in 99 patients. In univariate analysis, the prognostic nutritional index (< 42), lymph node metastasis, carbohydrate antigen 19-9 level (> 20 U/mL), preoperative cholangitis, tumor differentiation, operation time (≥ 360 min), and R1-2 resection were significant risk factors for overall survival. The prognostic nutritional index (P = 0.027), lymph node metastasis (P = 0.040), and tumor differentiation (P = 0.006) were independent prognostic factors in multivariate analysis. A combined score of the prognostic nutritional index and pathological findings outperformed each marker alone, in terms of discriminatory power. CONCLUSIONS: The prognostic nutritional index, lymph node metastasis, and tumor differentiation were independent prognostic factors after surgical resection in patients with biliary tract cancer. A combined prediction model using the prognostic nutritional index and pathological findings accurately predicted prognosis, and can be used as a novel prognostic factor in patients with biliary tract cancer.

Preoperative Albumin-to-Globulin Ratio Predicts Prognosis in Hepatocellular Carcinoma: A Cohort Study Including Non-Hepatitis Virus-Infected Patients.

INTRODUCTION: We evaluated the prognostic significance of the preoperative albumin-to-globulin ratio (AGR) in patients with hepatocellular carcinoma (HCC) with various liver etiologies. METHODS: We retrospectively analyzed 157 patients with HCC between July 2010 and February 2021. The relationship between clinicopathological variables was investigated using univariate and multivariate analyses. Statistical significance was set at p < 0.05. RESULTS: The mean overall survival (OS) was 24.5 months. The 1-, 3-, and 5-year OS rates were 90.4%, 81.2%, and 68.7%, respectively. Patients were classified into 2 groups: AGR <1.16 (low-AGR group; n = 43) and AGR ≥1.16 (high-AGR group; n = 114). In univariate analysis, OS was significantly reduced in patients with a low AGR (AGR <1.16), an alpha-fetoprotein level ≥25 ng/mL, a tumor size ≥3.5 cm, microvascular invasion, and poor tumor differentiation. In multivariate analysis, a low AGR (hazard ratio [95% confidence interval]) (2.394 [1.092-5.213]; p = 0.030) and microvascular invasion (2.268 [1.019-5.169]; p = 0.045) were independent predictors of OS. DISCUSSION/CONCLUSION: A low AGR was significantly associated with poor OS in patients with HCC, regardless of liver etiology. This may assist in treatment stratification and better management of patients with HCC.

Chemical Genetics Reveals a Role of Squalene Synthase in TGFß Signaling and Cardiomyogenesis.

KY02111 is a widely used small molecule that boosts cardiomyogenesis of the mesoderm cells derived from pluripotent stem cells, yet its molecular mechanism of action remains elusive. The present study resolves the initially perplexing effects of KY02111 on Wnt signaling and subsequently identifies squalene synthase (SQS) as a molecular target of KY02111 and its optimized version, KY-I. By disrupting the interaction of SQS with cardiac ER-membrane protein TMEM43, KY02111 impairs TGFß signaling, but not Wnt signaling, and thereby recapitulates the clinical mutation of TMEM43 that causes arrhythmogenic right ventricular cardiomyopathy (ARVC), an inherited heart disease that involves a substitution of myocardium with fatty tissue. These findings reveal a heretofore undescribed role of SQS in TGFß signaling and cardiomyogenesis. KY02111 may find its use in ARVC modeling as well as serve as a chemical tool for studying TGFß/SMAD signaling.

[Operative Technique for Gastric GIST According to the Tumor Location or Growth Pattern].

Gastric gastrointestinal stromal tumor(GIST)is rarely accompanied by lymph node metastasis. Therefore, partial gastrectomy generally proceeds with good indication for laparoscopic surgery. However, surgical procedures can be complicated by the tumor location or growth type. Furthermore, laparoscopy and endoscopy cooperative surgery(LECS)has recently been developed, with good results. In this study, we aimed at determining the applicability of various types of laparoscopic surgery to gastric GIST based on the tumor location and growth type. Between 2005 and 2020, 52 patients underwent surgery for preoperatively suspected or pathologically confirmed GIST. Tumors were found in the upper, middle, and lower portions of the stomach of 32, 16 and 4 patients, respectively. The types of tumor growth were intraluminal, extraluminal, and mixed for 21, 14, and 17 patients, respectively. The surgical procedures were open and laparoscopic for 26 patients each. After the laparoscopic surgery, the surgical duration, blood loss, and tumor size were significantly lower, while the hospital stay was significantly shorter. For the laparoscopic surgery, we adopted simple wedge resection, transillumination and serosal dissection methods(TSDM), or LECS. Two patients underwent TSDM using single incisional laparoscopic surgery(SILS)for tumors with intraluminal growth in the cardiac region, while 7 underwent LECS. The selection of the method for laparoscopic surgery was based on the tumor location or growth type, resulting in good outcomes.

