Nucleic acid-triggered tumoral immunity propagates pH-selective therapeutic antibodies through tumor-driven epitope spreading.

Important roles of humoral tumor immunity are often pointed out; however, precise profiles of dominant antigens and developmental mechanisms remain elusive. We systematically investigated the humoral antigens of dominant intratumor immunoglobulin clones found in human cancers. We found that approximately half of the corresponding antigens were restricted to strongly and densely negatively charged polymers, resulting in simultaneous reactivities of the antibodies to both densely sulfated glycosaminoglycans (dsGAGs) and nucleic acids (NAs). These anti-dsGAG/NA antibodies matured and expanded via intratumoral immunological driving force of innate immunity via NAs. These human cancer-derived antibodies exhibited acidic pH-selective affinity across both antigens and showed specific reactivity to diverse spectrums of human tumor cells. The antibody-drug conjugate exerted therapeutic effects against multiple cancers in vivo by targeting cell surface dsGAG antigens. This study reveals that intratumoral immunological reactions propagate tumor-oriented immunoglobulin clones and demonstrates a new therapeutic modality for the universal treatment of human malignancies.

The Kelch repeat protein KLHDC10 regulates oxidative stress-induced ASK1 activation by suppressing PP5.

Reactive oxygen species (ROS)-induced activation of Apoptosis signal-regulating kinase 1 (ASK1) plays crucial roles in oxidative stress-mediated cell death through the activation of the JNK and p38 MAPK pathways. However, the regulatory mechanism of ASK1 in the oxidative stress response remains to be elucidated. Here, we identified the kelch repeat protein, Slim, as an activator of ASK1 through a Drosophila misexpression screen. We also performed a proteomics screen and revealed that Kelch domain containing 10 (KLHDC10), a mammalian ortholog of Slim, interacted with Protein phosphatase 5 (PP5), which has been shown to inactivate ASK1 in response to ROS. KLHDC10 bound to the phosphatase domain of PP5 and suppressed its phosphatase activity. Moreover, KLHDC10 was required for H(2)O(2)-induced sustained activation of ASK1 and cell death in Neuro2A cells. These findings suggest that Slim/KLHDC10 is an activator of ASK1, contributing to oxidative stress-induced cell death through the suppression of PP5.

[Primary Lung Cancer Associated with Dilated Phase of Hypertrophic Cardiomyopathy;Report of a Case].

A 66-year-old man diagnosed as dilated phase of hypertrophic cardiomyopathy (D-HCM) was pointed out an abnormal shadow on routine chest radiography. The patient had past medical history of hypertension, congestive heart failure and chronic obstructive pulmonary disease. The computed tomography showed a 3.8 cm-sized tumor in the left lower lobe of the lung, and histopathological examination revealed squamous cell carcinoma (cT2aN0-1M0, cStage I B-II A). Cardiosonography showed diffuse hypokinesis from basal to mid area, and ejection fraction was 36.3%. Sporadic ventricular premature contraction was seen by the Holter electrocardiogram. The patient underwent left lower lobectomy with node lymph node dissection (ND1b). The circulatory condition of the patient was stable during surgery. After surgery, careful management of electrolytes and fluid infusion, and the regular medication was started again on the next day of surgery.

[Tension Pneumothorax Developing Hemothorax after Chest Tube Drainage].

A 61-year-old man visited a physician complaining of progressive chest pain and dyspnea. The chest radiography showed complete collapse of the right lung suggesting tension pneumothorax. The patient was transferred to our hospital. A small amount of the right pleural effusion was also seen in addition to pulmonary collapse on the chest radiography. Chest drainage was performed, and continuous air leakage was seen. At 2 hours later, air leakage was disappeared but the bloody effusion was noted. The chest radiography revealed massive effusion and the enhanced computed tomography showed active bleeding. The emergency surgery was conducted. The bleeding point was a ruptured vessel between the apical parietal pleura and the pulmonary bulla. Hemostasis and the resection of the bullae was performed. Careful observation after chest drainage is necessary to prepare unexpected hemothorax in case of tension pneumothorax with pleural effusion.

