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Background:Cardiovascular disease is one of the most important problems in long-term follow-up for Noonan syndrome. We examined cardiovascular issues and clinical manifestations, with a focus on the cardiovascular disease and prognosis of patients with Noonan syndrome.Methods:This single-centre study evaluated patients who were clinically and genetically diagnosed with Noonan syndrome.Results:Forty-three patients diagnosed with Noonan syndrome were analysed. The most prevalent responsible mutation was found in PTPN11 (25/43). The second and third most prevalent causative genes were SOS1 (6/43) and RIT1 (5/43), respectively, and 67.4% of genetically diagnosed patients with Noonan syndrome had structural cardiovascular abnormalities. Pulmonary valve stenosis was prevalent in patients with mutations in PTPN11 (8/25), SOS1 (4/6), and RIT1 (4/5). Hypertrophic cardiomyopathy was found in two of three patients with mutations in RAF1. There was no difference in the cardiovascular events or cardiovascular disease prevalence in patients with or without PTPN11 mutations. The proportion of RIT1 mutation-positive patients who underwent intervention due to cardiovascular disease was significantly higher than that of patients with PTPN11 mutations. Patients who underwent any intervention for pulmonary valve stenosis exhibited significantly higher pulmonary flow velocity than patients who did not undergo intervention, when they visited our hospital for the first time. All patients who underwent intervention for pulmonary valve stenosis had a pulmonary flow velocity of more than 3.0 m/s at first visit.Conclusions:These findings suggest that genetic information can provide a clinical prognosis for cardiovascular disease and may be part of genotype-based follow-up in Noonan syndrome.

A 68-year-old male patient with lung adenocarcinoma, who was treated with chemotherapy and immune checkpoint inhibitors (ICIs), developed lymphadenopathy during treatment. His para-aortic lymph nodes increased to 2.0 cm in diameter. Both inguinal lymph nodes were 1.5 cm in diameter, and multiple hepatic masses appeared. After the ICI readministration, both inguinal lymph nodes increased to 2.0 cm in diameter, but the para-aortic lymph nodes and hepatic masses remained. Angioimmunoblastic T-cell lymphoma (AITL) diagnosis was established after the right inguinal lymph node biopsy, which was accompanied by an infiltration of Epstein-Barr virus (EBV)-encoded small ribonucleic acid-positive B-cells. After the ICI discontinuation, the inguinal lymph nodes decreased to 1.5 cm in diameter, but the para-aortic lymph nodes remained, and hepatic masses increased. Hepatic lesions were possibly lung cancer metastasis. The ICI administration and EBV reactivation were potentially associated with AITL development in the present case. The natural shrinkage of lymphoma after the ICI cessation implied the immunological mechanism like that of the methotrexate-related lymphoproliferative disease.

We present a case of a 35-year-old woman with breast cancer in lactation 3 months after childbirth, in which a lactation inhibitor was useful for 18F-FDG PET/CT examination. Via ultrasonography and biopsy with histopathology, we diagnosed the lesion in the upper region of the left breast as invasive ductal carcinoma. She stopped breastfeeding and was administered cabergoline to suppress lactation. Two days after the administration, 18F-FDG PET/CT revealed segmental uptake (10 cm in diameter) and no lactation-related uptakes. Dynamic MRI also revealed a segmental enhancement of the same size as 18F-FDG PET/CT. The lactation inhibitor was useful to delineate the extent of the lesion during the 18F-FDG PET/CT examination.

