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Background and Aims: Eribulin is a cytotoxic anti-cancer agent targeting microtubule dynamics, which improves the prognosis of patients with metastatic breast cancer. Preclinical studies have shown that eribulin enhances anti-tumor immunity by inhibiting regulatory T cells and M2 macrophages. Along with advances of immunotherapy for breast cancer, there has been growing interest in such immunologic effects of eribulin. Here we investigated the association between the immunological status of peripheral blood and survival outcomes in patients receiving eribulin for metastatic breast cancer. Methods: Medical records of 125 patients who received eribulin for metastatic breast cancer at Hiroshima City Hiroshima Citizens Hospital between July 2011 and April 2019 were retrospectively reviewed. We collected the data on patients’ baseline characteristics, laboratory tests and clinical courses. Absolute lymphocyte count (ALC) and neutrophil-lymphocyte ratio (NLR) in peripheral blood at the start of treatment with eribulin were calculated, and their association with progression-free survival (PFS) and overall survival (OS) were analyzed with log-rank test. The cutoff values for ALC and NLR were determined based on their distribution in this cohort. Subgroup analyses by breast cancer subtypes were also conducted. Results: The mean age was 57 years (range, 28-88). Eighty (64%) and 14 (11.2%) patients were positive for hormone receptors and HER2 overexpression. One hundred and ten patients (88%) had received one or more lines of chemotherapy for metastatic disease. We divided the entire cohort into three groups, using the cutoff values of 1500 /µL for ALC and 5 for NLR. Accordingly, 30 patients (24%) had favorable immune status (i.e., ALC ≥1500 /µL), whereas immune systems were considered to be suppressed (i.e., NLR ≥5) in 19 patients (15.2%); the rest 76 patients (60.8%) had neutral immune status (i.e., ALC Citation Format: Ayako Ueno, Shoichiro Ohtani, Kensuke Kawasaki, Mitsuya Ito, Takanori Kin, Reina Maeda. Survival benefit of eribulin for metastatic breast cancer depends on absolute lymphocyte count and neutrophil-lymphocyte ratio in peripheral blood [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-10-30.

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/m 2 ) 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. World J Oncol. 2020;11(5):197-203 doi: https://doi.org/10.14740/wjon1333

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 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

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.

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 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.

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. 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

e13082 Background: In a phase 3 trial (Study 301), which compared eribulin and capecitabine for metastatic breast cancer did not show the superiority of one to the other on overall survival. Recently, a post-hoc analysis has revealed that efficacy of eribulin was greater in patients with high levels of absolute lymphocyte count (ALC), probably because the drug has immunologic mechanisms of action. Here we investigated whether the favorable impact of high ALC levels on the efficacy was specific to eribulin or shared with capecitabine. Methods: A total of 275 patients with metastatic breast cancer who were treated with eribulin (n = 125) or capecitabine (n = 150) in our hospital between July 2011–April 2019 were retrospectively analyzed. Progression-free survival (PFS) was compared between patients with higher ALC levels (≥1500/μL) and those with lower ALC levels ( < 1500/μL) in each treatment group. Then, we investigated how hazard ratio (HR) of PFS (eribulin vs. capecitabine) changed when we excluded patients with low ALC levels one by one; a scatter plot was made (X = cut-off value of ALC, Y = adjusted HR). PFS was compared by using the Cox proportional hazards model and covariates included age, hormonal and HER2 status, presence/absence of liver and other visceral metastasis, the number of involved organs and the number of previous chemotherapy regimens. Results: In eribulin group, PFS was significantly better in patients with higher ALC than those with lower ALC (adjusted HR, 0.50 [95% confidence interval (CI), 0.29–0.85]; p = .010). Contrarily, in capecitabine group, PFS was not significantly different between the two groups (adjusted HR, 0.86 [95% CI, 0.58–1.28], p = .456). According to the scatter plot, as the cut-off value of ALC (X) was increased, the hazard ratio of PFS (Y) changed biphasically, being almost flat when X was less than 1500, and a linear decrease when X was 1500 or more. Adjusted HR were (i) 1.07 [95% CI, 0.64–1.82], (ii) 0.79 [95% CI, 0.29–2.11] and (iii) 0.67 [95% CI, 0.18–2.41] when inclusion criteria of patients were (i) ALC ≥1500/μL, (ii) ALC ≥1900/μL and (iii) ALC ≥2200/μL, respectively. Conclusions: The efficacy of eribulin was significantly better in patients with higher ALC levels, whereas that of capecitabine was not significantly different. “The more, the better” relationship between ALC and the efficacy of eribulin (vs. capecitabine) was recognized when ALC was 1500/μL or more.

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.

MRI-guided surgical ablation has been used as a novel technique to achieve minimally invasive glioma resection. In this surgery, low-power thermal energy is supplied via a laser probe, which is inserted into the patients brain to coagulate the tumor region. To position the laser probe precisely, intraoperative MRI is performed. However, MRI images cannot provide suf- �cient details regarding theber tracts. In order for surgeons to know the spatial distribution of subcortical nerve tracts and im- prove safety during surgery, we propose the use of subcortical mapping to support MRI-guided surgical ablation. Conventional electrical stimulation using biphasic rectangular pulses has poor selectivity in nerve recruitment, and precise spatial distribution of nervebers in the subcortical region is difcult to obtain. In this study, we conducted computer simulations to determine which waveform of stimulation results in better spatial selectivity. We used a multi-layer volume conductor model of the human skull and neocortex, in which a mathematical model of a human myelinated nerveber was embedded. We numerically calcu- lated the nerve responses to extracellular stimulation provided by an electrode attached to the laser probe inserted into the white matter. We evaluated the distance and diameter selectivity of a solitary test pulse alone and that of conditioning stimuli consist- ing of a triangular waveform and burst pulses followed by the test pulse. The results showed that the distance and diameter se- lectivity are markedly improved when using conditioning stimuli prior to the test pulse. A mechanism for improvement of selec- tivity can be explained based on the nonlinear dynamic properties at the axonal node. These results suggest that the novel conditioning waveform has the potential to provide detailed information of nerveber tracts to surgeons during MRI-guided sur- gical ablation.