Cannulation needle-induced anterior wall tenting of internal jugular vein causing posterior wall penetration.

Unintentional posterior venous wall penetration during internal jugular vein (IJV) cannulation may cause critical arterial injuries in spite of ultrasound guidance. We aimed to evaluate whether small venous diameter and anterior venous wall tenting by a needle would be associated with posterior venous wall penetration, and to seek factors related to the venous wall tenting. We conducted a retrospective review in patients who underwent IJV cannulation. Using an ultrasound view obtained when puncturing, venous diameter, venous wall thickness, anterior venous wall tenting length, and needle angle were measured, and posterior venous wall penetration was determined. Eleven cannulations in 56 patients were assigned to posterior venous wall penetration. Small venous diameter (p = 0.004), and long anterior venous wall tenting (p = 0.007) were associated with posterior venous wall penetration. The longer anterior venous tenting would be expected with reducing needle angle (p = 0.004) or increasing anterior venous wall thickness (p = 0.006). In conclusion, small IJV and anterior venous wall tenting lead to posterior venous wall penetration. Anterior venous wall tenting is longer with reducing needle angle, or increasing the anterior venous wall thickness.

[Results of non-rigid prosthetic reconstruction with expanded polytetrafluoro-ethylene( ePTFE) soft tissue patch following chest wall resection for malignant tumors].

Twenty patients underwent chest wall reconstruction using expanded polytetrafluoroethylene(ePTFE) soft tissue patch following resection between June 1996 and December 2012. The patients included 15 men and 5 women, aged 18 to 80 years. The indications for resection included 4 primary tumors, 8 metastatic tumors, and 8 infiltrating tumors. The lesions were located anteriorly in 10 patients, laterally in 5 patients and posteriorly in 5 patients. Skeletal resection involved an average of 2 ribs in 19 patients, and a partial sternectomy in 1 patient. The size of chest wall defects ranged from 20 to 210 cm2( mean, 69.8 cm2). Lung resection was performed in 7 patients included a wedge resection, 5 lobectomy, and a bilobectomy. Chest wall defects were closed primarily with ePTFE soft tissue patch. There were no critical complications or postoperative mortalities. The mean follow-up in all patients is 72.7 months. Recurrence of malignancy occurred in 10 patients included a local recurrence in 1 patient, and metastases in 9 patients. The overall postoperative 5-year survival rate is 61.0%. Non-rigid prosthetic reconstruction with ePTFE soft tissue patch provides satisfactory outcome. New prosthetic materials have to be examined whether they are superior to ePTFE soft tissue patch.

[Hemopneumothorax after thoracic sympathetic nerve block; report of a case].

A 72-year-old man, who had been treated pneumothorax 50 years ago, visited a physician complaining of dyspnea after thoracic sympathetic nerve block for postherpetic neuralgia. The patient was diagnosed as pneumothorax, and was consulted to our hospital. Clinical sign and the chest radiography suggested tension hemopneumothorax, and the chest drainage was immediately performed. Although bloody fluid of 1,100 ml was initially drained, no further increase was noted. The patient was discharged on the 21st hospital day.

p38 MAPKs regulate the expression of genes in the dopamine synthesis pathway through phosphorylation of NR4A nuclear receptors.

