Tumor-Informed Approach Improved ctDNA Detection Rate in Resected Pancreatic Cancer.

Pancreatic cancer is one of the cancers with very poor prognosis; there is an urgent need to identify novel biomarkers to improve its clinical outcomes. Circulating tumor DNA (ctDNA) from liquid biopsy has arisen as a promising biomarker for cancer detection and surveillance. However, it is known that the ctDNA detection rate in resected pancreatic cancer is low compared with other types of cancer. In this study, we collected paired tumor and plasma samples from 145 pancreatic cancer patients. Plasma samples were collected from 71 patients of treatment-naïve status and from 74 patients after neoadjuvant therapy (NAT). Genomic profiling of tumor DNA and plasma samples was conducted using targeted next-generation sequencing (NGS). Somatic mutations were detected in 85% (123/145) of tumors. ctDNA was detected in 39% (28/71) and 31% (23/74) of treatment-naïve and after-NAT groups, respectively, without referring to the information of tumor profiles. With a tumor-informed approach (TIA), ctDNA detection rate improved to 56% (40/71) and 36% (27/74) in treatment-naïve and after-NAT groups, respectively, with the detection rate significantly improved (p = 0.0165) among the treatment-naïve group compared to the after-NAT group. Cases who had detectable plasma ctDNA concordant to the corresponding tumor showed significantly shorter recurrence-free survival (RFS) (p = 0.0010). We demonstrated that TIA improves ctDNA detection rate in pancreatic cancer, and that ctDNA could be a potential prognostic biomarker for recurrence risk prediction.

Extraction of apex beat waveform from acoustic pulse wave by sound sensing system using stochastic resonance.

With a sound sensing system using stochastic resonance (4SR), it became possible to obtain an acoustic pulse wave (APW)-a waveform created via a mixture of apex beat and heart sound. We examined 50 subjects who were healthy, with no underlying cardiovascular diseases. We could determine boundary frequency (BF) using APW and phonocardiogram signals. APW data was divided into two bands, one from 0.5 Hz to BF, and a second one from BF to 50 Hz. This permitted the extraction of cardiac apex beat (CAB) and cardiac acoustic sound (CAS), respectively. BF could be expressed by a quadratic function of heart rate, and made it possible to collect CAB and CAS in real time. According to heart rate variability analysis, the fluctuation was 1/f, which indicated an efficient cardiac movement when heart rate was 70 to 80/min. In the frequency band between 0.5 Hz and BF, CAB readings collected from the precordial region resembled apex cardiogram data. The waveforms were classified into five types. Therefore, the new 4SR sensing system can be used as a physical diagnostic tool to obtain biological pulse wave data non-invasively and repeatedly over a long period, and it shows promise for broader applications, including AI analysis.

Discrepant Diagnostic Results of Nested Polymerase Chain Reaction-based Genotyping in a Patient with Hepatitis C Virus and Human Immunodeficiency Virus Coinfection.

Accurate genotyping is important to improve the treatment of hepatitis C virus (HCV) infection. We herein report a 44-year-old Japanese man with hemophilia A and coinfection of HCV and human immunodeficiency virus (HIV) who was diagnosed with HCV genotype 4 by direct sequencing. Two genotyping tests based on the nested polymerase chain reaction method that we used misdiagnosed his genotype as 2b and 1b. Although several HCV genotyping tests are available in Japan, it is important to recognize that some cannot detect genotype 4. Care should be taken when genotyping HCV patients who have received non-heated coagulation factor preparations or were infected abroad.

Loxoprofen sodium induces the production of complement C5a in human serum.

