A randomized, double-blinded, placebo-controlled, crossover study of the HCN channel blocker ivabradine in a capsaicin-induced pain model in healthy volunteers.

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels have been focused on as a potential therapeutic target for inflammatory and neuropathic pain in rodent models. However, roles of HCN channels in human pain states have been scarcely investigated. We evaluated analgesic effects of 2-day administration of ivabradine, the only clinically available HCN channel blocker, on a capsaicin pain model in a randomized, double-blinded, placebo-controlled, crossover study. Twenty healthy adult subjects (18 males, 2 females) received ivabradine (5-7.5 mg) or a placebo 3 times in 2 days. Then capsaicin (0.5%) was topically applied on the volar forearm for 30 min. The primary outcome was capsaicin-induced spontaneous pain. The secondary outcomes included heat-pain threshold (HPT), flare size, and areas of secondary punctate mechanical hyperalgesia (PMH) and secondary dynamic mechanical allodynia (DMA). There was no significant difference in spontaneous pain (p = 0.7479), HPT (p = 0.7501), area of PMH (p = 0.1052) or flare size (p = 0.5650) at 30 min after capsaicin application between the groups. In contrast, the area of DMA in the ivabradine group was significantly smaller (p < 0.001) than that in the placebo group. HCN channels may be differentially involved in the various pain signal transmission pathways in humans.

Plasma ropivacaine concentration after TAP block in a patient with cardiac and renal failure.

We report a successful ultrasound-guided transversus abdominis plane (TAP) block as an analgesic option for minor abdominal surgery in a 66-year-old patient with cardiac, respiratory, and renal dysfunction caused by primary systemic amyloidosis. Bilateral TAP blocks with 120 mg (1.8 mg/kg) of ropivacaine provided sufficient intra- and postoperative analgesia for insertion of a continuous ambulatory peritoneal dialysis catheter. However, the plasma concentration of ropivacaine reached a maximum of 2.5 µg/mL at 15 minutes after the TAP block, a concentration that was potentially neurotoxic. Although apparent signs of local anesthetic systemic toxicity (LAST) such as convulsion or changes in an electrocardiogram were not observed, the patient became drowsy after the TAP block, which might be one of the mild symptoms of LAST. A TAP block by itself can thus be an anesthetic option for patients undergoing minor abdominal surgery. However, cardiac and renal dysfunction might influence the pharmacokinetics of a local anesthetic used, and attention should be paid to the possibility of LAST even with a low dose of a local anesthetic for patients with cardiac and renal failure.

Gastric cancer initially presenting as bone metastasis: Two case reports and a literature review.

Gastric cancer frequently spreads to the regional lymph nodes, liver and lungs following surgery or late in the clinical course. However, an initial clinical presentation of bone metastasis in gastric cancer patients is relatively rare. The current study presents two cases of gastric cancer diffusely metastasized to the spinal vertebrae and with a single metastasis to the trapezium, respectively. The initial presentations were an increased alkaline phosphatase level without any symptoms associated with bone metastasis in the first case and a swelling in the right carpometacarpal joint of the thumb in the second case. These clinical manifestations are also extremely rare in gastric cancer with bone metastasis. The study emphasizes that a diagnosis of gastric cancer should be considered in patients with increased alkaline phosphatase without clinical symptoms or with a single bone metastasis.

Signet Ring Cell Carcinoma of Unknown Primary Origin Detected Incidentally by Lymph Node Purification for Thyroid Carcinoma.

A 63-year-old woman underwent thyroidectomy for papillary thyroid adenocarcinoma and cervical lymph node resection. Pathological analyses revealed the presence of signet cell carcinoma in a resected lymph node, which were apparently different from the pathological findings of thyroid carcinoma. No evidence of a primary tumor could be found elsewhere despite detailed examinations, including esophagogastroduodenoscopy, colonoscopy, capsule endoscopy, CT scan, and fluorodeoxyglucose-positron emission tomography. Two and half years later, the patient developed multiple bone metastases and the pathological findings confirmed the presence of signet cell carcinoma. The primary origin remained undetermined. Metastatic signet ring cell carcinoma of unknown primary origin is extremely rare.

