The impact of rare cancer and early-line treatments on the benefit of comprehensive genome profiling-based precision oncology.

BACKGROUND: Comprehensive genome profiling (CGP) serves as a guide for suitable genomically matched therapies for patients with cancer. However, little is known about the impact of the timing and types of cancer on the therapeutic benefit of CGP. MATERIALS AND METHODS: A single hospital-based pan-cancer prospective study (TOP-GEAR; UMIN000011141) was conducted to examine the benefit of CGP with respect to the timing and types of cancer. Patients with advanced solid tumors (>30 types) who either progressed with or without standard treatments were genotyped using a single CGP test. The subjects were followed up for a median duration of 590 days to examine therapeutic response, using progression-free survival (PFS), PFS ratio, and factors associated with therapeutic response. RESULTS: Among the 507 patients, 62 (12.2%) received matched therapies with an overall response rate (ORR) of 32.3%. The PFS ratios (≥1.3) were observed in 46.3% (19/41) of the evaluated patients. The proportion of subjects receiving such therapies in the rare cancer cohort was lower than that in the non-rare cancer cohort (9.6% and 17.4%, respectively; P = 0.010). However, ORR of the rare cancer patients was higher than that in the non-rare cancer cohort (43.8% and 20.0%, respectively; P = 0.046). Moreover, ORR of matched therapies in the first or second line after receiving the CGP test was higher than that in the third or later lines (62.5% and 21.7%, respectively; P = 0.003). Rare cancer and early-line treatment were significantly and independently associated with ORR of matched therapies in multivariable analysis (P = 0.017 and 0.004, respectively). CONCLUSION: Patients with rare cancer preferentially benefited from tumor mutation profiling by increasing the chances of therapeutic response to matched therapies. Early-line treatments after profiling increase the therapeutic benefit, irrespective of tumor types.

Association Between Nonadherence and Transient Hyperuricemia in Pediatric Kidney Transplantation.

BACKGROUND: Nonadherence among pediatric transplant recipients is a significant problem that reduces graft survival and leads to poor kidney graft outcomes. It is, however, extremely difficult to detect during a regular follow-up. This study, therefore, aimed to investigate the risk factors involved in nonadherence, focusing on unexplained transient hyperuricemia in pediatric kidney transplant (KTx) recipients at a single pediatric center. METHODS: This retrospective study included 167 patients who underwent KTx at our pediatric center. A Cox proportional hazards analysis was performed to evaluate the risk of nonadherence using the following factors: age, sex, body mass index SD score, transient hyperuricemia, hypertension, and follow-up period. RESULTS: Nonadherence was identified in 19 patients (11%), with the average (SD) age and post-KTx duration at diagnosis being 17.21 (4.73) years and 79.21 (38.77) months, respectively. Thirty-four patients (20%) were diagnosed with transient hyperuricemia at a median of 14 months after KTx. On multivariate Cox regression analysis, transient hyperuricemia was the only independent risk factor for nonadherence after KTx. CONCLUSIONS: Transient hyperuricemia was identified as one of the risk factors for nonadherence after KTx; therefore, careful monitoring for transient hyperuricemia may allow early detection of nonadherence.

Serum levels of hepatocyte growth factor and epiregulin are associated with the prognosis on anti-EGFR antibody treatment in KRAS wild-type metastatic colorectal cancer.

BACKGROUND: Ligands of transmembrane receptor tyrosine kinases have important roles in cell proliferation, survival, migration and differentiation in solid tumours. We conducted this study to evaluate the relationship between concentration of serum ligands and prognosis of patients with metastatic colorectal cancer (mCRC) treated with anti-epidermal growth factor receptor (EGFR) antibodies. METHODS: Between August 2008 and August 2011, serum samples were obtained from KRAS wild-type patients who met the inclusion criteria and received an anti-EGFR antibody treatment. Serum concentration of ligands was measured by an enzyme-linked immunosorbent assay, and somatic mutations of KRAS, BRAF, PIK3CA and BRAF were analysed by direct sequencing. RESULTS: A total of 103 patients were enrolled in the present study. At the pretreatment serum levels, patients with high levels of hepatocyte growth factor (HGF) had shorter progression-free survival (PFS) and overall survival (OS) compared with those with low levels of HGF (median PFS: 6.4 months vs 4.4 months; P<0.001, median OS: 15.3 months vs 8.0 months; P<0.001, respectively). Patients with high levels of epiregulin (EREG) also had shorter PFS and OS compared with those with low levels of EREG (median PFS: 6.6 months vs 4.9 months; P=0.016, median OS: 13.8 months vs 7.4 months; P=0.048, respectively). In addition, patients whose serum levels of ligands were elevated at progressive disease had shorter PFS and OS compared with other patients. CONCLUSIONS: Our study indicated that high levels of HGF and EREG were associated with resistance to treatment with anti-EGFR antibodies in KRAS wild-type patients with mCRC. Our findings will contribute to the newly combination therapy on the treatment of anti-EGFR antibodies.