In Drosophila, the melanization reaction is an important defense mechanism against injury and invasion of microorganisms. Drosophila tyrosine hydroxylase (TH, also known as Pale) and dopa decarboxylase (Ddc), key enzymes in the dopamine synthesis pathway, underlie the melanin synthesis by providing the melanin precursors dopa and dopamine, respectively. It has been shown that expression of Drosophila TH and Ddc is induced in various physiological and pathological conditions, including bacterial challenge; however, the mechanism involved has not been fully elucidated. Here, we show that ectopic activation of p38 MAPK induces TH and Ddc expression, leading to upregulation of melanization in the Drosophila cuticle. This p38-dependent melanization was attenuated by knockdown of TH and Ddc, as well as by that of Drosophila HR38, a member of the NR4A family of nuclear receptors. In mammalian cells, p38 phosphorylated mammalian NR4As and Drosophila HR38 and potentiated these NR4As to transactivate a promoter containing NR4A-binding elements, with this transactivation being, at least in part, dependent on the phosphorylation. This suggests an evolutionarily conserved role for p38 MAPKs in the regulation of NR4As. Thus, p38-regulated gene induction through NR4As appears to function in the dopamine synthesis pathway and may be involved in immune and stress responses.

[Elderly Bochdalek hernia found out by intestinal obstruction].

A 78-year-old man, who had been pointed out elevation of the diaphragm by chest radiography, visited local physician complaining of abdominal pain and vomiting. He was referred to our hospital and was diagnosed as intestinal obstruction. The patient had neither respiratory symptoms nor findings of peritonitis. The radiography revealed intestinal gas with neveau formation in the left thorax. The computed tomography showed dilatation of the stomach and small intestine, and a diaphragmatic hernia was suspected. Although conservative treatment was started, radiographic and laboratory findings got worse on the 5th hospital day. The patient underwent surgery for a left diaphragmatic hernia with the intestinal obstruction. Diagnosis of Bochdalek hernia with hernia sac was established. The content of hernia was the perforated small intestine. Postoperative course was almost uneventful, and the patient was discharged on the 35th postoperative day without pyothorax. In treatment of adult Bochdalek hernia, early surgery is important because patients with incarceration or perforation often experience severe postoperative complication.

[Bronchioloalveolar carcinoma producing CA19-9].

A 76-year-old man, who had underwent radiation for laryngeal cancer 5 years before, was pointed out abnormal pulmonary lesion on computed tomography. The 4.6 cm-sized lesion was seen in the upper lobe of the left lung. Endoscopic brushing cytology revealed adenocarcinoma. The patient was diagnosed as primary lung cancer of T2N0M0, clinical stage IB. Preoperative serum CA19-9 was elevated to 250 U/ml, although other tumor markers were within normal limits. The patient underwent left upper lobectomy with mediastinal lymph node dissection. Histologically, the lesion was diagnosed as well differentiated adenocarcinoma, mucinous subtype of bronchioloalveolar carcinoma (BAC) in World Health Organization (WHO) classification. Immunohistochemistry shows positive for CA19-9 and thyroid transcription factor-1 (TTF-1).

[Surgical treated pulmonary metastasis from prostatic cancer; report of a case].

A 74-year-old man who had been treated by endocrine therapy for prostatic cancer for 7 years was pointed out an abnormal shadow on the chest X-ray. Computed tomography showed solitary tumor in the lower lobe of the left lung. Transbronchial lung biopsy revealed pulmonary metastasis form prostatic cancer. Because no other metastatic lesions were detected, the patient underwent surgery for pulmonary lesion. The wedge resection of the left lung was performed. Microscopically, the diagnosis of pulmonary and multiple pleural metastases was established. The pulmonary metastasis without bone nor lymph node metastasis is rare. Pleural metastasis should be considered in case of pulmonary metastasis from prostatic cancer. Surgical indication for pulmonary metastasis from prostatic cancer has to be decided carefully.

[Multiple nodular pulmonary amyloidosis complicated with Sjögren syndrome].

A 67-year-old woman, who had been treated for Sjögren syndrome and rheumatoid arthritis for 10 years, was consulted for examination of multiple nodular pulmonary nodules. She has been pointed out multiple pulmonary nodules on chest computed tomography (CT) for 7 years, of which the number and the size gradually increased. When visuting our hospital, approximately 20 nodules up to 10 mm in size were noted. Thoracoscopic resection of the nodule was performed and histological diagnosis was amyloid, which was negative for A- and P- component and positive for transthyretin. Neither amyloid deposition in other organs nor abnormal protein in serum and urine was detected. The diagnosis of localized nodular pulmonary amyloidosis was established. As far as our knowledge, this is the 1st report of transthyretin amyloidosis with Sjögren syndrome.