Basophil activation test (BAT) is an in vitro allergy test that is useful to identify allergens that cause IgE-dependent allergies. The test has been used to detect not only food allergies and allergies caused by environmental factors but also to detect drug hypersensitivity, which has been known to include IgE-independent reactions. In our preliminary studies in which BAT was applied to detect hypersensitivity of loxoprofen, a non-steroidal anti-inflammatory drug (NSAID), conventional BAT with incubation for 30min did not show basophil activation by means of increased CD203c expression. In this study, we extended the incubation time to 24h on the basis of the hypothesis that loxoprofen indirectly activates basophils. Basophils from healthy control donors as well as allergic patients showed up-regulation of CD203c after incubation with loxoprofen for 24h. Activation was induced using loxoprofen-treated serum. Proteomic and pharmacologic analyses revealed that serum incubation with loxoprofen generated an active complement component C5a, which induced CD203c expression via binding to the C5a receptor on basophils. Because C3a production was also detected after incubation for 24h, loxoprofen is likely to stimulate the complement classical pathway. Our findings suggest that the complement activation is involved in drug hypersensitivity and the suppression of this activation may contribute to the elimination of false positive of BAT for drug allergies.

Discrepant diagnostic results using two genotyping methods in a chronic hepatitis C patient in serogroup 1.

We present the case of a chronic hepatitis C (CHC) patient who was originally diagnosed with genotype 2a on serogroup 1 CHC genotype testing, but who was subsequently confirmed to have genotype 1b when using the hepatitis C virus (HCV) monitor genotype assay. The genotype 2a diagnosis was attributed to the fact that the type 2a-specific primer used in Okamoto et al.'s method (HCV genotype primer kit) has relatively high homology, which caused the amplification reaction to proceed, rendering a HCV RNA genotype test result of 2a. Genotype testing is important in determining whether a patient is indicated for concomitant dual oral therapy; however, the potential for different diagnoses such as described in this report highlights the importance of serogroup confirmation.

Proteomic identification of autoantibodies in sera from patients with ovarian cancer as possible diagnostic biomarkers.

BACKGROUND/AIM: Accumulating evidence shows that various types of cancers induce a specific immune response resulting in the production of antibodies against self-components (autoantibodies). The aim of the present study was to identify antigens for autoantibodies in sera from patients with ovarian cancer, especially clear cell carcinoma (CCC), as novel diagnostic markers for the disease. MATERIALS AND METHODS: The reactivity of individual sera from patients was examined by two-dimensional (2-D) immunoblotting using lysates of CCC cell lines, ES-2 and RMG-1, as antigens to identify autoantigens. ELISA was established to quantitatively measure autoantibody titer of patients' sera. RESULTS: Autoantibodies against RhoGDI were induced in sera of ovarian cancer patients. Elevated levels of autoantibodies against heterogeneous nuclear ribonucleoprotein L (hnRNPL) and a mitochondrial protein, dihydrolipoamide dehydrogenase (DLD), were detected in patients with CCC. CONCLUSION: Autoantibodies against RhoGDI and hnRNPL and DLD may serve as novel diagnostic markers for ovarian cancer and CCC, respectively.

Proteomic identification of dihydrolipoamide dehydrogenase as a target of autoantibodies in patients with endometrial cancer.

BACKGROUND/AIM: Accumulating evidence shows that various types of cancers induce a specific immune response, resulting in the production of antibodies against self-components (autoantibodies). The aim of the present study was to identify antigens for autoantibodies in sera from endometrial cancer patients as novel diagnostic markers for the disease. MATERIALS AND METHODS: The reactivity of individual sera from patients was examined by 2-dimensional (2-D) immunoblotting using HeLa cell lysates as antigens to identify autoantigens. ELISA was established to quantitatively measure autoantibody titer of patients' sera. RESULTS: A mitochondrial protein, dihydrolipoamide dehydrogenase (DLD), was identified as an autoantigen specific to endometrial cancer patients. The levels of immunoglobulin (Ig)A but not IgG autoantibody to DLD were significantly increased in the sera of endometrial cancer patients. CONCLUSION: IgA autoantibody against DLD could be a novel diagnostic marker for endometrial cancer.

Pseudoperipheral palsy due to infarction in the internal capsule.