Successful and long-term response to trastuzumab plus paclitaxel combination therapy in human epidermal growth factor receptor 2-positive extramammary Paget's disease: A case report and review of the literature.

A 58-year-old woman with a histologically confirmed diagnosis of vulvar extramammary Paget's disease (EMPD) was referred to our hospital due to locally advanced and relapsed EMPD. The patient had undergone surgical resection three times for relapsed vulvar EMPD over a period of 12 years, but developed locally advanced and unresectable EMPD. As pathological examination indicated that the lesion was positive for human epidermal growth factor receptor 2 (HER2) on immunohistochemical staining, the patient was treated with trastuzumab plus paclitaxel. The primary tumor mass and lymph node metastasis regressed successfully with combined trastuzumab and paclitaxel therapy, and the disease has been stable for >2 years after the initiation of treatment. These observations suggest that HER2 status must be determined in patients with advanced and/or metastatic extramammary Paget's disease and therapy with HER2 inhibitors should be considered as an option for the treatment of HER2-positive EMPD.

Relapsed and unresectable inflammatory myofibroblastic tumor responded to chemotherapy: A case report and review of the literature.

A 63-year-old female patient who had undergone cholecystectomy for inflammatory myofibroblastic tumor (IMT) in the gallbladder was referred to our hospital. The patient's disease relapsed, involving the pancreas, and was diagnosed as inoperable IMT 13 months after the cholecystectomy. The patient failed to respond to steroid and non-steroidal anti-inflammatory drug therapy, but subsequently exhibited a good response to vinorelbine and methotrexate combination chemotherapy. Little information is currently available on the efficacy of chemotherapy for adult-onset IMT. The present case suggests that chemotherapy with vinorelbine and methotrexate is a viable therapeutic option for adult patients with unresectable IMT.

Plasma L-carnitine levels in terminally ill cancer patients receiving only palliative care.

BACKGROUND: Several studies indicated that plasma L-carnitine (LC) levels are significantly decreased during chemotherapy or chemoradiation and that LC supplementation can improve the fatigue score in some cancer patients. However, the LC levels in end-stage cancer patients treated only with palliative care remained unclear. The present study was performed to examine the plasma LC levels of terminally ill and hospitalized patients. METHODS: Twenty-one terminally ill cancer patients in our hospital, with expected survival of several months, were enrolled in the present study. Blood samples were taken for measurement of total, free, and acyl-LC. These values were compared with those in 22 chemo-naive cancer patients scheduled to receive cisplatin-containing chemotherapy as first-line therapy. We examined the relationships with body mass index, albumin and CRP levels, the presence of general fatigue, and body weight loss. RESULTS: Median survival in terminally ill cancer patients after enrollment was 38.5 days. Plasma concentrations of total, free, and acyl-LC in terminally ill cancer patients were 59.5±16.0, 46.1±14.2, and 13.4±5.9 µmol/L, respectively. These values were not significantly different from those in chemo-naive patients (58.3±18.1, 48.7±16.3, and 9.6±3.3 µmol/L, respectively). In addition, plasma LC levels in terminally ill patients showed no correlations with albumin or CRP values nor with other clinical parameters, such as fatigue or body weight loss. CONCLUSIONS: The present study suggested that plasma LC levels remain normal and its deficiency is not always common even in terminally ill and hospitalized palliative cancer patients.

Dynamics of L-Carnitine in Plasma and Urine in Patients Undergoing Cisplatin Chemotherapy.