OBJECTIVEThe pathomechanism of C5 palsy after cervical open-door laminoplasty is unknown despite the relatively common occurrence of this condition postoperatively. The aim of this study was to review clinical and imaging findings in patients with C5 palsy and to propose countermeasures for prevention of this complication.METHODSBetween 2001 and 2018, 326 patients with cervical myelopathy underwent cervical laminoplasty at the authors’ hospital, 10 (3.1%) of whom developed C5 palsy. Clinical features and radiological findings of patients with and without C5 palsy were analyzed.RESULTSIn patients with C5 palsy, the width of the C5 intervertebral foramen was narrower and the position of the bony gutter was wider beyond the medial part of the C5 facet joint. The distance between the lateral side of the spinal cord and bony gutter was significantly greater in patients with C5 palsy. Patient characteristics, disease, cervical alignment, spinal canal expansion rate, anterior protrusion of the C5 superior articular process, high-intensity area in the spinal cord on T2-weighted MR images, posterior shift of the spinal cord, and operative time did not differ significantly between patients with and without C5 palsy.CONCLUSIONSThe position of the bony gutter may have a central role in the pathomechanism of postoperative C5 palsy, especially in patients with a narrow C5 intervertebral foramen. Making an excessively lateral bony gutter might be a cause of C5 nerve root kinking at the intervertebral foramen. To prevent the occurrence of C5 palsy, it is important to confirm the medial line of the facet joint on the preoperative CT scan, and a high-speed burr should be started from inside of the facet joint and manipulated in a direction that allows the ligamentum flavum to be identified.

There has been an increase in the use of extracorporeal membrane oxygenation for severe neonatal cardiac failure. However, the frequency of complications is high, particularly in preterm and low-birth-weight neonates. Herein, we present combination treatment with transcatheter balloon atrioseptostomy and bilateral pulmonary artery banding in a collapsed preterm neonate. This strategy can be an alternative to circulatory support using extracorporeal membrane oxygenation.

Background Treatment-free remission (TFR), the ability to maintain a molecular response (MR), occurs in approximately 50% of patients with chronic myelogenous leukemia (CML) treated with tyrosine kinase inhibitors (TKIs). Methods A multicenter phase 2 trial (Delightedly Overcome CML Expert Stop TKI Trial: DOMEST Trial) was conducted to test the safety and efficacy of discontinuing imatinib. Patients with CML with a sustained MR of 4.0 or MR4.0-equivalent for at least 2 years and confirmed MR4.0 at the beginning of the study were enrolled. In the TFR phase, the international scale (IS) was regularly monitored by IS-PCR testing. Molecular recurrence was defined as the loss of MR4.0. Recurrent patients were immediately treated with dasatinib or other TKIs including imatinib. Results Of 110 enrolled patients, 99 were evaluable. The median time from diagnosis to discontinuation of imatinib was 103 months, and the median duration of imatinib therapy was 100 months. Molecular recurrence-free survival rates were 69.6%, 68.6% and 64.3% at 6, 12, and 24 months, respectively. After discontinuation of imatinib therapy, 26 patients showed molecular recurrence, and 25 re-achieved deep MR after dasatinib treatment. Molecular response MR4.0 was achieved in 23 patients within 6 months and 25 patients within 12 months. Multivariate analysis revealed that a longer time from diagnosis to discontinuation of imatinib therapy (p = 0.0002) and long duration of imatinib therapy (p = 0.0029) predicted a favorable prognosis. Conclusions This DOMEST Trial showed the feasibility of TKI discontinuation in a Japanese clinical setting.

Objectives The aim was to clarify the sensitivity and specificity of diffusion-weighted imaging, as well as of that in combination with magnetic resonance cholangiopancreatography for pancreatic tumor diagnosis in real-world clinical setting. Methods Subjects were 217 consecutive patients who underwent both magnetic resonance imaging and contrast-enhanced ultrasound sonography. Cases positive for a pancreatic tumor were confirmed based on pathological diagnosis, whereas negative cases were defined when no solid pancreatic tumor was detected by contrast-enhanced ultrasound sonography or a solid mass was detected but the diagnosis was ultimately denied based on pathological results. Diffusion-weighted imaging-positive was defined as a case with high signals and magnetic resonance cholangiopancreatography-positive when localized main pancreatic duct stenosis with caudal dilation was detected.We calculated sensitivity and specificity of each modality and those in combination based on sequential use for pancreatic tumor diagnosis. Results Diffusion-weighted imaging showed a sensitivity of 94.4% and specificity of 94.5%, whereas those values for magnetic resonance cholangiopancreatography alone were 83.3% and 99.0%, respectively, and for the modalities in combination were 100% and 94.5%, respectively. Conclusions Diffusion-weighted imaging was more sensitive than magnetic resonance cholangiopancreatography, whereas those used in combination resulted in increased sensitivity.