[Anastomotic Recurrence after Curative Resection for Transverse Colon Cancer-A Case Report].

The rate of local and anastomotic recurrence after curative resection for colon cancer is quite low, at 2.1%. We describe an anastomotic recurrence that rapidly increased after transverse colon cancer resection. An 80-year-old man underwent laparoscopic- assisted transverse colon resection with D3 lymph node dissection. The pathological diagnosis was pT4aN1bM0, pStage Ⅲb. We diagnosed the patient with anastomotic recurrence and liver metastasis 4 months after the procedure based on PET-CT findings. Partial colon resection(small intestine and stomach combined)was performed at 6 months after the procedure. The patient's quality of life(QOL)was reduced by complications after the second procedure and continuing with chemotherapy became difficult. Although the prognosis of curative resection of local and anastomotic recurrence after transverse colon cancer surgery can be good, combined resection of an adjacent organ can result in a decline in patient QOL. Surgical intervention should be minimally invasive and neo-adjuvant chemotherapy might offer 1 option.

Photoredox-Catalyzed Site-Selective α-C(sp3 )-H Alkylation of Primary Amine Derivatives.

The synthetic utility of tertiary amines to oxidatively generate α-amino radicals is well established, however, primary amines remain challenging because of competitive side reactions. This report describes the site-selective α-functionalization of primary amine derivatives through the generation of α-amino radical intermediates. Employing visible-light photoredox catalysis, primary sulfonamides are coupled with electron-deficient alkenes to efficiently and mildly construct C-C bonds. Interestingly, a divergence between intermolecular hydrogen-atom transfer (HAT) catalysis and intramolecular [1,5] HAT was observed through precise manipulation of the protecting group. This dichotomy was leveraged to achieve excellent α/δ site-selectivity.

[Local Recurrence of Rectal Cancer under Perineal Skin after Abdominoperineal Resection].

A woman in her early 50s underwent abdominoperineal resection with left lateral lymph node resection for advanced rectal cancer. The pathological diagnosis was RC, RbP, well-differentiated, type 5, 65×47mm, pT3(A), pN0(0/40), M0, pStage Ⅱ. The local recurrence discovered under the perineal skin 2 months later was treated by resecting the tumor and both inguinal lymph nodes. Adjuvant chemotherapy containing UFT plus LV was also initiated for 6 months. She remains free of recurrence 1 year after resection of the local recurrence.

Palladium-Catalyzed Insertion of Isocyanides into the C-S Bonds of Heteroaryl Sulfides.

Insertion of tert-butyl isocyanide into the C(sp2 )-S bonds of heteroaryl sulfides is catalyzed by a palladium diphosphine complex. Thioimidates generated through this reaction could be readily hydrolyzed under acidic conditions to yield the corresponding thioesters, which are of synthetic use. This insertion is useful because starting heteroaryl sulfides were readily prepared by either conventional ways or through sulfur-specific extended Pummerer reactions.

Fractionated stereotactic radiotherapy for metastatic brain tumors that recurred after gamma knife radiosurgery results in acceptable toxicity and favorable local control.

BACKGROUND: To treat local recurrence of brain metastases after gamma knife radiosurgery (GKS), we have used fractionated stereotactic radiotherapy (SRT). The purpose of this study was to evaluate the efficacy and toxicity of SRT in these patients. METHODS: Fifty locally recurrent metastatic brain tumors in 47 patients were treated with SRT. The median prescribed dose of GKS was 20 Gy at the periphery. The median interval between the GKS (the last session in cases in which multiple GKS procedures were performed) and recurrence was 7.5 (range 1-33) months. Several dose-fractionation protocols were used for SRT, depending on the size and location of the tumor and previous GKS dose. The median prescribed dose of the SRT at the isocenter was 30 Gy with a median of ten fractions. RESULTS: Among the 50 lesions treated with SRT, 26 did not recur locally before the patient's death or the last follow-up examination, and 24 recurred locally. The median follow-up period for the surviving patients was 24 months after the first GKS procedure, and the overall survival rate was 80% at 1 year and 57% at 2 years. The median time to local re-recurrence after the SRT (16 months) was significantly longer than the median interval between the last GKS and recurrence (7.5 months; P < 0.001). Only two patients developed ≥grade 2 radiation necrosis. CONCLUSIONS: Stereotactic radiotherapy appeared to be an effective treatment for recurrent metastatic brain tumors and yielded relatively good local control. The associated adverse events were generally acceptable.

