Colorectal cancer in adolescent and young adults: epidemiology in Japan and narrative review.

Background and Objective: Although only a small proportion of colorectal cancer (CRC) cases develop in adolescents and young adults (AYAs), its incidence has increased recently. We aimed to conduct a narrative literature review and summarize the epidemiology, clinicopathological features, genetics, and treatments for AYA-CRCs. Methods: We searched the articles published in the PubMed database until November 30, 2022, with keywords, "((adolescent and young adult) OR AYA) AND ((colorectal cancer) OR (colon cancer) OR (rectal cancer))" and "young-onset AND ((colorectal cancer) OR (colon cancer) OR (rectal cancer))". Key Content and Findings: In Japan, the annual incidence of AYA-CRC was approximately 1,200 in the 1970s, but has increased to 2,000 nowadays. An increased incidence of AYA-CRC has also been reported in other countries. AYA-CRC tends to be a more advanced disease at presentation than CRC in older patients, with more adverse histological features and variability in molecular characteristics. Diagnosis of CRC is often delayed in AYAs because they are not invited to undergo cancer screening. Three to five percent of patients with AYA-CRC have hereditary cancer syndromes such as Lynch syndrome and familial adenomatous polyposis (FAP), and a family history should be obtained. Additionally, providing information on fertility preservation and social systems before starting treatment is important for sustainable treatment and life after cancer treatment. Conclusions: The number of AYA-CRC cases is increasing in Japan. Before initiating treatment for AYA-CRC, we should know that these patients may have a hereditary disease and fertility preservation should be explained. More physicians should be aware of the importance of AYA-CRC.

Risk factors of local recurrence following implant-based breast reconstruction in breast cancer patients.

BACKGROUND: The number of patients desiring implant-based breast reconstruction has been increasing. While local recurrence is observed in patients with breast reconstruction, only a few reports have focused on the risk factors for local recurrence and the prognosis after developing local recurrence. METHODS: We analyzed 387 patients who underwent implant-based breast reconstruction during the period from 2004 to 2017 in Hiroshima City Hospital. We retrospectively examined the risk factors for local recurrence and the outcomes of patients developing such recurrence after implant-based breast reconstruction. RESULTS: The median follow-up time was 59 months. The local recurrence rate was 3.1% (n = 12). The most common reason for detecting local recurrence was a palpable mass. Four patients with local recurrence had recurrence involving the skin just above the primary lesion and needle biopsy tract. All patients with local recurrence received surgery and systemic therapy and most patients received radiation therapy, all have remained free of new recurrence to date. Multivariate analysis showed lymphatic vessel invasion (HR, 6.63; 95% CI, 1.40-31.36; p = 0.017) and positive or < 2 mm vertical margin (HR, 9.72; 95%CI, 1.23-77.13; p = 0.047) to be associated with significantly increased risk of local recurrence. CONCLUSIONS: The risk factors for local recurrence following implant-based breast reconstruction were lymphatic vessel invasion and positive or < 2 mm vertical margin. Removal of the skin just above the primary lesion and needle biopsy tract and adjuvant radiation therapy might improve local outcomes. Patients with local recurrence following implant-based breast reconstruction appear to have good outcomes with appropriate treatment.

Nab-Paclitaxel Followed by 5-Fluorouracil, Epirubicin and Cyclophosphamide in Neoadjuvant Chemotherapy for Resectable Breast Cancer: A Phase II Trial.