Since the conventional methodof electrical stimulation deliveredusing an extracellular electrode has poor selectivity in terms of nerve fiber type, it is difficult to avoid recruiting antitarget nerve fibers. For example, recruitment of motor fibers by electrical stimulation frequently causes unpleasant symptoms such as pain sensation andnumbness. Many electrical stimulation method s have been proposedto achieve nerve type- specific recruitment based on diameter dependence ; however, experimental evaluations have suggested insufficient selectivity of these methods. In this study, we evaluated diameter-selective recruitment using triple- cuff electrodes, which are composed of a single cathodic cuff electrode sandwiched between two anodic cuff electrodes with various anode-to-cathode distances, De . Using numerical simulations, we determined the stimulation-response characteristics as functions of stimulus intensity (IC) andfiber d iameter D (1-20 μmϕ), when De values were set at infinite and2-mm distances. We observedthat thinner axons were recruitedas IC in- creased and that the thresholds for cathodic excitation and anodal block were dependent on De. The dependence of threshold intensities for cathodic excitation and anodal block on various axon diameters at each De was analyzed . The results confirmedthat thin axons hadhigher threshold s andthat thresholdintensities were nonmonotonically dependent on De . When De was set to infinite distance (corresponding to a single-cuff electrode) and IC was relatively low, only thick axons (≥10 μmϕ ,e . g., Aα fiber group) were selectively recruited. By decreasing De to about 2 mm andincreasing the stimulus intensity, thicker axons were suppressedby anodal block ; in contrast, thinner axons (≤10 μmϕ) became selectively recruited. It was possible to recruit either moderately thick (5-9 μmϕ ,e . g., Aβ fiber group) or thin (2-4 μmϕ ,e . g., Aδ fiber group) axons by scrutinizing the De and IC dependence of nerve recruitment. Axon response was robust against radial position in the nerve bundle. These results suggest that electrical stimulation using a triple-cuff electrode properly adjusted for both stimulus intensity and distance between the anodic and cathodic electrodes has the potential for nerve-specific recruitment within a nerve bundle.

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.

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.

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 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.

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.

The aim of this research is to evaluate vascular access (VA) using shunt sounds. We measured the blood flow volume in the brachial artery (FV) and the resistance index (RI) by using ultrasonic diagnostic equipment, and the frequency and spectrum characteristic to the shunt sounds by using an electronic stethoscope. The subjects were fifty hemodialysis patients who had been treated with arteriovenous fistura (AVF). An electronic stethoscope was used for all the subjects to record the shunt sounds of arteriovenous anastomosis with an 8 kHz sampling frequency for 8 seconds. The digitized sound was analyzed by the Fourier transform, and every 10 Hz spectra were examined for acoustic amplitude and spectral energy distribution. Based on the ultrasonographic data, subjects FV >= 500 mL/min) and II (FV = 0.6). Spectra distribution on frequency bands were compared between two different groups. The spectra in 41–270 Hz were significantly higher in Group I than in Group II. In Group I, the spectra in 111–160Hz were significantly higher than those in other frequency bands. In Group II, the spectra in 121–140 Hz were significantly higher than in the other frequency bands. Comparing Groups A and B, Group A showed a significantly higher spectrum in the 51–270 Hz, and in particular, the spectra of 121–160 Hz showed significantly higher compared with those of the other frequency bands. In group B, spectra of 131–140 Hz showed significantly higher compared with those of the other frequency bands. From these results, shunt sounds acquired in patients with good AVF function (FV >= 500 mL/min or RI = 0.6). It was found that analyzing the amplitude and frequency features of spectra in shunt sounds would be used for identifying FV and RI.

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.

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.

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.

Background It has recently been suggested that RhoA plays an important role in the enhancement of the Ca2+ sensitization of smooth muscle contraction. In the present study, a participation of RhoA-mediated Ca2+ sensitization in the augmented bronchial smooth muscle (BSM) contraction in a murine model of allergic asthma was examined. Methods Ovalbumin (OA)-sensitized BALB/c mice were repeatedly challenged with aerosolized OA and sacrificed 24 hours after the last antigen challenge. The contractility and RhoA protein expression of BSMs were measured by organ-bath technique and immunoblotting, respectively. Results Repeated OA challenge to sensitized mice caused a BSM hyperresponsiveness to acetylcholine (ACh), but not to high K+-depolarization. In α-toxin-permeabilized BSMs, ACh induced a Ca2+ sensitization of contraction, which is sensitive to Clostridium botulinum C3 exoenzyme, indicating that RhoA is implicated in this Ca2+ sensitization. Interestingly, the ACh-induced, RhoA-mediated Ca2+ sensitization was significantly augmented in permeabilized BSMs of OA-challenged mice. Moreover, protein expression of RhoA was significantly increased in the hyperresponsive BSMs. Conclusion These findings suggest that the augmentation of Ca2+ sensitizing effect, probably via an up-regulation of RhoA protein, might be involved in the enhanced BSM contraction in antigen-induced airway hyperresponsiveness.