Glottal incompetence, i.e., reduced ability to produce effective glottal closure, is a problem often associated with aging. The study protocol is presented to determine whether blood substance P (SP) serves as an indicator of glottal closure function among the elderly. SP is involved in the neuromuscular mechanisms of cough; reduced concentration of SP may be a marker for increased risk of aspiration pneumonia. The antihypertensive angiotensin-converting enzyme inhibitor, which also inhibits degradation of SP, has been found to be effective in preventing aspiration pneumonia by strengthening the cough reflex. In this study, we will employ National Hospital Organization self-controlled vocal exercise (NHOEx), which has been shown to improve glottal closure by strengthening the laryngeal adduction muscles. We hypothesize that improved glottal closure by NHOEx may lead to the increase in the plasma concentration of SP, which reflects effective cough reflex. Maximum phonation time (MPT), an indicator of glottal closure, will be measured to assess improvement of glottis-closing function. The study will include 180 patients over 65 years old with dysphonia, dysphagia, or MPT of less than 15 seconds. Based on the speculation that the improved MPT may be associated with changes in SP expression, we will measure the plasma SP before and after 6-month treatment of glottal incompetence using NHOEx. The goal is to verify the reliability of SP as an indicator for glottal closure and swallowing function. Measurement of plasma SP may be helpful for earlier detection of subjects with higher risk of aspiration pneumonia among the elderly.

OBJECTIVE This multicenter cooperative study aimed to analyze the adverse events (AEs) associated with tyrosine kinase inhibitors (TKIs) used as initial treatment for chronic-phase chronic myeloid leukemia (CML-CP) and their impact on outcome. METHODS We retrospectively evaluated 450 patients with CML-CP who received TKIs between 2004 and 2014. RESULTS The 5-year overall survival (OS) and event-free survival (EFS) rates were 95.1% and 89.0%, respectively. Patients with comorbidities (46.4%) and aged ≥60 years (50.4%) at diagnosis had significantly inferior OS to those without comorbidities and aged

There is sometimes controversy over whether or not statistically significant responses produced in carcinogenicity studies have biologically significance. Ambiguous results from our previous two-year oral carcinogenicity study on acotiamide hydrochloride hydrate (acotiamide-HH), a prokinetic drug for functional dyspepsia, in rats made it unclear whether the drug may exhibit uterine carcinogenicity. To check this finding, we performed a second long-term carcinogenicity study using two identical control groups to more accurately evaluate uterine carcinogenesis by considering the incidence of spontaneous neoplasms. Female Fischer 344 rats were divided into three groups: the two control groups (control 1 and 2) were administered vehicle (0.5% w/v methylcellulose) and the acotiamide-HH-treated group was administered 2,000 mg/kg/day of acotiamide-HH by oral gavage for two years. Among all groups, the incidence of endometrial adenocarcinoma (EmA) was highest in the control 2 group, followed by the acotiamide-HH-treated group and the control 1 group. Moreover, acotiamide-HH did not affect the incidence of precursor lesions of EmA. In cases where an ambiguous difference is observed, the use of two control groups allows for a more informed interpretation of the findings in the drug-treated groups. The outcomes in this study strongly support the hypothesis that the increase in EmA in rats treated with acotiamide-HH in our previous study is unrelated to administration of the drug.

