Efficacy and safety of chemoradiation therapy using one-shot cisplatin via hepatic arterial infusion for advanced hepatocellular carcinoma with major macrovascular invasion: a single-arm retrospective cohort study.

BACKGROUND: Patients with hepatocellular carcinoma (HCC) and macrovascular invasion (MVI) who receive systemic chemotherapy have a poor prognosis. This study aimed to determine if one-shot cisplatin (CDDP) chemotherapy via hepatic arterial infusion (HAI) combined with radiation therapy (RT) prior to systemic chemotherapy could improve the outcomes of these patients. METHODS: This study consisted of 32 HCC patients with the following eligibility criteria: (i) portal vein invasion 3/4 and/or hepatic vein invasion 2/3; (ii) received one-shot CDDP via HAI; (iii) received RT for MVI, (iv) a Child-Pugh score ≤ 7; and (v) an Eastern Clinical Oncology Group Performance Status score of 0 or 1. To determine the therapeutic effect, we collected information on patient characteristics and took contrast-enhanced computed tomography at the start of the therapy and every 2 to 4 months after the start of therapy. We evaluated the overall response of the tumor and tumor thrombosis according to modified Response Evaluation Criteria in Solid Tumors. We assessed patient data using the Mann-Whitney U and Fisher exact tests and evaluated overall survival and progression-free survival using the log-rank test. RESULTS: The overall response rate at the first evaluation performed a median of 1.4 weeks after HAI was 16% for the main intrahepatic tumor and 59% for the MVI. The best responses were the same as those of the first-time responses. The duration of median survival was 8.6 months, and progression-free survival of the main intrahepatic tumor was 3.2 months. Predictive factors for overall survival were the relative tumor volume in the liver and the first therapeutic response of MVI. There were no severe adverse events or radiation-induced hepatic complications. CONCLUSIONS: One-shot CDDP via HAI and RT were well tolerated and showed immediate and favorable control of MVI. Thus, this combination shows potential as a bridging therapy to systemic chemotherapy.

Underestimation of impaired glucose tolerance and usefulness of a continuous glucose monitoring system in chronic liver disease.

BACKGROUND AND AIM: The prevalence of glucose intolerance in chronic liver disease patients is high, but glucose intolerance may be overlooked in a single blood test. The purpose of this study is to evaluate blood glucose variability in patients with chronic liver disease by a continuous glucose monitoring system (CGMS) and to examine the discrepancy between hemoglobin A1c (HbA1c) levels estimated from average blood glucose levels and HbA1c. METHODS: This study included 335 patients with chronic liver disease associated with glucose intolerance. A fasting blood test and 72-h CGMS were performed. The estimated HbA1c was calculated from the average blood glucose level, and the correlation between hepatic functional reserve and blood glucose-related parameters was analyzed. From the obtained data, we created a new formula to calculate HbA1c without using CGMS. RESULTS: As hepatic functional reserve decreased, average blood glucose and insulin resistance increased while HbA1c decreased (P < 0.0001). The discrepancy between the estimated HbA1c calculated from the mean blood glucose level and the serum HbA1c (ΔHbA1c) increased as the liver reserve decreased. Using multiple regression analysis, a formula based on fasting blood glucose, HbA1c, body mass index, albumin, and liver function was constructed, and its validity was demonstrated in a study using a different control group. CONCLUSIONS: Hemoglobin A1c may be underestimated because of decreased hepatic functional reserve. CGMS was useful in assessing accurate glycemic control of blood glucose and in detecting postprandial hyperglycemia and nocturnal hypoglycemia. Patients with chronic hepatic impairment should be corrected for hepatic functional reserve before glycemic control.

Efficacy and Safety of Lenvatinib-Transcatheter Arterial Chemoembolization Sequential Therapy for Patients with Intermediate-Stage Hepatocellular Carcinoma.