BACKGROUND: The aim of this phase II study was to evaluate combined nab-paclitaxel (nab-PTX) with sequential anthracycline-based therapy as a neoadjuvant chemotherapy. METHODS: We enrolled 41 patients with advanced breast cancer (stage IIA - IIIC). All patients were to receive three-weekly nab-PTX (260 mg/m2) for four cycles followed by three-weekly 5-fluorouracil, epirubicin and cyclophosphamide (FEC) for four cycles. Trastuzumab administration was permitted in human epidermal growth factor receptor 2 (HER2)-positive patients. RESULTS: The overall pathological complete response (pCR) rate was 24% (10 of 41). In patients with luminal A, luminal B (HER2-), luminal B (HER2+), triple-negative and HER2, the pCR rates were 0% (0/2), 7% (1/14), 42% (3/7), 25% (4/16) and 100% (2/2), respectively. The most significant toxicities of nab-PTX were grade 2/3 peripheral sensory neuropathy (24%) and grade 3/4 neutropenia (26%). Febrile neutropenia was not observed in any patient. The most significant toxicities of FEC were grade 3/4 neutropenia (24%) and grade 3 febrile neutropenia (9%). One patient died of sepsis secondary to pneumonia during FEC treatment. CONCLUSIONS: Neoadjuvant chemotherapy using nab-PTX with trastuzumab every 3 weeks followed by FEC was suitably tolerated and associated with a high pCR rate of 55% for patients with HER2-positive breast cancer.

[Appendiceal Goblet Cell Carcinoid Successfully Treated with Bevacizumab plus mFOLFOX6 Regimen-A Case Report].

A 67-year-old man presented with abdominal distention and vomiting.Computed tomography revealed bowel obstruction due to a cecal tumor.We performed laparoscopic ileocecal resection after decompression with an ileus tube. Intraoperative findings included multiple disseminated nodules on the mesenterium surrounding the cecal tumor.The histopathologic diagnosis was poorly differentiated adenocarcinoma, which consisted of glandular proliferation of atypical epithelial cells and dispersed infiltration of goblet cells. Immunohistochemistry showed positively stained neuroendocrine markers, such as CD56, chromogranin, and synaptophysin.The patient was diagnosed with goblet cell carcinoid of the appendix and treated with combination chemotherapy of bevacizumab, fluorouracil, folinic acid, and oxaliplatin.He remained free from progression for over 1 and half years with this treatment.Subsequent chemotherapy was ineffective, and he passed away.There is no established chemotherapy regimen for goblet cell carcinoid, which has the aspects of both adenocarcinoma and neuroendocrine tumors.However, the present case suggested the efficacy of the mFOLFOX6 regimen in combination with bevacizumab for appendiceal goblet cell carcinoid.

Clinical significance of circulating soluble immune checkpoint proteins in sorafenib-treated patients with advanced hepatocellular carcinoma.

In hepatocellular carcinoma (HCC), the clinical significance of soluble immune checkpoint protein levels as predictors of patient outcomes or therapeutic responses has yet to be defined. This study profiled the baseline levels of sixteen soluble checkpoint proteins and their changes following sorafenib treatment for HCC. Plasma samples were obtained from 53 patients with advanced HCC at baseline, week 1, 2 and 4 of sorafenib treatment and tested the concentrations of 16 soluble checkpoint proteins using multiplexed fluorescent bead-based immunoassays. Multivariate analysis showed high sBTLA levels at baseline were an independent predictor of poor overall survival (p = 0.038). BTLA was highly expressed in T cells and macrophages in peritumoral areas. At week 2, sCD27 levels were decreased compared to baseline. By contrast, the concentrations of most inhibitory proteins, including sBTLA, sLAG-3, sCTLA-4, sPD-1, sCD80, sCD86 and sPD-L1, had significantly increased. The fold-changes of soluble checkpoint receptors and their ligands, including sCTLA-4 with sCD80/sCD86, sPD-1 with sPD-L1; and the fold-changes of sCTLA-4 with sBTLA or sPD-1 were positively correlated. sBTLA may be a good biomarker for predicting overall survival in HCC patients. Sorafenib treatment in patients with advanced HCC revealed dynamic changes of soluble checkpoint protein levels.

Sarcopenia as a risk factor of severe laboratory adverse events in breast cancer patients receiving perioperative epirubicin plus cyclophosphamide therapy.