Resection of left atrial appendage aneurysm and full maze procedure as curative management for stroke recurrence.

Left atrial appendage aneurysm (LAAA) is a rare congenital heart anomaly that frequently becomes apparent after middle age. We report a case of LAAA in a 63-year-old woman with stroke. After stabilization of ischemic cerebral stroke, the patient underwent left atrial appendectomy with full maze procedure and tricuspid annuloplasty under cardiac arrest with cardiopulmonary bypasss. She has been living a healthy life without anticoagulants postoperatively. Resection and the full-maze procedure is an efficacious and durable procedure for LAAA with chronic atrial fibrillation.

Frontotemporal dermoid cyst with incomplete dermal sinus tract in an adult: A case report.

BACKGROUND: Non-midline supratentorial dermoid cyst with dermal sinus tract has been rarely reported especially in adults. We recently experienced a noteworthy patient with frontotemporal dermoid cyst with incomplete dermal sinus tract. CASE DESCRIPTION: A 43-year-old female presented with recurrent subcutaneous mass in the left superolateral orbital region. She had a history of active bronchial asthma, which precluded her from contrast-enhanced imaging studies. Plain imaging studies showed a subcutaneous mass which was continuous with an intrasylvian fissure mass by a tract in the sphenoid ridge and the lesser wing of the sphenoid bone. Frontotemporal craniotomy was performed to reset the mass and the tract. Intraoperative finding showed no intradural tumor components. Extradural component was carefully removed focusing attention on the frontal branch of the facial nerve. The pathology was consistent with dermoid cyst and dermal sinus tract. Postoperatively, she had mild facial palsy of the corrugator supercilii (House and Brackmann Grade II). She was discharged home with modified Rankin scale 1. CONCLUSION: Dermoid cyst needs to be included in the differential diagnosis of adult-onset subcutaneous mass in the frontotemporal regions. After thorough imaging studies for the presence and extent of the sinus tract, the symptomatic lesion should be excised completely once and for all.

Surgical complications associated with spinal decompression surgery in a Japanese cohort.

The aim of the present study was to identify risk factors for perioperative complications associated with spinal surgery for cervical, thoracic, and lumber spinal stenosis in a Japanese cohort. Patients with spinal stenosis who underwent spinal surgery between 2008 and 2012 were included. Neurological and/or surgical site complications within 30 days of index surgery were retrospectively collected, and the rates of complications were calculated. Using univariate and multivariate logistic regression analyses, risk factors for complications were identified. A total of 364 patients underwent 407 spinal surgeries. Of the 407 surgeries performed, 236 were cervical, 28 were thoracic, and 143 were lumbar surgeries. Ossification of the ligamentum flavum was the most common diagnosis in patients with thoracic stenosis (85%), whereas spinal degenerative stenosis and disc herniation were the two most common diagnoses in patients with cervical and lumbar stenosis. Laminoplasty and laminectomy alone were the two most frequently performed procedures. The rate of complications was greater in patients with thoracic stenosis (36%) than in those with cervical (16%) or lumbar stenosis (13%, p=0.013). After a multivariate analysis, only thoracic stenosis (odds ratio 2.87) remained an independent risk factor for surgical complications. The novel result of the present study was that the level of stenosis in the spine had a significant impact on complications after spinal surgery in a Japanese cohort. The result can be explained by the fact that challenging ossified lesions are a common cause of thoracic stenosis in eastern Asia.

Indications and Timings of Re-operation for Residual or Recurrent Hemifacial Spasm after Microvascular Decompression: Personal Experience and Literature Review.