INTRODUCTION: We evaluated the efficacy and safety of lenvatinib-transcatheter arterial chemoembolization (LEN-TACE) sequential therapy for patients (n = 88) with intermediate-stage hepatocellular carcinoma (HCC). METHODS: Eighty-eight patients who obtained tumor control by LEN treatment were analyzed; 30 received LEN followed by TACE (LEN-TACE sequential therapy), and 58 received LEN monotherapy. Propensity score matching was performed, and the outcomes of 19 patients in the LEN-TACE group and 19 patients in the LEN-alone group were compared. Objective response rate (ORR), progression-free survival (PFS), overall survival (OS), incidence of adverse events (AEs), and change in albumin-bilirubin (ALBI) score were evaluated. RESULTS: After matching, baseline characteristics were similar between the groups. The ORR was 63.2% with LEN-TACE group and 63.2% with the LEN-alone group. Multivariate analysis showed that addition of TACE during LEN treatment (hazard ratio [HR] 0.264, 95% confidence interval [CI] 0.087-0.802, p = 0.019) and Child-Pugh score 5 (HR 0.223, 95% CI 0.070-0.704, p = 0.011) were the significant factors for PFS. Median PFS was 11.6 months with LEN-TACE and 10.1 months with LEN-alone. The survival rate of the LEN-TACE group was significantly higher than that of the LEN-alone group (median survival time; not reached vs. 16.9 months, p = 0.007). The incidence of common LEN-associated AEs was similar between groups. Although elevated aspartate aminotransferase/alanine aminotransferase and fever were more frequent with LEN-TACE group, these events were manageable. CONCLUSION: For patients with intermediate-stage HCC, LEN-TACE sequential therapy may provide a deep response and favorable prognosis.

Comparison of the Clinical Outcome of Ramucirumab for Unresectable Hepatocellular Carcinoma with That of Prior Tyrosine Kinase Inhibitor Therapy.

INTRODUCTION: The clinical outcome of ramucirumab in multi-molecular targeted agent (MTA) sequential therapy for unresectable hepatocellular carcinoma (u-HCC) was assessed in comparison with that of prior tyrosine kinase inhibitor (TKI) therapy. METHODS: Sixteen patients who received ramucirumab as part of multi-MTA sequential therapy for u-HCC were enrolled in a retrospective, cohort study. Ramucirumab was started as 2nd line in 7 patients, 3rd line in 5 patients, and 4th line in 4 patients. RESULTS: The overall response rate was 6.3%, the disease control rate (DCR) was 50.0%, median progression-free survival was 2.0 months (evaluated by mRECIST), median overall survival (OS) with ramucirumab was 7.9 months, and the median OS from 1st-line therapy was 28.1 months. One month after the start of ramucirumab, α-fetoprotein (AFP) decreased in 6 of 12 cases (50.0%), and the DCR in AFP-decreased cases was 83.3%. The DCR of ramucirumab was 66.7% in cases in which disease control was obtained by prior TKI therapy, whereas it was 0.0% in the cases in which disease control was not obtained by prior TKI therapy. Examining the adverse events, no new safety concerns were confirmed. CONCLUSION: The AFP response to ramucirumab and the treatment response to prior TKI therapy are associated with treatment response to ramucirumab.

Clinical Outcomes of 2nd- and 3rd-Line Regorafenib for Advanced Hepatocellular Carcinoma.

INTRODUCTION: This study compared clinical outcomes of 2nd- and 3rd-line regorafenib in patients with unresectable hepatocellular carcinoma. METHODS: In this retrospective cohort study, 48 patients were treated with regorafenib for unresectable hepatocellular carcinoma. Thirty-five and 13 patients were initiated on 2nd- and 3rd-line therapy, respectively. We assessed the responses to and safety of the therapy. RESULTS: There were no statistically significant differences in clinical characteristics at the start of 2nd- or 3rd-line regorafenib therapy. The overall response rate of 2nd- and 3rd-line regorafenib was 20 and 8%, respectively. The disease control rate was 57 and 54%, respectively. Median overall survival (mOS) from the start of 2nd-line regorafenib was 17.5 months. mOS from the start of 3rd-line regorafenib was not obtained. Median progression-free survival of 2nd- and 3rd-line regorafenib was 4.9 and 2.3 months, respectively. mOS from 1st-line therapy with tyrosine kinase inhibitor plus sorafenib-regorafenib-lenvatinib was 29.5 months; that with lenvatinib-sorafenib-regorafenib was not obtained. Patients on 3rd-line therapy tended to have better Child-Pugh scores and tumor factors at the start of 1st-line therapy than other patients. CONCLUSION: Patients on 2nd- and 3rd-line regorafenib showed favorable responses. Good Child-Pugh scores and tumor factors may be associated with a better response rate and OS.

[A Case of Peritoneal Dissemination of Colorectal Cancer in Which Conversion Surgery Could Be Performed after Reduction with CAPOX/Bevacizumab].