Risk factors for infantile atopic dermatitis and recurrent wheezing.

BACKGROUND: The pathogenic mechanisms of atopic dermatitis (AD) and recurrent wheezing (RW) during infancy are not fully understood. OBJECTIVE: We evaluated immunological markers associated with AD and RW during infancy. METHODS: We followed a cohort (n = 314) from birth to 14 months of age. Some of the participants underwent a physical examination and blood test at 6 and 14 months of age. Univariate and multivariate logistic regression analysis and receiver operating characteristic curve analysis were performed to find which immunological markers could be risk factors for AD and RW. RESULTS: Of 16 immunological markers found in cord blood, only immunoglobulin (Ig) E was associated with AD at 6 months of age (adjusted OR [aOR], 1.607). None of the markers was associated with AD or RW at 14 months of age. Of 23 immunological markers at 6 months of age, total IgE (aOR, 1.018) and sensitization to egg white (aOR, 23.246) were associated with AD at 14 months of age. Phytohemagglutinin (PHA)-induced production of interleukin (IL) 4 from peripheral blood mononuclear cells (PBMCs) (aOR, 1.043) was associated with RW at 14 months of age. CONCLUSION: Cord blood IgE was a risk factor for AD at 6 months of age. Total IgE and sensitization to egg white at 6 months of age were risk factors for AD at 14 months of age. PHA-induced IL-4 production in PBMCs at 6 months of age was a risk factor for RW at 14 months of age.

Localization of acupuncture points on the Lung Meridian using Bi-Digital O-Ring Test electromagnetic field resonance phenomenon between 2 identical substances.

Using Bi-Digital O-Ring Test electromagnetic field resonance phenomenon between 2 identical substances, it is possible to draw on the surface of the human body several points similar to the acupuncture points of Traditional Chinese Medicine-TCM with the help of histological slides of 12 organs of the main TCM Meridians, using the method first described by Yoshiaki Omura Sc.D. M.D. To determine the relationship of the Lung Meridian of TCM and the points drawn with a histological human Lung slide by BDORT, it was mapped the upper limb in 41 healthy individuals. There were almost identical matches in all points in 26 subjects (63.4%). In 15 subjects there were no identical matches at any point (36.5%). In all cases of no identical matches of the points, the new Lu1 point is displaced in the direction of midpoint of thorax below the clavicle. On the arm there was a medially deviation in comparison to the line obtained from the TCM points, for example the new Lu9 point was located on the midpoint of the wrist.

A prolonged course of Group A streptococcus-associated nephritis: a mild case of dense deposit disease (DDD)?

We herein report the case of a 12-year-old boy with dense deposit disease (DDD) evoked by streptococcal infection. He had been diagnosed to have asymptomatic hematuria syndrome at the age of 6 during school screening. At 12 years of age, he was found to have macrohematuria and overt proteinuria with hypocomplementemia 2 months after streptococcal pharyngitis. Renal biopsy showed endocapillary proliferative glomerulonephritis with double contours of the glomerular basement membrane. Hypocomplementemia and proteinuria were sustained for over 8 weeks. He was suspected to have dense deposit disease due to intramembranous deposits in the first and the second biopsies. 1 month after treatment with methylprednisolone pulse therapy, proteinuria decreased to a normal level. Microscopic hematuria disappeared 2 years later, but mild hypocomplementemia persisted for more than 7 years. Nephritis-associated plasmin receptor (NAPlr), a nephritic antigen for acute poststreptococcal glomerulonephritis, was found to be positive in the glomeruli for more than 8 weeks. DDD is suggested to be caused by dysgeneration of the alternative pathway due to C3NeF and impaired Factor H activity. A persistent deposition of NAPlr might be one of the factors which lead to complement dysgeneration. A close relationship was suggested to exist between the streptococcal infection and dense deposit disease in this case.

Loss of cytokeratin 13 expression in squamous cell carcinoma of the tongue is a possible sign for local recurrence.