Although acotiamide hydrochloride hydrate (acotiamide-HH) has not been reported to have genotoxic findings in any of the genotoxicity studies or treatment-related toxicological findings in reproductive and developmental studies, suspicious uterine tumorigenesis was observed in the results of a long-term rat carcinogenicity study. To clarify the uterine tumorigenesis of acotiamide-HH, we performed a 2-stage uterine carcinogenicity model in the transgenic rasH2 mouse initiated by N-Ethyl-N-nitrosourea (ENU). This model facilitated the short-term detection of uterine carcinogenic potential, and it appears to be a very useful testing method for assessing the safety of chemicals that may affect uterine tumorigenesis. However, there have not been many reports on this model, and accumulation of case studies using this model is recommended to support its usability. In this study, we performed this carcinogenesis model to not only confirm uterine tumorigenesis of acotiamide-HH but also to confirm the reliability of the model. The results of this study revealed that the endometrial adenocarcinoma found in the long-term rat carcinogenicity study possibly arose spontaneously. Also, we confirmed early induction of a uterine tumor as in previous reports and confirmed that 26 weeks is the appropriate treatment period for this rasH2 mouse model according to time-course observations of uterine tumor development.

Cholangiolocellular carcinoma is a minor primary cancerous tumor of the liver and its coexistence with intrahepatic cholangiocarcinoma in the liver is rare. We herein report a case of concurrent cholangiolocellular carcinoma and intrahepatic cholangiocarcinoma in the liver, in addition to a rectal G1 neuroendocrine tumor, a so-called carcinoid. The intrahepatic tumors showed a different uptake in the 18F-fluoro-2-deoxyglucose (FDG) positron-emission tomography (PET)/computed tomography (CT) findings. In addition to conventional dynamic contrast-enhanced CT, we concluded that FDG PET/CT could therefore be a helpful modality to identify the properties of both cholangiolocellular carcinoma and intrahepatic cholangiocarcinoma.

Seroma formation is a relatively rare complication seen after a modified Blalock–Taussig shunt. Herein, we report a rare case of seroma formation on the posterior aspect of the left atrium without it touching the graft, and presenting with shock, due to pulmonary vein compression.

Objectives: To evaluate the effect of a self-controlled vocal exercise in elderly people with glottal closure insufficiency. Design: Parallel-arm, individual randomized controlled trial. Methods: Patients who visited one of 10 medical centers under the National Hospital Organization group in Japan for the first time, aged 60 years or older, complaining of aspiration or hoarseness, and endoscopically confirmed to have glottal closure insufficiency owing to vocal cord atrophy, were enrolled in this study. They were randomly assigned to an intervention or a control group. The patients of the intervention group were given guidance and a DVD about a self-controlled vocal exercise. The maximum phonation time which is a measure of glottal closure was evaluated, and the number of patients who developed pneumonia during the six months was compared between the two groups. Results: Of the 543 patients enrolled in this trial, 259 were allocated into the intervention group and 284 into the control; 60 of the intervention group and 75 of the control were not able to continue the trial. A total of 199 patients (age 73.9 ±7.25 years) in the intervention group and 209 (73.3 ±6.68 years) in the control completed the six-month trial. Intervention of the self-controlled vocal exercise extended the maximum phonation time significantly ( p < 0.001). There were two hospitalizations for pneumonia in the intervention group and 18 in the control group, representing a significant difference ( p < 0.001). Conclusion: The self-controlled vocal exercise allowed patients to achieve vocal cord adduction and improve glottal closure insufficiency, which reduced the rate of hospitalization for pneumonia significantly. Clinical Trial.gov Identifier-UMIN000015567