A woman in her 60s underwent lower endoscopy due to a positive fecal occult blood test. A type 2 tumor was found in the cecum, and a biopsy resulted in the diagnosis of adenocarcinoma(tub2). Contrast-enhanced CT showed an enlarged paracolonic lymph node but no distant metastasis, so the patient underwent a laparoscopic-assisted ileocolic resection and D3 lymph node dissection for cecum cancer. The pathology was pT3, pN2b, pM0, pStage Ⅲc, and 12 courses of FOLFOX were administered as adjuvant chemotherapy. Twenty-four months after the completion of adjuvant chemotherapy, an elevated CEA was observed, and a PET-CT was performed, which showed multiple peritoneal disseminated nodules with FDG accumulation. Based on this finding, CAPOX/bevacizumab therapy was introduced, and on completion of 4 courses, the PET-CT showed a decrease in the size of the nodules and the disappearance of FDG accumulation. Based on this, the patient underwent resection. A peritoneal dissemination resection and bilateral ovariectomy were laparoscopically performed, and the patient is currently under observation. In patients with metastatic recurrence of peritoneal dissemination who underwent complete resection, treatment with CAPOX/bevacizumab may allow for disease control and provide a long-term prognosis.

Management and risk factors for incomplete resection associated with jumbo forceps polypectomy for diminutive colorectal polyps: a single-institution retrospective study.

BACKGROUND: Cold forceps polypectomy is simple and widely used in clinical practice. However, there are concerns about the risk of incomplete resection using this technique. In recent years, it has been reported that polypectomy with jumbo forceps (JF) is an effective treatment modality for diminutive polyps (DPs) because JF are able to remove large tissue samples with the combined advantage of a higher complete histological resection rate for DPs than standard forceps. To our knowledge, no studies have evaluated the risk factors for incomplete resection when polypectomy with JF is performed for DPs. METHODS: From among 1129 DPs resected using JF at Hiroshima City Asa Citizens Hospital between November 2015 and December 2016, we retrospectively evaluated the clinical outcomes of 999 tumors with known histopathology and investigated the relationship between incomplete resection and clinicopathological factors. RESULTS: Most lesions [985 (87%)] were low-grade dysplasia and 14 (1%) were high-grade dysplasia. The en bloc resection rate was 92% (918/999) and the histological en bloc resection rate was 78% (777/999). Multivariate analysis showed that the significant independent predictors of incomplete resection were tumor size ≥ 4 mm [odds ratio (OR) 3.8; 95% confidence interval (CI) 2.65-5.37; p < 0.01], non-tangential direction of forceps in relation to the tumor (OR 1.73; 95% CI 1.21-2.45; p < 0.01), and lack of muscularis mucosae in the pathological specimen (OR 15.7; 95% CI 9.16-27.7; p < 0.01). CONCLUSIONS: This study identified significant independent predictors of incomplete resection of DPs which may be helpful when planning polypectomy with JF.

[A case of ruptured posterior superior pancreaticoduodenal artery aneurysm successfully treated by emergency transcatheter embolization].

A man in his 40s with no remarkable past medical history was referred to our hospital with acute exacerbation of nonspecific epigastric pain by another hospital on the morning of the day of presentation. Though vital signs were stable, tenderness and guarding were observed over the entire abdomen. Contrast-enhanced computed tomography (CT) revealed a giant retroperitoneal hematoma due to a ruptured aneurysm close to the superior mesenteric artery. Emergency angiography of the superior mesenteric artery detected a ruptured 2-mm pseudoaneurysm of the posterior superior pancreaticoduodenal artery, for which embolization was immediately performed. The postoperative course was good, with the patient complaining only of transient abdominal pain due to exclusion of the hematoma on hospital day 6. His clinical symptoms disappeared with conservative treatment, and the patient was discharged on hospital day 18. Complete occlusion of the aneurysm and reduction of the hematoma was confirmed on follow-up CT. Pancreaticoduodenal artery aneurysm is an uncommon visceral artery aneurysm, and ruptured aneurysms typically result in fatal hemorrhage and high mortality. We herein report a case of ruptured aneurysm of the posterior pancreaticoduodenal artery where emergency transcatheter arterial embolization was able to save the patient's life. We also review 116 cases of pancreaticoduodenal artery aneurysm reported in Japanese literature.

Deriving theoretical phase locking values of a coupled cortico-thalamic neural mass model using center manifold reduction.