Cytokeratin (CK) 13 is an intermediate filament protein that is expressed in a cell-type-specific manner, in the tongue and occasionally in tongue squamous cell carcinoma (SCC). Correlations between the clinical features of patients with SCC and CK13 expression in the tumor are here investigated along with CK13's utility as a marker for tongue cancer status. Samples from 121 patients with SCC of the tongue were examined by immunohistochemistry with antibodies against CK13. Correlations between the expression level of CK13 in the tumor and the patients' clinical features were statistically analyzed by univariate and multivariate methods. Univariate analysis showed a more relevant number of local recurrence (P = 0.04) in CK13-negative staining patients. In addition, CK13-negative cases were associated with local recurrence by multiple logistic regression analysis (OR: 3.36; 95% CI: 1.044-10.78; P = 0.04). Our results suggest that the loss of CK13 expression indicates tumors with a high potential for recurrence, and thus CK13 could be useful for determining the best course of treatment.

[Total anomalous pulmonary venous connection showing an unusual shape of the pulmonary vein successfully repaired in a neonate; report of a case].

A 10-day-old neonate with Darling type Ia of total anomalous pulmonary venous connection is presented. The left pulmonary vein entered the right thoracic cavity behind the right atrium and drained into the innominate vein together with the right lower, middle and upper pulmonary veins. The patient was treated with right-sided approach. The postoperative course was uneventful. To our knowledge, this case is the first successful correction of this subtype of anomaly in Japan.

Peroxiredoxin I expression in tongue squamous cell carcinomas as involved in tumor recurrence.

Peroxiredoxin (Prx) I is an antioxidant protein expressed in proliferating cells. We investigated Prx I as marker for tongue cancer status by correlating clinical features with Prx I expression. Samples from 132 patients with squamous cell carcinoma in the tongue were examined by immunohistochemistry with an anti-Prx I antibody. Correlations between Prx I expression and the clinical features of tumors were statistically determined using univariate and multivariate analyses. Univariate analysis showed Prx I was significantly associated with local recurrence (P=0.033). By multiple logistic regression analysis, Prx I expression was associated with local recurrence (odds ratio: 2.84; 95% confidence interval: 1.09-7.43; P=0.034) and lymph node recurrence (odds ratio: 2.86; 95% confidence interval: 1.02-8.01; P=0.046). Our results suggested that Prx I expression indicates tumors with a high potential for recurrence. Prx I may be used clinically to guide treatment for squamous cell carcinoma of the tongue.

[Critical hypertrophic obstructive cardiomyopathy patient with improved hemodynamics following mitral valve replacement: report of a case].

A 75-year-old man with dyspnea was admitted to our hospital in critical condition. Catheterization showed normal coronary arteries and good left ventricular function. Transesophageal echocardiography showed left ventricular hypertrophy and severe mitral regurgitation. We decided to perform mitral valve replacement because the patient was in critical condition and it was necessary to complete the operation smoothly. During the operation, we could see the dilated mitral valve annulus and hypertrophic mitral valve, which was restricted. The patient's hemodynamics showed improvement after mitral valve replacement with a mechanical prosthesis, and he was discharged on postoperative day 21. In conclusion, mitral valve replacement is a beneficial method for the treatment of patients with critical hypertrophic obstructive cardiomyopathy.

[An anastomosis assist mirror; a new device for off-pump coronary artery bypass].

An anastomosis assist mirror for off-pump coronary artery bypass (OPCAB) is described. This new device is designed to make a view of the circumflex coronary artery which is often troublesome to access during OPCAB. It is composed of 3 parts: a small circular mirror, a paper clip and a flexible arm between the mirror and the clip. The paper clip is situated at an edge of a sternal retractor. The mirror is positioned beside the sheer surface of the lateral wall of the heart by regulating the flexible arm. It shows a flat, reflective view of the anastomotic site and makes an anastomosis easy. The device enables us to avoid excessive manipulation on the heart and hemodynamic instability, thereby reducing unnecessary volume overload, inotropic drugs or mechanical cardiac assistance.

[The efficiency of nifekalant hydrochloride for the prevention of ventricular tachycardia during cardiac surgery].