The gastrointestinal tract is a common site for the occurrence of non-Hodgkin's lymphoma (NHL). NHL with gastrointestinal lesions may lead to clinically relevant intestinal complications such as obstruction, perforation, and exsanguination during the course of the disease. Consequently, patients with NHL are often examined by means of upper and lower gastrointestinal endoscopy at the initial visit. There are no clear guidelines regarding which patients should undergo capsule endoscopy (CE) and balloon enteroscopy for detecting small intestinal lesions. We retrospectively examined the feasibility of detecting small intestinal lesions in NHL using upper and lower gastrointestinal endoscopy. Between January 2007 and October 2015, 198 patients with primary NHL were admitted to our hospital. We collected data from 51 patients with NHL with gastrointestinal lesions diagnosed through upper and lower gastrointestinal endoscopy, CE, or double balloon enteroscopy (DBE). We chosed these cases that gastrointestinal lesions was doubted by an examination for image. Nineteen of these patients presented with lymphoma at the duodenal bulb/descending part when examined by upper gastrointestinal endoscopy and at the distal ileum when examined by lower gastrointestinal endoscopy. Ectopic jejunoileal lymphoma was simultaneously detected in 13 of the 19 patients (68.4%) through the use of CE or DBE. Conversely, of the 32 patients who did not exhibit lesions at the duodenal bulb/descending part or at the distal ileum, 6 patients (18.8%) presented with small intestinal lesions, indicating a smaller percentage compared to the patients with ectopic jejunoileal lymphoma. Based on these findings, a proactive search for small intestinal lesions using CE or DBE is recommended in patients with NHL presenting with lymphoma at the duodenal bulb/descending part or at the distal ileum, as examined using both upper and lower gastrointestinal endoscopy during the initial visit.

A 75-year-old man was admitted to our hospital in May 2016 with progressive shortness of breath. We considered him to be experiencing acute heart failure caused by atrial fibrillation. Contrast-enhanced computed tomography showed a hypodense mass involving the right atrium and left ventricle, pericardial effusion, and lymphadenopathy of the groin. Histological finding from the groin and pericardial effusion analysis showed diffuse large B-cell lymphoma(DLBCL). We thus diagnosed this patient with cardiac tamponade owing to the involvement of the heart by DLBCL. Treatment was initiated with tetrahy- dropyranyldoxorubicin/cyclophosphamide/vincristine/prednisolone(THP-COP)therapy(50% dose)and continuous pericardial drainage. We carefully added rituximab 4 days after monitoring his symptoms and vital signs. There were a few adverse effects, and after treatment, the mass and pericardial effusion disappeared. Subsequently, 8 courses of THP-COP therapy accompanied by rituximab(R-THP-COP)(full dose)were administered, resulting in a complete response.

Cholangiolocellular carcinoma is a minor primary cancerous tumor of the liver and its coexistence with intrahepatic cholangiocarcinoma in the liver is rare. We herein report a case of concurrent cholangiolocellular carcinoma and intrahepatic cholangiocarcinoma in the liver, in addition to a rectal G1 neuroendocrine tumor, a so-called carcinoid. The intrahepatic tumors showed a different uptake in the 18F-fluoro-2-deoxyglucose (FDG) positron-emission tomography (PET)/computed tomography (CT) findings. In addition to conventional dynamic contrast-enhanced CT, we concluded that FDG PET/CT could therefore be a helpful modality to identify the properties of both cholangiolocellular carcinoma and intrahepatic cholangiocarcinoma.

BiRd combination therapy, which comprises clarithromycin(CAM: Biaxin®), lenalidomide(LEN: Revlimid®), and dexamethasone( DEX), is a highly effective treatment for newly diagnosed symptomatic multiple myeloma(MM). However, its efficacy against recurrent myeloma refractory to LEN and DEX combination therapy(Rd therapy)remains unclear. In this study, we retrospectively analyzed the data of 7 patients(4 men and 3 women, median age of 76 years)with MM, who had clarithromycin added to their Rd regimen. In all patients, the starting dose of clarithromycin was 400 mg daily and the median number of prior therapies was 3(range, 1-4). Patients received a median of 9 cycles of Rd(range, 6-27 cycles)for a median duration of 8 months. Then, patients received a median of 14 cycles of BiRd(range 2-36 cycles). One patient showed partial response(PR), which was the best response, while the others showed stable disease(SD). Our results demonstrated that the addition of clarithromycin to Rd could overcome resistance to Rd and lead to durable responses, without exacerbating hematological or non-hematological toxicities. Thus, BiRd therapy may represent a therapeutic option for symptomatic MM resist- ant to Rd therapy.