Cognitive functions such as sensory processing and memory processes lead to phase synchronization in the electroencephalogram or local field potential between different brain regions. There are a lot of computational researches deriving phase locking values (PLVs), which are an index of phase synchronization intensity, from neural models. However, these researches derive PLVs numerically. To the best of our knowledge, there have been no reports on the derivation of a theoretical PLV. In this study, we propose an analytical method for deriving theoretical PLVs from a cortico-thalamic neural mass model described by a delay differential equation. First, the model for generating neural signals is transformed into a normal form of the Hopf bifurcation using center manifold reduction. Second, the normal form is transformed into a phase model that is suitable for analyzing synchronization phenomena. Third, the Fokker-Planck equation of the phase model is derived and the phase difference distribution is obtained. Finally, the PLVs are calculated from the stationary distribution of the phase difference. The validity of the proposed method is confirmed via numerical simulations. Furthermore, we apply the proposed method to a working memory process, and discuss the neurophysiological basis behind the phase synchronization phenomenon. The results demonstrate the importance of decreasing the intensity of independent noise during the working memory process. The proposed method will be of great use in various experimental studies and simulations relevant to phase synchronization, because it enables the effect of neurophysiological changes on PLVs to be analyzed from a mathematical perspective.

Thrombolysis, Complete Recanalization, Diffusion Reversal, and Luxury Perfusion in Hyperacute Stroke.

A 59-year old man was admitted to our stroke care unit 1.8 hours after onset of cardioembolic stroke. Administration of issue-plasminogen activator achieved complete recanalization, and his lesion on diffusion-weighted imaging (DWI) disappeared and single photon emission computed tomography showed luxury perfusion. DWI reversal and luxury perfusion were sometimes observed in hyperacute stroke patients, especially timely reperfusion was achieved. However, the relationships between DWI reversal and luxury perfusion were not well known. Transient DWI reversal may be associated with luxury perfusion in patients treated with t-PA, via early complete recanalization achieved by thrombolysis.

Accurate connection strength estimation based on variational bayes for detecting synaptic plasticity.

Connection strength estimation is widely used in detecting the topology of neuronal networks and assessing their synaptic plasticity. A recently proposed model-based method using the leaky integrate-and-fire model neuron estimates membrane potential from spike trains by calculating the maximum a posteriori (MAP) path. We further enhance the MAP path method using variational Bayes and dynamic causal modeling. Several simulations demonstrate that the proposed method can accurately estimate connection strengths with an error ratio of less than 20%. The results suggest that the proposed method can be an effective tool for detecting network structure and synaptic plasticity.

Minimally invasive surgery for esophagogastric junction cancer with Leriche's syndrome-induced ischemic enteritis in the rectum: A case report.

The incidence of esophagogastric junction cancer has been increasing, leading to growing interest in surgical treatment. Leriche syndrome, characterized by occlusion limited to the infrarenal aorta, has not been reported to be associated with ischemic enteritis, and there are no previous reports on the surgical approaches for esophagogastric junction cancer in this disease.We describe the case of a male patient in his fifties with lower abdominal pain and melena who was diagnosed with esophagogastric junction cancer, Leriche syndrome, and ischemic enteritis. Contrast-enhanced computed tomography (CT) showed a hemorrhage from the cancer, occlusion of the abdominal aorta beyond the renal artery branches, and rectal contrast deficiency. Three-dimensional (3D)-CT angiography revealed occlusion from the lumbar artery bifurcation to the distal portions of both common iliac arteries plus numerous collateral pathways, indicating a precarious rectal blood supply. Based on 3D-CT angiography, minimally invasive surgery (MIS) using laparoscopy and thoracoscopy for esophagogastric junction cancer was performed after whole-body control. The patient was discharged without any postoperative complications.Esophagogastric junction cancer with Leriche syndrome can be complicated by ischemic enteritis due to tumor bleeding and fragile collateral pathways. MIS using laparoscopy and thoracoscopy guided by 3D-CT angiography can be safely performed for this disease.

Sodium-glucose cotransporter-2 inhibitors improve FibroScan-aspartate aminotransferase scores in patients with nonalcoholic fatty liver disease complicated by type 2 diabetes.