Many cases have been successfully treated by us with experimented nifekalant hydrocholoride to prevent ventricular tachycardia (VT) during cardiac surgery. The 13 patients who underwent cardiac surgery at our hospital from 1999 to 2002 were retroactively given nifekalant hydrocholoride against VT. Lidocaine hydrochloride was not effective for VT, and it was difficult for 3 patients to be weaned for cardio-pulmonary bypass, while 6 patients needed aortic balloon pumping or percutaneous cardio-pulmonary support. Nifekalant hydrochloride suppressed VT induction in 9 patients (69.2%). Blood pressure and heart rate did not change, but QTc intervals were significantly increased with nifekalant hydrochloride (p < 0.005). Proarrhythmic events (Torsades de pointes) occurred in 2 patients, but none of the cases showed drug-induced worsening of cardiac function. Nifekalant hydrochloride is a class III antiarrhythmic drug that has been found to be effective against VT and ventricular fibrillation. While class I antiarrhythmic drugs are usually ineffective and induce severe heart failure, nifekalant hydrochloride can be effective.

[Apico-aortic conduit for severe aortic stenosis in elderly].

We described a case of an 84-year-old woman with end stage aortic stenosis in whom favorable results were obtained after constructing apico-aortic conduit bypass. The patient admitted due to complete atrio ventricular(AV) block and respiratory insufficiency. Although a permanent pacemaker was implanted, heart failure did not improve. Echocardiograms showed small aortic annulus and severe calcific aortic stenosis with a measured trans valve gradient of 100 mmHg. Since cardiac failure deteriorated and she lapsed into hypotension and acute renal failure, an emergency operation was performed. The left lateral thoracotomy was performed with cardiopulmonary bypass. A bioprosthetic valved conduit was anastmosed to the left ventricle apex. Another graft was anastomosed to the discending thoracic aorta. The operation was completed by anastomosing the tailored ends of the grafts together. Although the patient required hemodialysis for 2 weeks after operation, she was discharged on 57th day after operation without any complications. Apico-aortic conduit is considered to be an useful procedure for elderly patients who were not good candidates for conventional valve replacement.

[Usefulness of silicone blake drains after cardiac surgery].

In the present study, the drainage system consisting of a silicon blake drain and a portable suction reservoir (J-vac system) was applied to the patients who received cardiac surgery (SD group). Postoperative drainage volume, postoperative pericardial effusion volume, and postoperative length of hospital stay in SD group were compared with those in the patients who received cardiac surgery and were applied a conventional chloroethlene drain (CD group). There were no significant differences in postoperative drainage volume, postoperative pericardial effusion volume, or postoperative length of hospital stay between SD and CD groups. Therefore, its was thought that a silicon back drain could be safely used as a drainage system after heart surgery. Recently the development of less-invasive cardiac surgery made the early hospital discharge possible, and J-vac system might be very useful in view of its portability under such clinical settings.

[Clinical outcome of emergency off-pump coronary artery bypass grafting].

From January 2001 to January 2003, we performed 25 emergency off-pump coronary artery bypass grafting (CABG) procedures for patients with acute myocardial infarction (AMI) or unstable angina pectoris. During the same period, we also performed 2 emergency on-pump beating CABG procedures for patients with left main coronary trunk (LMT) shock syndrome. For the present study, we evaluated the operative results of the 25 cases of emergency or urgent off-pump CABG. The patients were divided into 3 groups, those with acute AMI with cardiogenic shock (group 1; n = 8), acute myocardial infarction without shock (group 2; n = 8), and unstable angina (group 3; n = 9). There were no differences between groups 1 and 2 with regard to age, number of diseased vessels, and preoperative use of an intraaortic balloon pump, however, patients in group 1 had a higher number of completely obstructed coronary arteries. Patients in groups 1 and 2 underwent off-pump CABG within 3.5 hours after a coronary angiography or coronary intervention procedure, while those in group 3 underwent off-pump CABG within 2 days of coronary angiography. The mean number of grafts per patient was 1.8, 2.1, and 2.3 in groups 1, 2, and 3, respectively. One group 1 patient with an LMT lesion was transferred to on-pump beating CABG because of hemodynamic instability. The 30-day mortality rate was 38% (3 of 8) in group 1, whereas it was 0% in groups 2 and 3. Intubation time, ICU stay, and postoperative stay were similar among the 3 groups. An early angiographic study was undertaken in all surviving patients and the results demonstrated patency in all of the examined grafts. Although our results are limited, emergency off-pump CABG was found to be safe and feasible for AMI without cardiogenic shock or unstable myocardial ischemia. However, the outcome of this procedure for patients with preoperative cardiogenic shock was not satisfactory, therefore, a combination therapy of appropriate mechanical circulatory support, prior revascularization by catheter intervention, and emergency surgical revascularization are considered to improve survival of those patients.