PURPOSE: Sarcopenia has been reported to be associated with higher mortality and increased toxicity of chemotherapy in breast cancer patients. However, evidence from Asian countries is scarce. Here, we investigated the association between sarcopenia and the frequency of severe laboratory adverse events due to perioperative chemotherapy in Japanese breast cancer patients. METHODS: Eighty-two patients with breast cancer receiving perioperative epirubicin plus cyclophosphamide therapy were evaluated. Skeletal muscle of the cross-sectional area at the third lumbar vertebra was measured by computed tomography, and sarcopenia was defined as skeletal muscle index < 40 cm2/m2. Laboratory toxicity during all cycles of perioperative chemotherapy was assessed. The study endpoint was the frequency of severe (grade 3 or more) laboratory adverse events. RESULTS: Overall, 10 patients (12.2%) were classified as sarcopenic. The frequency of severe laboratory adverse events was 28.0%, and this was significantly higher in sarcopenic patients compared to non-sarcopenic patients (70% vs. 22.2%, odds ratio 7.9 (95% CI, 1.6-52.8), p = 0.004). Neither of body weight, body mass index, area of visceral adipose tissue, subcutaneous adipose tissue, nor skeletal muscle density was significantly associated with the frequency of severe laboratory adverse events. CONCLUSION: Sarcopenia was a significant risk factor of severe laboratory toxicity in breast cancer patients receiving perioperative epirubicin plus cyclophosphamide therapy. This finding raises the potential use of body composition assessment to predict the risk of chemotherapy toxicity and determine an individualized treatment strategy.

Switching to tenofovir disoproxil fumarate vs continuing treatment in patients with chronic hepatitis B who maintain long-term virological response to entecavir therapy: A randomized trial.

No controlled trial in patients with chronic hepatitis B virus (HBV) infection on long-term entecavir (ETV) treatment, comparing switching to tenofovir disoproxil fumarate (TDF) with continuing the therapy, has been reported. Twenty-seven nucleos(t)ide-naïve patients with chronic HBV who underwent ETV therapy for ≥5 years and maintained virological response were included and randomized into two groups: one group continued ETV, and the other switched to TDF, in a 1:2 ratio. The primary endpoint was changed from baseline in serum hepatitis B surface antigen (HBsAg) level at week 48. The baseline characteristics were not different between nineteen patients in the TDF group and eight patients in the ETV group. Mean decreases in HBsAg level at week 48 were 0.023 and 0.042 log10 IU/mL in the TDF and ETV groups, respectively (P = 0.94). The mean drops in hepatitis B core-related antigens were also not different between the TDF and ETV groups at week 48 (P = 0.80). HBV DNA was sustainedly <2.1 log 10 copies/mL in all patients throughout the study period. In contrast, the mean aminotransferase levels were significantly higher in the TDF group than in the ETV group at weeks 12, 24, and 36, although being within the reference range. Estimated glomerular filtration rate was lower in the TDF group than in the ETV group at weeks 24 (P = 0.016) and 48 (P = 0.003). In conclusion, we could not find the effect on reducing HBsAg level by switching to TDF in chronic hepatitis B patients with maintained virological response to ETV for ≥5 years.

Utility of the Absolute Lymphocyte Count and Neutrophil/Lymphocyte Ratio for Predicting Survival in Patients with Metastatic Breast Cancer on Eribulin: A Real-World Observational Study.