Pseudoperipheral palsy can be caused by cerebral cortical infarctions; however, it is rarely caused by lacunar infarctions, including those in the posterior limb of the internal capsule. Meanwhile, the somatotopic localization of the corticospinal tract in the posterior limb of the internal capsule remains unknown. We herein report the case of an 81-year-old Japanese woman who presented with a left hand drop. Brain magnetic resonance imaging revealed an acute infarction as the causative lesion at the inferior level of the anteromedial portion of the posterior limb of the right internal capsule. This case report indicates the topography of hand fibers in the internal capsule.

Evaluation of basophil CD203c as a predictor of carboplatin-related hypersensitivity reaction in patients with gynecologic cancer.

The incidence of hypersensitivity reaction (HR) to carboplatin has been reported to increase after repeated use of the drug. However, a reliable ex vivo test to predict HR to carboplatin is not currently available. We evaluated the clinical usefulness of measuring basophil CD203c to predict carboplatin-related HR in this prospective case-control study conducted at Mie University Hospital between October 2009 and September 2010. Eleven patients had history of carboplatin-related HR within the past 3 years, and 19 had no history of HR after receiving more than 5 courses of carboplatin therapy. Six of these 19 patients developed carboplatin-related HR during the study period. The CD203c+ basophils (%) and the mean fluorescence intensity (MFI) were analyzed on a flow cytometer and compared between patients with and without HR. Changes in the CD203c expression on basophils before and after HR were also assessed in patients who developed HR during the study period. The median CD203c+ basophils (%) and ΔMFI after 30-min exposure to 50 µg/mL carboplatin were significantly higher in patients with HR (3.5% and ΔMFI 9.0) compared with those without (2.2% and ΔMFI 0.4) (p<0.05). In particular, these values were significantly higher in patients with grade 4 anaphylaxis (10.6% and ΔMFI 22.0). All five patients who developed grade 2-4 anaphylaxis during the study period had high CD203c+ basophils (%) and/or increased ΔMFI on the day before HR. The results suggest that basophil CD203c may be a promising biomarker for the prediction of severe carboplatin-related anaphylaxis.

Noninvasive biological sensor system for detection of drunk driving.

Systems capable of monitoring the biological condition of a driver and issuing warnings during instances of drowsiness have recently been studied. Moreover, many researchers have reported that biological signals, such as brain waves, pulsation waves, and heart rate, are different between people who have and have not consumed alcohol. Currently, we are developing a noninvasive system to detect individuals driving under the influence of alcohol by measuring biological signals. We used the frequency time series analysis to attempt to distinguish between normal and intoxicated states of a person as the basis of the sensing system.

Dopamine agonist-induced antecollis in Parkinson's disease.

Few cases of dopamine agonist-induced antecollis in Parkinson's disease (PD) have been reported. Literature review of 16 PD patients including our 3 cases with dopamine agonist-induced antecollis showed predominance of (1) Japanese, (2) women, and (3) Hoehn-Yahr stage of >or=3. We experienced three Japanese PD patients who subacutely exhibited antecollis following increased dopamine agonist dose that improved just after withdrawal of the agonist. One patient developed antecollis during increasing pramipexole dose in combination with cabergoline. Antecollis in another patient appeared during increasing pramipexole dose; it worsened after substituting pergolide for pramipexole, but improved after withdrawal of pergolide. Our cases indicate that there is no specific dopamine agonist causing antecollis, and it is possibly caused by a number of single dopamine agonists or a combination of them. Dopamine agonist-induced antecollis should be considered when encountering antecollis in PD patients being treated with dopamine agonists and withdrawal of the agonist can improve symptoms.

Thrombo-occlusion of inferior vena cava filter in a patient with polycythemia vera.