BACKGROUND AND AIMS: Several studies have indicated that cisplatin (cis-diamminedichloroplatinum II; CDDP) causes urinary excretion of L-carnitine (LC). However, the underlying cofactors affecting the increased urinary excretion remain unclear. The present study was performed to evaluate the dynamics of LC in plasma and urine after CDDP chemotherapy and to examine the relations with clinical parameters, such as gender, body mass index (BMI), and renal function. METHODS: Twenty-two patients treated with CDDP therapy were selected. Blood and urine samples were taken from patients before starting CDDP treatment (day 0), on the next day (day 1), and on the seventh day (day 7). We measured plasma and urine concentrations of total, free, and acyl-LC, and examined the relationships with gender, age, treatment cycle, skeletal muscle mass, BMI, glomerular filtration rate, and change in creatinine concentration after CDDP administration. RESULTS: Both urinary and plasma concentrations of 3 types of LC increased markedly on day 1 and subsequently reverted to the pre-CDDP level on day 7. There was a positive correlation between the % changes in plasma and urine LC (correlation coefficient 0.59, p = 0.003) on day 1, but no significant relations were seen in other clinical parameters. CONCLUSIONS: CDDP transiently increased plasma LC levels. The mechanism seemed to involve recruitment for marked urinary loss of LC. However, these changes in plasma and urinary LC levels were not related to clinical factors, suggesting that the dynamics of LC were independent of preexisting physical parameters.

Effectiveness of Imatinib Mesylate Treatment in a Patient with Dermatofibrosarcoma Protuberans with Pulmonary and Pancreatic Metastases.

We herein encountered a case of abdominal wall dermatofibrosarcoma protuberans (DFSP) that developed pulmonary and pancreatic metastases 5 years after complete resection. Because specific rearrangements of the platelet-derived growth factor beta (PDGFB) locus by a novel fluorescence in situ hybridization method was detected, the patient was treated with imatinib mesylate at 400 mg/day. A partial response was achieved by imatinib without any specific toxicity. Although metastatic DFSP is an extremely rare disease, an evaluation of PDGFB fusion is essential and imatinib mesylate should be considered as an optimal therapeutic choice in patients with metastatic or locally advanced DFSP.

Effectiveness of subarachnoid drug infusion for pediatric tumor-related pain.

Although the effectiveness of subarachnoid continuous drug infusion has been established in cancer pain management, its clinical use in children is rare. A 14-year-old girl with neurofibromatosis type I complained of right leg pain stemming from a growing tumor on her right buttock. Continuous and breakthrough right leg pain were unbearable, even at high doses of systemic opioids that caused severe constipation and deep sedation. Subsequent continuous infusion of bupivacaine and morphine through a subarachnoid catheter effectively relieved the girl's pain. The corresponding decrease in systemic opioid also improved her activities of daily living. The patient eventually died of cachexia due to the rapidly growing buttock lesion that was pathologically confirmed post-mortem as a malignant peripheral nerve sheath tumor. Subarachnoid continuous drug infusion may be very useful in controlling severe pain with few side-effects, even in the field of pediatric palliative care.

Alectinib-Induced Alopecia in a Patient with Anaplastic Lymphoma Kinase-Positive Non-Small Cell Lung Cancer.

Alectinib, a novel alternative anaplastic lymphoma kinase (ALK) inhibitor, is highly effective against ALK-positive non-small cell lung cancer (NSCLC) and is well tolerated. Molecular targeted agents generally have little contribution to alopecia. We encountered a case of alopecia that developed gradually over 2 months after initiation of alectinib administration for the treatment of ALK-positive NSCLC. The patient had no history of alopecia in previous treatments of cisplatin + pemetrexed and crizotinib. The present case indicates that alopecia should be taken into consideration as toxicity during alectinib treatment, which could adversely affect the psychological and emotional condition and quality of life even in patients treated with specific molecular targeted agents.

[Palliative Care with Regional Alliance by a University Hospital].