A 47-year-old man presented at a local ophthalmological hospital with blurred vision. He had been diagnosed with hypertensive retinopathy and renal failure and was referred to our hospital for treatment. A renal biopsy was done to evaluate pathology of high proteinuria, hematuria, and rapidly progressive glomerulonephritis. Blood pressure remained high despite antihypertensive therapy; anemia and thrombocytopenia gradually progressed. Thrombotic microangiopathy (TMA) was suspected based on red blood cell fragmentation due to hemolytic anemia, thrombocytopenia, and renal failure. However, plasma exchange resolved neither thrombocytopenia nor renal failure, and anemia gradually progressed. Backache suddenly developed 13 days later, and CT findings indicated a retroperitoneal hematoma secondary to bleeding from the kidney. Selective renal artery embolization via angiography stopped the bleeding, but the patient went into hemorrhagic shock. Pathological findings on renal biopsy were identical to those in malignant hypertension, namely an edematous membrane lining, thickened arterioles, and stenosis. We diagnosed thrombotic microangiopathy due to malignant hypertension, without decrease in activities of ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 motif) or its antibodies. Renal failure did not improve, and continuous hemodiafiltration was needed. This procedure stabilized blood pressure and improved the TMA.

A 71-year-old woman who had been treated with methotrexate (MTX) and prednisolone for rheumatoid arthritis since 2010 presented with hematuria. Cystitis was diagnosed. Chest and abdominal CT images revealed a bladder tumor, with lung and bilateral adrenal metastases. Transurethral resection of the bladder tumor (TUR-BT) confirmed these findings in September 2014. Histological findings of the bladder included large atypical lymphoid cells indicating diffuse large B-cell lymphoma. After TUR-BT, CT imaging showed that the tumor had shrunk. Still, MTX was continued. She was diagnosed with MTX-related lymphoproliferative disorders in November 2014 and MTX was discontinued. Fluorodeoxyglucose-positron emission tomography on March 2015 showed a complete response.

The prognosis for adult T cell leukemia/lymphoma (ATL) is very poor, and only allogeneic hematopoietic stem cell transplantation (allo-SCT) has been considered to be a curative treatment for ATL. In this study, we retrospectively analyzed data for patients who had received allo-SCT for ATL in Hokkaido, the northernmost island of Japan, to determine prognostic factors. Fifty-six patients with a median age of 57 years received allo-SCT. Twenty-eight (50.0%) patients had acute type and 22 (46.4%) had lymphoma type. Twenty-three (41.1%) patients received allo-SCT in complete remission (CR), whereas the others were in non-CR. Seventeen (30.4%) patients received myeloablative conditioning and the others received reduced-intensity conditioning. With a median follow-up period of 48 months (range, 17 to 134 months), 1-year overall survival (OS) and 5-year OS rates were 55.4% and 46.1%, respectively. The survival curve reached a plateau at 22 months after stem cell transplantation (SCT). Male sex, high level of serum soluble interleukin-2 receptor (sIL-2R) at SCT, and non-CR at SCT were determined to be significant risk factors for OS. A high level of sIL-2R at SCT was a risk factor for poor OS in patients with non-CR at SCT by univariate analysis (P = .02), and it remained significant after adjustment by sex (hazard ratio, 2.73 [95% confidence interval, 1.07 to 7.90]). A high level of sIL-2R at SCT was also determined to be a risk factor for disease progression (P = .02). This region-wide study showed encouraging results for survival after allo-SCT for ATL and demonstrated for the first time that a high level of sIL-2R at SCT predicts worse SCT outcome. (C) 2014 American Society for Blood and Marrow Transplantation.

Positron emission tomography (PET) is widely available and its application with 2-[(18)F] fluoro-2-deoxy-D-glucose ((18)F-FDG) in oncology has become one of the standard imaging modalities in diagnosing and staging of tumors, and monitoring the therapeutic efficacy in hepatic malignancies. Recently, investigators have measured glucose utilization in liver tumors using (18)F-FDG and positron emission tomography/computer tomography (PET/CT) in order to establish a diagnosis of tumors, assess their biologic characteristics and predict therapeutic effects on hepatic malignancies. The PET/CT with (18)F-FDG may further enhance the hepatic malignancy diagnostic algorithm by accurate diagnosis, staging, restaging and evaluating its biological characteristics, which can benefit the patients suffering from primary and metastatic hepatic tumors such as hepatocellular carcinoma (HCC), cholangiocarcinoma (CCC), and metastatic liver tumor.