[Assessment of Short-Term Outcomes of Laparoscopic-Assisted Distal Gastrectomy in Elderly Patients Using Comorbidities as Predictive Factors].

Laparoscopic-assisted distal gastrectomy(LADG)is a recently developed minimally invasive surgery for management of early gastric cancer. We describe short-term results obtained from a retrospective study of LADG, performed in elderly patients, using comorbidities as predictive factors. We studied 160 patients diagnosed with gastric cancer who underwent LADG between January 2005 and October 2016. We compared 48 patients, aged≥75 years(elder group), with 112 patients, aged <75 years(non-elder group), who underwent LADG. Preoperative physical status was assessed using the American Society of Anesthesiologists physical status(ASA-PS)score, Charlson comorbidity index(CCI), and the prognostic nutritional index (PNI). Demographics of patients, primarily, sex, tumor lesion, and histology did not significantly differ between the groups. However, the mean ASA-PS score and CCI were significantly higher, and the PNI was significantly lower in the elder group. Surgical duration, volume of blood loss, lymph node clearance, and length of postoperative hospital stay did not significantly differ between the groups. Cardiorespiratory and surgical complications developed in 2(4.2%)and 3(2.7%), and in 5(10%) and 12(11%)patients in the elder and non-elder groups, respectively. However, the rates of intra and postoperative complications were not significantly different between them. LADG can be considered a safe and effective minimally invasive surgical procedure for management of early gastric cancer in elderly patients.

[Case Report of Long-Term Survival for Stage IV Advanced Sigmoid Colon Cancer with Para-Aortic Nodes by R0 Resection and Chemotherapy].

The patient was a man in his early 30s. He underwent sigmoidectomy with D3+ #216 for advanced sigmoid colon cancer with metastatic para-aortic lymph nodes. The pathological diagnosis was colon cancer(S), type 2, moderately differentiated, pT4a(SE), pN3(19/33), pM1a(LYM), pStage IV , KRAS wild-type, EGFR(+). He received FOLFOX plus bevacizumab(Bmab) as adjuvant chemotherapy. One year postoperatively, he experienced recurrence as multiple lung metastases. FOLFIRI plus panitumumab, SOX plus Bmab, CapeOX, nivolumab and FOLFIRI plus ramucirumab were then administered. The patient has survived for 4 years and 11 months from operation.

Nickel-Catalyzed Boron Insertion into the C2-O Bond of Benzofurans.

Treatment of benzofurans with bis(pinacolato)diboron and Cs2CO3 under nickel-NHC catalysis resulted in the insertion of a boron atom into the C2-O bond of benzofurans to afford the corresponding oxaborins. The scope of benzofuran substrates is wide, and the reactions proceeded without loss of functional groups such as fluoro, methoxy, and ester that are potentially reactive under nickel catalysis. The boron-inserted products proved to be useful building blocks and subsequently underwent a series of transformations, one of which led to the synthesis of fluorescent π-expanded oxaborins.

Metal-Free Approach to Biaryls from Phenols and Aryl Sulfoxides by Temporarily Sulfur-Tethered Regioselective C-H/C-H Coupling.

We have developed metal-free regiocontrolled dehydrogenative C-H/C-H cross-coupling of aryl sulfoxides with phenols by means of trifluoroacetic anhydride. Because the reaction would proceed through an interrupted Pummerer reaction followed by sulfonium-tethered [3,3]-sigmatropic rearrangement, the C-H/C-H coupling takes place exclusively between the ortho positions of both substrates. Various functional groups including carbonyl, halo, siloxy, and even boryl moieties are compatible. The biaryl products naturally possess hydroxy and sulfanyl groups, which allows the products to be useful synthetic intermediates, as evidenced by the syntheses of π-expanded heteroarenes such as unprecedented 7,12-dioxa[8]helicene.