This is a case of a thrombo-occlusion occurring below an inferior vena cava (IVC) filter inserted in a patient with polycythemia vera and deep vein thrombosis. The patient was a 48-year-old man with polycythemia vera and a chief complaint of swelling, redness, and bursting pain in his right leg. After admission, contrast-enhanced computed tomography scanning demonstrated a pulmonary artery thrombus and deep vein thrombosis. We inserted a Gunther tulip vena cava filter on day 1 for the prevention of pulmonary embolism (PE), and started anticoagulation therapy based on the guideline of the Japanese Circulation Society for DVT. In addition to intravenous anticoagulants, we started therapeutic phlebotomy to improve the hypercoagulability state. On day 4, our patient complained of back pain caused by thrombo-occlusion below the IVC filter, despite the anticoagulation therapy and two therapeutic phlebotomies. From this case, we concluded it is important to lower hemoglobin level and hematocrit as early as possible for IVC-filter-insertion in patients with polycythemia vera.

Truncal polyradiculopathy due to sarcoidosis.

We report the case of a 43-year-old woman who developed multiple cranial nerve palsy, the symptoms of which included hyposmia, visual loss, facial hypoesthesia, facial weakness, dysphagia, gustatory disturbance, and sensory disturbance of the trunk and ulnar side of the bilateral arms. The clinical features included swelling of the bilateral hilar lymph nodes, uveitis, an elevated serum angiotensin-converting enzyme level, and negative tuberculin reactions, which led to a diagnosis of neurosarcoidosis. Her symptoms improved after administration of steroids. An elevated cerebrospinal fluid cell count and protein level, a low-frequency F-wave and slightly decreased sensory nerve action potentials in bilateral ulnar nerves by nerve conduction studies, and normal findings in the spine by magnetic resonance imaging suggested that truncal hypoesthesia was caused by polyradiculopathy. Although rare, in patients with neurosarcoidosis, truncal polyradiculopathy is noteworthy findings in addition to cranial nerve palsy.

Intradural extramedullary tuberculoma of the thoracic spine: paradoxical response to antituberculous therapy.

Intradural extramedullary tuberculoma of the spinal cord (IETSC) is a rare complication of tuberculosis, which can occur as a paradoxical response to antituberculous therapy. A 46-year-old woman with tuberculosis meningitis developed an acute sensory disturbance and paraplegia eight weeks after the antituberculous treatment was started. MRI revealed a cystic lesion at the Th 2 and 3 vertebrae levels, and continuous dural thickening. Laminectomy was performed; soft granulomas were unexpectedly observed inside the dura matter. After the operation, the patient experienced progressive improvement in motor strength. IETSC should be known as rare but possible complication of tuberculous meningitis.

A atrial flutter consisted of two different conduction pathways.

The patient is a 64-year-old male who had been implanted with a DDD-pacemaker for sick sinus syndrome in 2003. In January 2006, he experienced palpitations and visited a local hospital on the second day of occurrence. After an electrocardiography (ECG) revealed atrial flutter (AFL) during palpitation, which was resistant to administered verapamil, the patient was admitted to our hospital for curative treatment. Electrophysiological study revealed a common AFL (AFL1) initiated by atrial burst pacing. We performed isthmus radiofrequency (RF) ablation against AFL1 successfully, after which another common AFL (AFL2) with differing atrial rate was detected. A second ablation operation with standard catheterization techniques was successful, suggesting that two pathways with differing conduction times existed.

A congenital absence of the pericardium diagnosed by echocardiography.

A 29-year-old man visited our office after experiencing palpitations at night. The electrocardiogram revealed premature ventricular contractions (PVCs), and he was admitted to our hospital for further tests. The echocardiography revealed paradoxical motion of the interventricular septum. After considering results from a previous cardiac catheter test, we suspected that the patient may have a congenital absence of the pericardium. A CT scan and magnetic resonance imaging were inconclusive, but through echocardiography and ECG performed during three positional changes we diagnosed a congenital absence of the pericardium.

[Thyroid crisis and protein C deficiency in a case of superior sagittal sinus thrombosis].