We have explored the potential of cyclopentyl methyl ether (CPME) as a solvent for radical reactions. Hydrostannation, hydrosilylation, hydrothiolation, and tributyltin hydride mediated reductions were successfully carried out in CPME. GC–MS analysis indicated that CPME degraded into methyl pentanoate, cyclopentanone, 2-cyclopenten-1-ol, and cyclopentanol under thermal radical conditions, albeit only slightly. We also achieved radical-containing one-pot reactions in CPME as a demonstration of its applicability to multi-step reactions.

An 80-year-old man received a diagnosis of anemia and a decreased platelet count from his physician in 2008, and was referred to our department where primary myelofibrosis was diagnosed.The patient was classified into the lower risk group according to the International Prognostic Scoring System(IPSS), and was followed up without treatment.In June 2010, pancytopenia progressed, and the patient was reclassified into the higher risk group.Blood count did not increase with metenolone treatment, but increased with zoledronic acid(ZA)that he started receiving from January 2012. After ZA treatment, circulating levels of vascular endothelial growth factor(VEGF)and transforming growth factor-b(TGF-b)decreased, and bone marrow biopsy showed an absence of reticular fibers and collagen fibers.In the present case, we observed that the blood count increased because of ZA-induced improvements in myelofibrosis.

Muscle cramps are side effects commonly associated with tyrosine kinase inhibitor (TKI) treatment. Patients suffering from muscle cramps are treated with various medications such as calcium, magnesium and vitamin supplements, but these therapies are often ineffective. We report two patients with chronic myelogenous leukemia who developed muscle cramps caused by TKI. These patients were treated successfully with levocarnitine. Both of our cases revealed the beneficial effects of levocarnitine treatment on TKI-induced muscle cramps.

A 75-year-old woman consulted her doctor in January 2014 because of pain in the dorsum of the hands, elbows, shoulders, and knees, bilaterally, and was diagnosed as having remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome. Although the joint pain improved with low-dose prednisolone administration, she was referred to our department in April of 2014 because she had become aware of swelling of the right cervical lymph node. Biopsy of the lymph node demonstrated that she had Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (DLBCL) of the elderly, and colonoscopy revealed early colon cancer. Also, both the lymphoma and colon cancer stained positive for vascular endothelial growth factor (VEGF). Complete remission was achieved after two courses of R-CHOP, and RS3PE syndrome did not relapse. This case suggested the involvement of VEGF produced by EBV-positive DLBCL in the pathogenesis of RS3PE syndrome.

A practical route to 6-bromo-5,7-dihydroxyphthalide 5-methyl ether, a versatile intermediate in the synthesis of hericenones and related bioactive polyphenols, was developed. The synthesis features a combination of tandem Michael addition-Claisen condensation and CuBr 2 -mediated multi-step reactions. With this product in hand, total syntheses of hericenone J and 5′-deoxohericenone C (hericene A) were achieved.

The potential of the oxy-Favorskii rearrangement to form branched cis-fused bicyclic ethers was explored. Both tertiary and quaternary centers were constructed in highly stereospecific manners. Methanol and primary amines were effective nucleophiles for the rearrangement. The total synthesis of (±)-communiol E was achieved based on this method.

Three exterilium larvae (18.2 mm notochord length to 113.3 mm standard length) of an ophidiid, Lamprogrammus shcherbachevi, from the western North Pacific are described. The specimens had a highly specialized morph with a remarkably elongate trailing gut and ventral coracoid process, and many elongate anterior dorsal fin rays, as occur in other exterilium larvae, but were characterized by unique melanophore patterns (a cluster of melanophores on the back of the stalked pectoral fin base, a row of clusters midlaterally on the trunk and caudal region, and further clusters on the trailing gut). Although the largest specimen (113.3 mm standard length, much larger than the previously recorded maximum size of exterilium larvae) retained typical features of the exterilium stage, the ventral coracoid process was significantly reduced in size compared with that of a smaller specimen (37.8 mm standard length). Comparison of the largest specimen with an adult suggests that the anterior dorsal fin rays would disappear during the transformation stage.