INTRODUCTION: Previous studies have suggested that the efficacy of eribulin is influenced by the activity of antitumor immunity of patients. Absolute lymphocyte count (ALC) and the neutrophil/lymphocyte ratio (NLR) are easily available parameters associated with the immunological status of patients. OBJECTIVE: Here we tried to classify patients' immunological status by using the scatter plot of ALC and NLR, and investigated its utility for predicting survival among patients with metastatic breast cancer receiving eribulin. METHODS: The medical records of 125 patients who received eribulin for metastatic breast cancer at our hospital between July 2011 and April 2019 were retrospectively reviewed. Uni- and multivariate analyses were performed to determine the association between baseline ALC/NLR and progression-free survival (PFS)/overall survival (OS). The cutoff values for ALC and NLR were determined using scatter plot analysis. RESULTS: The entire cohort was classified into immunologically favorable (ALC ≥1,500/µL, 30 patients), intermediate (ALC <1,500/µL, NLR <5.0, 76 patients), and unfavorable (NLR ≥5.0, 19 patients) groups. Univariate analysis showed significant differences in PFS and OS between the groups, whereas multivariate analysis revealed that ALC ≥1,500/µL and NLR ≥5.0 were independent predictors of PFS, with adjusted hazard ratios (95% CI) of 0.57 (0.33-0.99) and 1.78 (1.00-3.15), respectively. NLR ≥5.0 was also associated with worse OS (adjusted hazard ratio: 0.55; 95% CI 0.35-0.88; p = 0.013). CONCLUSIONS: Among patients with metastatic breast cancer receiving eribulin, survival outcomes were well stratified according to baseline peripheral blood ALC and NLR. Accordingly, high ALC and NLR can be used as predictive markers for longer disease control and worse survival, respectively.

Changes in plasma interleukin-8 and tumor necrosis factor-α levels during the early treatment period as a predictor of the response to sorafenib in patients with unresectable hepatocellular carcinoma.

PURPOSE: This study aimed to identify a biomarker for predicting the response to sorafenib in patients with hepatocellular carcinoma (HCC). METHODS: Of 100 patients with unresectable HCC who received sorafenib treatment in our institute (Cohort A), 48 had stored plasma samples collected within 28 days before the start of treatment (Cohort B). Concentrations of 18 plasma cytokines were measured in plasma samples using a sandwich immunoassay with multiplexed fluorescent bead-based technology. Among 27 patients with follow-up plasma samples taken at 5-10 days of treatment (Cohort C), changes in the 18 cytokines were also evaluated. RESULTS: In Cohort A, progressive disease (PD) according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST) was associated with poor overall survival by multivariate analysis (p = 0.024). In Cohort B, no significant differences in baseline concentrations of α-fetoprotein, des-γ-carboxy prothrombin, or the 18 cytokines were found between patients with PD and those with stable disease (SD) or partial response (PR). In Cohort C, the increase in interleukin-8 and tumor necrosis factor-α (TNF-α) was significant in the PD group (p = 0.0063 and p < 0.001, respectively) but not in the SD + PR group (p = 0.67 and p = 0.15, respectively). In addition, the fold changes in interleukin-8 and in TNF-α were correlated (p < 0.001, r = 0.67). CONCLUSIONS: Changes in plasma interleukin-8 and TNF-α levels during the first few days could predict the response to sorafenib therapy in HCC patients.

[A Case of HER2-Positive Breast Cancer with Liver Metastases Showing Three Years of Complete Response to Combination Therapy with Trastuzumabplus Pertuzumab].

A 48-year-old woman with severe interstitial pneumonitis was diagnosed with right breast cancer(invasive ductal carcinoma, T1aN1M0, ER+, PgR-, HER2 3+)and underwent modified radical mastectomy.The patient was administered tamoxifen as adjuvant therapy.However, 1 year after the mastectomy, multiple liver metastases were found and the patient received 2 anti-HER2 agents, trastuzumab and pertuzumab.A complete response(CR)was observed with the disappearance of the liver metastases in 7 months.CR was maintained for 2 years after the initiation of treatment, and then, we started trastuzumab monotherapy, which has resulted in long-term disease control.

Hepatitis B virus infection and alcohol consumption.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, and the second most common cause of cancer deaths worldwide. The top three causes of HCC are hepatitis B virus (HBV), hepatitis C virus (HCV), and alcoholic liver disease. Owing to recent advances in direct-acting antiviral agents, HCV can now be eradicated in almost all patients. HBV infection and alcoholic liver disease are expected, therefore, to become the leading causes of HCC in the future. However, the association between alcohol consumption and chronic hepatitis B in the progression of liver disease is less well understood than with chronic hepatitis C. The mechanisms underlying the complex interaction between HBV and alcohol are not fully understood, and enhanced viral replication, increased oxidative stress and a weakened immune response could each play an important role in the development of HCC. It remains controversial whether HBV and alcohol synergistically increase the incidence of HCC. Herein, we review the currently available literature regarding the interaction of HBV infection and alcohol consumption on disease progression.