In this chapter, we described what the palliative care in the university hospital is doing; the role of the palliative care doctors in the university hospital, how should we consider the palliative care as a sub-speciality for anesthesiologists in the university hospital, how should we act to make the palliative care in the university hospital cooperating with community and what kind of task should anesthesiologists do cooperating with the community. In Japan, the aging of the society will be more ac- celerated in future, and our medical system for the home care and the out-of-hospital terminal care will be revised. Therefore it is necessary for the university hospitals to lead the preparation of the palliative care as a part of the community combined care system.

Opioid withdrawal presenting only nausea during tapering of oxycodone after celiac plexus block: a case report.

Celiac plexus block (CPB) is an effective treatment for patients suffering pain. CPB may allow for a reduction in opioid dosage, and may alleviate some of the unwanted side effects of these drugs. However, there is a substantial risk of withdrawal symptoms after reduction of opioid dose. We describe a case of pancreatic cancer developing opioid withdrawal after CPB, who presented only nausea. A 70-year-old man was referred to our hospital due to severe pancreatic cancer pain. He was administered oxycodone (oxycontin®) at 240 mg per day, and presented nausea and anorexia as side effects. CPB was performed due to insufficient pain relief. His pain disappeared on the same day as treatment. Oxycodone was reduced to 160 mg/day, and further reduced two days later to 80 mg/day. However, he complained of more severe nausea and loss of appetite even after tapering of oxycodone. Physical examination, blood chemistry examination, and brain computed tomography (CT) showed no abnormalities. Administration of fast-release oxycodone (Oxinome®) at a dose of 10 mg immediately improved his nausea. There have been no previous reports of nausea as the sole symptom of opioid withdrawal. The present case indicates that unless opioid side effects improve after dosage reduction, the possibility that they may be withdrawal symptoms should also be considered.

Two Cases of Thymic Carcinoma Initially Presenting as Bone Metastasis: A Clinical Report and the Usefulness of CD5 Immunohistochemistry for Assessing Bone Lesions.

Thymic carcinoma frequently spreads to the pleural space, regional lymph nodes, liver and lungs. However, an initial clinical presentation involving spinal or multiple bone metastases in patients with thymic carcinoma is extremely rare. We experienced two cases of thymic carcinoma that initially presented with spinal compression and severe pain due to multiple bone metastases, respectively. Both patients were histologically diagnosed with metastatic thymic squamous cell carcinoma based on the findings of specimens resected from the metastatic bone lesions. We herein describe the clinical courses of these cases and review the characteristics of bone metastasis of thymic carcinoma.

Transversus abdominis plane block with 0.25 % levobupivacaine: a prospective, randomized, double-blinded clinical study.

PURPOSE: Because blood concentrations of local anesthetics sometimes reach toxic levels after transversus abdominis plane (TAP) block, reduction of the dose has been necessary to reduce the risk of systemic toxicity. We therefore investigated the effects of TAP block with 0.25 % levobupivacaine (100 mg) on postoperative pain and measured its plasma concentration after gynecological surgery. METHODS: Forty women undergoing elective open gynecological surgery were randomized to receive bilateral TAP block with 20 ml 0.25 % levobupivacaine on each side (TAP group) or not (non-TAP group) before surgery. Postoperative pain was treated with intravenous patient-controlled analgesia by use of morphine. Patients were evaluated 3 and 24 h after the end of surgery. Visual analog scale (VAS) for pain at rest and with movement, and morphine consumption were recorded. Plasma concentrations of levobupivacaine after TAP block were measured. RESULTS: Three hours after surgery, total morphine consumption was significantly lower in the TAP group (2.8 ± 1.6 mg) than in the non-TAP group (6.4 ± 4.8 mg, P = 0.03). There were no significant differences between VAS in the two groups. Mean plasma concentration of levobupivacaine peaked 10 min after TAP block (0.99 ± 0.43 µg/ml), and the highest concentration was 1.99 µg/ml. CONCLUSION: TAP block with 100 mg levobupivacaine is a safe and efficacious multimodal analgesic regimen for postoperative pain after open gynecological surgery.