BACKGROUND AND AIM: Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease caused by excessive lipid accumulation in the liver, and its global incidence is increasing. Sodium-glucose cotransporter-2 inhibitors (SGLT2is) are oral antidiabetes drugs that promote glucose excretion into the urine and have been reported to exert therapeutic effects in NAFLD, but liver stiffness measurements (LSMs) determined by transient elastography are inconsistent. In addition, the effects of SGLT2is on the FibroScan-aspartate aminotransferase (FAST) scores have not been reported. We evaluated the effect of SGLT2is on patients with NAFLD complicated by type 2 diabetes using biochemical tests, transient elastography, and FAST scores. METHODS: Fifty-two patients with type 2 diabetes complicated by NAFLD who started SGLT2i treatment between 2014 and 2020 at our hospital were selected from the database. Pre- and post-treatment serum parameters, transient elastography, and FAST scores were compared. RESULTS: After 48 weeks of SGLT2i treatment, body weight, fasting blood glucose, hemoglobin A1c, AST, alanine aminotransferase, gamma-glutamyltransferase, uric acid, fibrosis-4 index, and AST to platelet ratio index improved. Median LSM decreased from 7.0 kPa to 6.2 kPa ( P  = 0.023) and the median controlled attenuation parameter decreased from 304 dB/m to 283 dB/m ( P  = 0.022). Median FAST score decreased from 0.40 to 0.22 ( P  < 0.001), and the number of cases with a cutoff value of ≥0.35 decreased from 15 to 6 ( P  = 0.001). CONCLUSION: SGLT2i use not only improves weight loss and blood glucose levels but also improves hepatic fibrosis by ameliorating hepatic steatosis and inflammation.

Clinical Outcomes of Switching from Zoledronic Acid to Denosumab for the Management of Severe Bone Metastasis from Hepatocellular Carcinoma: A Single-Center, Open-Label, Prospective Intervention Trial.

Background: Zoledronic acid reduces the risk of bone metastasis, but denosumab is a better option for treating bone metastases. However, few studies have evaluated the use of denosumab to treat bone metastasis originating from hepatocellular carcinoma. This study aimed to assess the clinical outcomes of switching from zoledronic acid to denosumab for treating bone metastasis in patients with hepatocellular carcinoma. Methods: This prospective study enrolled 10 patients with HCC and bone metastases. The levels of type 1 collagen cross-linked N-telopeptide (NTx) and tumor growth remained abnormal in these patients despite administration of zoledronic acid for over 3 months. We switched from zoledronic acid to 120 mg denosumab every 4 weeks and evaluated the clinical outcomes, including changes in the NTx level, pain level, and activities of daily living, as well as adverse events, after each administration. Results: Urinary NTx clearance was normal in all patients. The average urinary NTx clearance increased from 13.2 to 21.2 nmol BCE/nmol ·â€†Cre (P = 0.54) after the switch to denosumab. Serum NTx levels were abnormal in all cases. The serum NTx level decreased from 142 nmol BCE/L to 126 nmol BCE/L (P = 0.56). The answers to questionnaires on pain and activities of daily living did not change significantly. Some patients showed elevated transaminase levels, but this was not due to the drug switch. Conclusion: Switching to denosumab did not show a significant change of the pain and activity of daily living for the patients with severe bone metastasis from hepatocellular carcinoma, in whom the efficacy of zoledronic acid was limited.

Adjoint method provides phase response functions for delay-induced oscillations.

Limit-cycle oscillations induced by time delay are widely observed in various systems, but a systematic phase-reduction theory for them has yet to be developed. Here we present a practical theoretical framework to calculate the phase response function Z(θ), a fundamental quantity for the theory, of delay-induced limit cycles with infinite-dimensional phase space. We show that Z(θ) can be obtained as a zero eigenfunction of the adjoint equation associated with an appropriate bilinear form for the delay differential equations. We confirm the validity of the proposed framework for two biological oscillators and demonstrate that the derived phase equation predicts intriguing multimodal locking behavior.

Multiple paraovarian cysts requiring emergency surgery: A rare clinical finding.

This report presents an unusual case of multiple paraovarian cysts that required emergency surgery due to a paraovarian cyst being entrapped by another paraovarian cyst. Laparoscopic surgery is considered useful for diagnostic and therapeutic purposes and is, therefore, recommended owing to difficulty in differentiating paraovarian cysts from ovarian cysts.

Laparoscopic surgery for a hydrocele of the canal of Nuck with an ovarian tumor: An extremely rare clinical finding.

This clinical image presents an unusual report of simultaneous laparoscopic resection of a hydrocele of the canal of Nuck and an ovarian tumor. Laparoscopic treatment with a proper approach is a useful technique in some cases.

Acute psychiatric symptoms in a young woman with anti-N-methyl D-aspartate receptor encephalitis: A case of successful early diagnosis and therapeutic intervention.

This clinical image presents a report on the diagnosis and treatment of anti-NMDAR encephalitis, a rare disease. This report emphasizes the importance of a differential diagnosis for acute psychiatric symptoms. Accurate and timely diagnosis is critical for the selection and implementation of treatment and for optimal patient outcomes.