A 39-year-old man visited our department complaining of general malaise and appetite loss. He presented with anemia and marked thrombocythemia; his plasma transforming growth factor (TGF)-b concentration was markedly increased and his thrombopoietin (TPO)concentration was decreased. Since the patient's disease had progressed to acute myeloid leukemia (AML) with an increase in the peripheral blast count, he was diagnosed with AML along with t(3;3) (q21;q26.2) through a bone marrow aspiration sample. Remission induction therapy was performed using idarubicin/cytarabine. The patient achieved complete remission. His platelet count returned to the normal range, plasma TGF-b concentration decreased, and serum TPO concentration increased. The patient was treated with azacitidine as post-remission therapy for bone marrow transplantation, following which he underwent allogeneic hematopoietic cell transplantation.

A 75-year-old woman was diagnosed with symptomatic IgG-l multiple myeloma (good-prognosis group) in December 2010. A stringent complete response (sCR) was achieved by using induction therapy with bortezomib (BOR, Velcade®)+ dexamethasone (DEX)(VD) and consolidation therapy with BOR+lenalidomide (LEN, Revlimid®)+DEX(VRD). Although maintenance therapy with Revlimid®+DEX(Rd) was initiated, a pancreatic neuroendocrine tumor was detected in April 2013. Therefore, LEN was discontinued and distal pancreatectomy was performed in September 2013. Because discontinuation of LEN was followed by exacerbation of myeloma, LEN was resumed with the consent of the patient; however, she became resistant to the treatment. The course of this case suggests that some patients must continue to receive LEN even if a sCR is achieved.

We retrospectively investigated treatment outcomes with soluble recombinant thrombomodulin (rTM) for disseminated intravascular coagulation (DIC) associated with hematological malignancies (acute leukemia and malignant lymphoma) at our hospital. After rTM administration, DIC scores improved in 29 of 39 cases with hematological malignancies (74.36%). Although one case with recurrent and refractory APL died due to cerebral bleeding during rTM administration, no bleeding-associated adverse events were observed in the other 38 cases. DIC improvement was augmented in cases with acute leukemia when rTM was introduced in the pre-DIC state. CRP decreased in 26 of 36 cases with hematological malignancies (72.22%) after rTM introduction, and CRP decreased particularly significantly in cases with malignant lymphoma, suggesting rTM to exert anti-inflammatory activity. Taken together, these observations indicate that rTM, which rarely causes bleeding-associated adverse events, is an excellent agent in terms of both efficacy and safety for treating DIC associated with hematological malignancies, and the potential anti-inflammatory activity of this agent was also suggested.

A 62-year-old woman developed B lymphoblastic leukemia (B-ALL) in April 2010, and achieved complete remission after hyper-CVAD/high-dose-MA therapy combined with rituximab. ALL recurred in December 2011, and remission was again achieved with the Japan Adult Leukemia Study Group (JALSG) ALL202 protocol combined with rituximab. Owing to a fever and rash that persisted from July 2012, the patient was examined again. On examination, redness was observed in the pharynx, and poorly defined oval erythemas were seen on the cheeks, posterior region of the neck, and upper arms. Blood test results showed high levels of ferritin, tumor necrosis factor (TNF)-α, an d C-reactive protein (CRP), and mild hepatosplenomegaly was identified on abdominal computed tomography (CT), indicative of an adult-onset Still's disease-like condition. Prednisolone therapy was initiated in August 2012, and remission was achieved. A second recurrence of ALL developed in September 2012, and although remission was again achieved using the JALSG ALL202 protocol, a third recurrence of ALL occurred in April 2013, and the patient could not be saved. In this case, adult-onset Still's disease-like erythema developed during the remission phase of ALL.