We report the case of a 28-year-old woman who presented simultaneously with superior sagittal sinus thrombosis and thyroid crisis, and was subsequently found to have protein C deficiency. February 3, 2003, she admitted complaining of abdominal pain. The diagnosis of appendicitis was made, and she was operated on under lumbar anaesthesia. Day 7, she developed acute headache and distal weakness of the left lower limb. On examination she was alert, with a temperature of 38 degrees C, a sinus tachycardia of 124/min and blood pressure 164/84 mmHg. Neurological examination revealed neck stiffness and left hemiparesis, predominantly in her lower limb. Gadlinium-enhanced brain MRI revealed extensive superior sagittal sinus thrombosis. CT scan demonstrated infarction in the right frontal cortex, and subarachnoid hemorrhage adjacent to the right cerebellar tentorium. The patient was treated with a free radical scavenger edarabon, and glycerin. No anticoagulant therapy was instituted. Over the next 24 hours, her condition worsened. She became comatose, as well as developing a generalized tonic-clonic seizure. Day 12, laboratory examinations revealed an undetectable TSH-level CTSH (thyroid stimulating hormone) <0.005 mcIU/ml), with a level of free thyroxin 7.77 ng/dl (0.9-1.7), free triiodothyronin 29.6 pg/ml (2.3-4.3), and positive anti-TSH receptor antibodies determined subsequently. Coagulation factor VIII activity was 155% (normal range 60-150). Protein C deficiency (antigen 59%, activity 49%) was also present, suggesting a congenital type I heterozygous deficiency. A diagnosis of thyroid crisis on the basis of Graves' disease was made. The patient remained comatose and died on Day 16, with renal failure. The patient had protein C deficiency, a well-established risk factor for cerebral venous thrombosis (CVT). However, additional risk factors are required in most cases to precipitate CVT. In our case, this trigger was most likely thyroid crisis, suggesting that thyrotoxicosis, probably through hypercoagulability, may be a predisposing factor for the development of CVT.

Graft-versus-tumor effect against advanced pancreatic cancer after allogeneic reduced-intensity stem cell transplantation.

BACKGROUND: The prognosis of advanced pancreatic cancer is extremely poor and therefore a novel treatment strategy is desired. The authors thus started a prospective study of allogeneic reduced-intensity hematopoietic stem cell transplantation (RIST) for patients with advanced pancreatic cancer to evaluate the feasibility and efficacy of this approach for such patients. METHODS: Only patients with pathologically proven pancreatic cancer that was locally advanced or metastatic and not amenable to curative resection were included. The conditioning regimen consisted of gemcitabine, fludarabine, and busulfan. RESULTS: In the first stage of this study, the authors treated seven patients. Treatment-related mortality before day 100 was observed in one patient. The median survival after RIST was 229 days. An objective response on computed tomographic scan was observed in two patients and another had a tumor marker response. Marked tumor shrinkage was observed in one of the remaining patients after donor lymphocyte infusion. These antitumor effects appeared after the effect of the conditioning regimen had disappeared. In addition, some of these responses were associated with an increase in the serum anticarcinoembryonic antigen antibody level. CONCLUSIONS: Pancreatic cancer appeared to be sensitive to a graft-versus-tumor effect; therefore, a larger clinical study with a refined strategy is warranted.

Re-entry circuit in ventricular tachycardia due to focal fatty-fibrosis in a patient with myotonic dystrophy.

A 69-year-old man with a recurrent ventricular tachycardia (VT) was admitted. The patient was diagnosed as myotonic dystrophy type 1 (DM1) and DNA analysis revealed 1,800 CTG-repeat expansion in the myotonic dystrophy protein kinase (DMPK) gene. Ultrasonic cardiogram (UCG), left ventriculogram (LVG) and magnetic resonance imaging (MRI) did not show any abnormal sign including fatty infiltration. But, endomyocardial biopsy obtained from ventricular outflow tract revealed severe fatty infiltration and interstitial fibrosis. Radiofrequency catheter ablation at the biopsy site could eliminate VT, so it was strongly suggested that the re-entry circuit was formed by focal fatty-fibrosis. Careful observation should be continued for a long period.