We reviewed reports about the postoperative course of hemifacial spasm (HFS) after microvascular decompression (MVD), including in our own patients, and investigated treatment for delayed resolution or recurrence of HFS. Symptoms of HFS disappear after surgery in many patients, but spasm persists postoperatively in about 10-40%. Residual spasm also gradually decreases, with rates of 1-13% at 1 year postoperatively. However, because delayed resolution is uncommon after 1 year postoperatively, the following is advised: (1) In patients with residual spasms after 1 year postoperatively (incomplete cure) or who again experience spasm ≥ 1 year postoperatively (recurrence), re-operation is recommended if the spasms are worse than before MVD. (2) When re-operation is considered, preoperative magnetic resonance imaging (MRI) findings and intraoperative videos should be reviewed to ensure that no compression due to a small artery or vein was missed, and to confirm that adhesions with the prosthesis are not causing compression. If any suspicious findings are identified, the cause must be eliminated. Moreover, because of the risk of nerve injury, decompression of the distal portion of the facial nerve should be performed only in patients in whom distal compression is strongly suspected to be the cause of symptoms. (3) Cure rates after re-operation are high, but complications such as hearing impairment and facial weakness have been reported in 10-20% of cases, so surgery must be performed with great care.

A clinical study of the prognostic factors for postoperative early recurrence in patients who underwent complete resection for pulmonary adenocarcinoma.

PURPOSE: The 2-[F-18]-Fluoro-2-deoxy-D-glucose (FDG) uptake in positron emission tomography (PET) and serum neutrophil/lymphocyte ratio (NLR) are recently noteworthy prognostic factors. We studied the prognostic factor to predict early recurrence after curative resection for pulmonary adenocarcinoma including FDG uptake and NLR. METHODS: We performed a retrospective review of 23 patients who underwent a complete resection for pulmonary adenocarcinoma. The patients were divided into 2 groups: 19 patients in the disease-free group, and 4 patients in the recurrent group. Clinical and pathological factors concerning the recurrence within 1 year of surgery were analyzed between two groups. RESULTS: No significant differences between the recurrent group and disease-free group was seen in age, gender, CEA, NLR, CRP, pathological stage, pleural invasion, pathological grading, Ki-67 expression, venous invasion and lymphatic invasion. The SUVmax was significantly elevated in the recurrent group (12.5 ± 2.01 vs. 5.70 ± 3.97, p = 0.0094). Tumor size was significantly larger in the recurrent group (5.58 ± 0.71 vs. 3.62 ± 1.33 cm, p = 0.0058). The first, recurrent sites in 4 patients were brain, in 3 patients; and lung, in 1 patient. CONCLUSION: Both tumor size and SUVmax are possible predictors of early recurrence after curative resection in patients with pulmonary adenocarcinoma. Although it is impossible to determine the SUVmax as an independent prognostic factor, the SUVmax may be one of the predictors of early hematogenous recurrence in surgically treated pulmonary adenocarcinoma.

Hypoxia enhances the expression of plasminogen activator inhibitor-1 in human lung cancer cells, EBC-1.

Plasminogen activator inhibitor-1 (PAI-1) is one of the target genes of hypoxia inducible factor-1alpha (HIF-1alpha). Besides being an important physiological regulator of the fibrinolytic system PAI-1 is also involved in cancer invasiveness. HIF-1alpha is expressed in various types of pulmonary cells, but the relation of PAI-1 to HIF-1alpha under hypoxic condition in these cells are not fully elucidated. We, therefore, studied the effect of hypoxia on the expression of PAI-1 in a lung cancer cell line EBC-1. The expression of HIF-1alpha protein in EBC-1 cells was enhanced by hypoxia, and this was associated with increased secretion of PAI-1. Hypoxia did not affect the levels of HIF-1alpha mRNA but enhanced the PAI-1 mRNA. Pretreatment of the cells with MG132, which inhibits the proteasomal degradation of HIF-1alpha, increased the production of PAI-1 under both normoxia and hypoxia. We conclude that hypoxia induces PAI-1 expression, in EBC-1 cells, through the stabilization of HIF-1 complex and this may be related to cancer metastasis.