Development of distance-selective nerve recruitment for subcortical brain mapping by controlling stimulation waveforms.

During brain surgery, it is important to determine the functional brain area and cortico-cortical pathways so as to keep them intact and preserve patients' quality of life. Cortical and subcortical brain mappings are techniques that deliver direct current stimulation to the brain surface and beneath gray matter to identify the brain area and nerve fibers related to higher-order functions. However, because of the non-selective effect of conventional electrical stimulation methods, it has been difficult to obtain precise spatial distribution of nerve fibers in the subcortical region. We investigated the electrical stimulation of subcortical mapping to evaluate axon-to-electrode distance-selectivity. It was clarified that a conventional rectangular biphasic pulse activates axons non-selectively. We propose double exponential waveforms and show that they can recruit targeted fibers and change the location of a target by manipulating stimulus intensity. These results suggest the usefulness of introducing distance-selective stimulation into subcortical brain mapping.

[A case of paralytic ileus associated with varicella zoster virus infection].

A 79-year-old woman with a history of pyothorax was admitted with a 4-day history of abdominal distension. Physical examination revealed marked abdominal distention, absent bowel sounds, and a vesicular rash over the left Th8-10 dermatome. Abdominal radiography showed gaseous distension of the colon and ileum. Colonoscopy excluded any obstructive process of the colon. Laboratory findings yielded positive results for serum IgM and IgG against the varicella zoster virus (VZV) . Paralytic ileus associated with the VZV was therefore diagnosed. The ileus improved after conservative treatment with intravenous acyclovir. Although shingles is frequently encountered, it is a rare cause of paralytic ileus. In the future, the VZV should be considered as one of the causes of paralytic ileus, and complete resolution can be achieved with conservative management.

[A case of primary biliary cirrhosis with systemic lymph node enlargement].

A 40's woman was hospitalized with cervical lymph node enlargement. Laboratory examinations showed elevated serum bile duct enzymes and the presence of anti-mitochondrial antibody. Abdominal ultrasonography and computed tomography showed enlargement of not only perihepatic lymph nodes, but also axillary and cervical lymph nodes. FDG-PET showed intense uptake concordant with these lymph nodes. We performed endoscopic ultrasonographic fine-needle aspiration biopsy of a perihepatic lymph node, but detected no malignant cells. We then performed liver biopsy, and obtained a histological diagnosed primary biliary cirrhosis. Systemic lymph nodes decreased together with serum bile duct enzyme levels during treatment with ursodeoxycholic acid.

[A case of autoimmune pancreatitis with multifocal mass lesions].

We present a case of a 73-year-old man with multifocal autoimmune pancreatitis (AIP) in the pancreatic head and tail, and who had undergone sigmoidectomy and rectectomy 28 months before presenting to our department. Upon presentation, his serum IgG4 level was elevated at 267mg/dl, but tumor marker levels were within normal ranges. CT and MRI showed two localized pancreatic masses with delayed enhancement, but endoscopic retrograde pancreatography revealed neither stenosis nor dilatation of the main pancreatic duct. FDG-PET examination showed intense uptake in regions concordant with both tumors. The possibility of atypical AIP was a concern, but malignant tumor could not be clinically or radiologically excluded. Endoscopic ultrasonographic fine-needle aspiration biopsy was performed, but no malignant cells were detected. The patient underwent subsequent distal pancreatectomy. Histological evaluation of the tumors showed the presence of many IgG4-positive plasma cells without any evidence of malignancy.

Suppression of anodal break excitation by electrical stimulation with down-staircase waveform for distance-selective nerve recruitment.