Successful treatment of crizotinib-induced dysgeusia by switching to alectinib in ALK-positive non-small cell lung cancer.

We describe a case of dysgeusia that developed gradually over one week after initiation of crizotinib administration for treatment of ALK-positive non-small cell lung cancer, necessitating discontinuation of the agent. The symptom was accompanied by progressive loss in appetite and body weight. Alectinib, a novel alternative ALK inhibitor, was administered and has been successfully continued without any toxicity, including dysgeusia. The present case indicates that dysgeusia is an important toxicity associated with crizotinib, which could adversely affect nutritional condition and quality of life. We describe the clinical course and present a review of crizotinib-induced dysgeusia.

Successful salvage chemotherapy with amrubicin for invasive thymoma associated with myasthenia gravis.

Anthracycline-based regimens with cisplatin have been commonly used for inoperable and relapsed thymoma. However, little information is available regarding the usefulness of salvage chemotherapy. Here, we describe a case of invasive thymoma associated with myasthenia gravis that showed a marked response to third-line chemotherapy, with single-agent amrubicin, a synthetic anthracycline analog and potent deoxyribonucleic acid topoisomerase II inhibitor. Amrubicin appears to have significant activity against invasive thymoma.

[Case of parturient who underwent resection of a spinal Tumor].

Spinal tumors are rare in pregnancy, but they cause a serious problem in terms of continuing pregnancy. Here, we present a parturient with severe lumbago who underwent resection of a spinal tumor. A 42-year-old parturient at 26 weeks of gestation presented with acute onset of severe pain in the lumbar region and lower extremities. Magnetic resonance imaging revealed an intraspinal tumor from L4 to L5. Although sciatic nerve block and epidural anesthesia were performed to relieve the pain, their analgesic effects were insufficient. Since the continuation of pregnancy was difficult because of the severe pain, she was scheduled for the resection of the tumor under general anesthesia at 28 weeks gestation. Fetal heart monitoring was used to evaluate abnormal heart rate patterns in the operating room. In order to avoid a decrease in uteroplacental blood flow, the intraoperative systolic blood pressure was maintained at 100 mmHg or more and end-tidal carbon dioxide was maintained at 35-40 mmHg. She was placed on left lateral position to avoid aortocaval compression, and surgery was uneventfully completed. The pain was relieved after surgery, and the parturient could continue the pregnancy. She under- went cesarean section at 40 weeks of gestation, and gave birth to a healthy baby.

[Combined spinal and epidural anesthesia for cesarean delivery in a patient with a cervical fracture at C2].

There are only a few reports on cesarean section in a patient with cervical fracture without spinal cord injury (SCI). Such patients have high risks for deterioration of SCI following general or regional anesthesia. Here, we present a patient with a fracture of C2 vertebra who underwent cesarean section safely under combined spinal and epidural anesthesia(CSEA). A 30-year-old woman had a fracture of the C2 cervical vertebra (Hangman's fracture) due to a traffic accident at 34 weeks of gestation. Conservative immobilization of the head and neck was done with a neck collar (Philadelphia brace) in order to prevent subsequent SCI after the spine injury. Pre-viability amniorrhexis was seen at 37 weeks' gestation, and an emergency cesarean section was scheduled under combined epidural and spinal anesthesia (CSEA). Her neck and head were carefully fixed before, during and after surgery in order to prevent subsequent SCI. As a result, cesarean section under CSEA was successfully performed in the patient without any deterioration of the spine and/or SCI.

Efficacy of erlotinib plus concurrent whole-brain radiation therapy for patients with brain metastases from non-small cell lung cancer.

Treatment and control of brain metastases are important in patients with non-small cell lung cancer (NSCLC). Whole brain radiation therapy (WBRT) has a major role in the management of brain metastasis. Recently, efficacy erlotinib plus concurrent WBRT for patients with brain metastases from NSCLC was reported. Herein, we discussed the results and commented the clinical matters in future.