[Economic evaluation of off-pump coronary artery bypass grafting; compared to conventional coronary artery bypass grafting].

This study was undertaken to compare economic outcomes of off-pump coronary artery bypass grafting (off-pump CABG: OPCAB) and conventional CABG (CCABG). We reviewed the medical records of 5 patients with ischemic coronary disease (IHD) who underwent OPCAB and 5 patients with IHD who underwent CCABG. A hospital income which was based on a current Japanese health insurance system was indicated. There were significant differences in total cost (OPCAB = 208,200 +/- 7,383 yen versus CCABG = 324,300 +/- 10,290 yen, 35.8% decreased), costs of medical materials and transfusions (OPCAB = 14,760 +/- 3,270 yen versus CCABG = 87,540 +/- 3,326, 81.3% decreased) and charges of surgery and anesthesia (OPCAB = 130,400 +/- 1,853 yen versus CCABG = 147,650 +/- 4,167 yen, 12% decreased) OPCAB markedly reduces the cost of hospitalization. But charges of surgery and anesthesia of OPCAB seems to be valued properly in a current Japanese health insurance system.

[Aortic valve replacement with a freestyle stentless valve using the modified subcoronary technique and hemiarch replacement for bicuspid aortic valve and ascending aortic aneurysma; report of a case].

An association between bicuspid aortic valve disease and ascending aortic aneurysma has long been recognized. Root replacement with a composite valve graft for such disease is a well-established technique. But it may involve serious technical difficulties, and may be a more time-consuming procedure than separate valve replacement and graft replacement. We performed an aortic valve replacement with Freestyle stentless valve using the modified subcoronary technique and hemiarch replacement for a 72-year-old man with severe aortic stenosis and ascending aortic aneurysma. Angiographic studies after surgery showed no residual aortic regurgitation (AR) and no deformity of aorta. This technique is an acceptable option for an aortic disease and ascending aneurysma in elderly patients.

The importance of Bi-Digital O-Ring Test in the treatment of multiple hepatic abscesses: a case history.

The Bi-Digital O-Ring Test has been very useful in the identification of bacterial and viral infections, as well as other etiological agents, in difficult clinical cases. Case report of a patient with multiple hepatic abscesses (pylephlebitis induced hepatic abscess is the most difficult abscess to treat), in which the etiological agent was suggested through Bi-Digital O-Ring Test with excellent clinical evolution after modification of previously ineffective multi anti-microbial treatment is presented. 45 years old, female with a history of pain at right hypochondria for 15 days, with jaundice, oscillating fever and shivering. Computerized tomography showed liver with multiples nodules in the parenchyma with additional appendicitis. An appendectomy was performed with drainage of intra abdominal abscesses. Treatment with metronidazol, ceftazidim and amicacine was performed with no improvement while the general condition of the patient was deteriorating progressively in the following 3 weeks. Bi-Digital O-Ring Test was then performed to determine the etiological agent and the drug compatibility test among effective antimicrobial agents. Based on the Bi-Digital O-Ring Test, the main etiological agent was found to be Enterobacter aerogenes. Amongst the three antibiotics that were being used, only metronidazol was effective and the other 2 was cancelled its effect. Based on Bi-Digital O-Ring Test findings two new antibiotics (cefadroxil and imipenen), were added to metronidazol and additional cilantro tablets by Hayashibara, Japan was given, and Selective Drug Uptake Enhancement Method performed, with excellent clinical, laboratory testing and tomography improvement within 10 days. Bi-Digital O-Ring Test suggested the etiological agent, and effective and mutually compatible antibiotics for treating the abscesses which resulted in a good clinical evolution, characterized by relief of fever and reduction of the hepatic abscesses in a short period and followed complete disappearance of hepatic abscess.

[Graft holding system; a new device for coronary artery bypass grafting].

A new graft holding system for coronary artery bypass grafting was described. This system was an application of a memo-clip, which was composed of a flexible arm and 2 paper clips at both ends. A graft was wrapped by a piece of sponge and pinched indirectly by one of the clips. The other clip was fixed at an edge of the sternal retractor. Regardless of the size of the graft or the amount of the surrounding tissue, the graft can be fixed securely at one's pleased position due to a flexible arm of the device. Intimal injury can be avoided referring to the gentle holding of a piece of sponge. It enables us to place precise stitches and to minimize handling, anastomosis time, and leakage.