Electrical nerve stimulation using extracellular electrodes is widely performed in clinical medicine as well as basic medical science. It has been reported that selective recruitment of nerve fibers on the basis of the distance between the electrode and the axon is possible without moving the electrode and only by modifying the waveform of electrical stimulation. However, computer simulations have not reproduced the complete nature of the distance-selectivity of the stimulus owing to the difficulty in numerical analysis. In this paper, we propose a minor modification to the myelinated axon model to overcome this difficulty. We confirm that this modification improves the numerical stability of the simulation and enables us to obtain the spatio-temporal dynamics of axons, including the electrode-to-axon distance-dependency. In addition, we propose a novel stimulation method using a down-staircase waveform for distance-selective nerve recruitment. Simulations confirm that the method works well. We show the spatial distribution of axons activated by the down-staircase stimulation, which would be helpful to determine the stimulation parameters for distance-selective nerve recruitment.

Parameter exploration of staircase-shape extracellular stimulation for targeted stimulation of myelinated axon.

Spatio-temporal dynamics of a mathematical model of myelinated axon in response to staircase-shape extracellular electrical stimulation, which was developed for selective nerve stimulation, is investigated by the computer simulation. It is shown that the response is classified into four types: subthreshold response, cathodic excitation, anodal block and anodal break excitation. Based on the simulation results, simple diagrams representing the response characteristics of the axon are constructed as functions of stimulation parameters and distance between the axon and electrode. The diagram would be useful for determining simulation parameters for dynamic targeted stimulation of myelinated axon.

Increased expression of G alpha q protein in bronchial smooth muscle of mice with allergic bronchial asthma.

In the present study, the change in Gq protein level in bronchial smooth muscle of mice with antigen-induced airway hyperresponsiveness (AHR) was determined. BALB/c mice were actively sensitized and repeatedly challenged with ovalbumin antigen to induce bronchial smooth muscle hyperresponsiveness. The contraction induced by 10 microM AlF4(-) (generated by 10 microM AlCl3 plus 10 mM NaF) of bronchial smooth muscles isolated from the antigen-challenged mice was significantly augmented as compared with that from the control animals. The G alpha q protein level determined by immunoblotting was also significantly increased in bronchial smooth muscles of the antigen-challenged group. Thus, an upregulation of G alpha q protein may be involved in the pathogenesis of bronchial smooth muscle hyperresponsiveness, one of the causes of AHR in asthmatics.

An isocratic HPLC method for the simultaneous determination of novel stable lipophilic ascorbic acid derivatives and their metabolites.

2-O-alpha-D-glucopyranosyl-6-O-hexadecanoyl-L-ascorbic acid (6-sPalm-AA-2G), a novel stable lipophilic ascorbic acid derivative, was hydrolyzed to 2-O-alpha-D-glucopyranosyl-L-ascorbic acid (AA-2G), ascorbyl 6-palmitate (6-sPalm-AA) and ascorbic acid (AA) with alpha-glucosidase and lipase. An HPLC method for the simultaneous determination of AA, AA-2G, 6-sPalm-AA and 6-sPalm-AA-2G was developed using a cyanopropyl column with an isocratic solution of methanol-phosphate buffer (pH 2.1) (65:35, v/v) containing 20mg/l of dithiothreitol at a detection wavelength of 240 nm. The calibration curves were found to be linear in the range of 10-200 microM. Linear regression analysis of the data demonstrated the efficacy of the method in terms of precision and accuracy. This method was satisfactorily applied to the determination of 6-sPalm-AA-2G and its three metabolites in a 6-sPalm-AA-2G solution treated with purified enzymes or a small intestine post-mitochondrial supernatant and to the separation of novel stable lipophilic AA derivatives other than 6-sPalm-AA-2G and their metabolites. AA, AA-2G and other well-known stable AA derivatives, ascorbic acid 2-phosphate and ascorbic acid 2-sulfate, were also separated under the same conditions. The results show that the procedure is rapid and simple and that it can be employed for in vitro metabolic analysis of various AA derivatives.