Molecular profiling and genome‐wide analysis based on somatic copy number alterations in advanced colorectal cancers

To characterize somatic alterations in colorectal cancer (CRC), we conducted a genome‐scale analysis of 106 CRC specimens. We assessed comprehensive somatic copy number alterations (SCNAs) in these CRC specimens. In addition, we examined microsatellite instability (MSI; low and high), genetic mutations (KRAS, BRAF, TP53, and PIK3CA), and DNA methylation status (classified into low, intermediate, and high type). We stratified molecular alterations in the CRCs using a hierarchical cluster analysis. The examined CRCs could be categorized into three subgroups using hierarchical cluster analysis. Tumors in subgroup 1 were characterized by a low frequency of SCNAs and a high frequency of MSI‐high status, whereas tumors in subgroups 2 and 3 were closely associated with a high frequency of SCNAs. Tumors in subgroup 1 were preferentially present in the right‐sided colon and showed frequent MSI‐high status. Subgroup 3 was distinguished by specific alterations, including gains at 1q23‐44, 1p11‐36, 10q11‐26, 10p11‐13, 12q24‐24, and 13q33‐33. In contrast, tumors in subgroup 2 were characterized by copy‐neutral LOH at 12p12‐13, 1q24‐25, and 10q22. In addition, KRAS mutations were more frequently found in subgroup 3 than in subgroup 1. TP53 mutations and intermediate levels of DNA methylation were common alterations in the three subgroups. SCNAs contributed to sporadic CRC, and there were three subgroups based on SCNAs that played a different role in driving the development of this disease.     

Durable complete response in HER2-positive breast cancer: a multicenter retrospective analysis

Purpose

Though advanced and metastatic epidermal growth factor receptor 2 (HER2)-positive disease is not curable, a small proportion of patients with HER2-positive metastatic breast cancer remain in prolonged complete remission with anti-HER2 treatment. We hypothesized that some cases of HER2-positive metastatic breast cancer may be curable. In this large, multicenter retrospective study, we aimed to assess the long-term outcomes for patients with a durable response to trastuzumab.

Methods

We retrospectively evaluated the data of patients diagnosed with HER2-positive metastatic breast cancer who received trastuzumab for more than 2 years as the first-line treatment. Patients diagnosed between April 1, 2001 and December 31, 2014 at 19 institutions in Japan were included in the analysis. From 124 potential subjects, 16 were excluded and 108 were evaluated.

Results

The median follow-up length was 7.7 years. Disease progression occurred in 44/108 (40.7%) patients and 13/108 (12%) patients died. The median progression-free survival was 11.2 years, and as more than 80% of patients were alive 10 years after metastatic breast cancer diagnosis. Of the 108 patients, 57 achieved a clinical complete response. Trastuzumab therapy was interrupted for 27 (47.4%) of these patients (based on the doctor’s recommendation for 19 patients, owing to adverse events for 4 patients, owing to unknown reasons for 3 patients, and at the request of 1 patient). Disease progression occurred in 4 of the 27 patients after the interruption of trastuzumab treatment. The median duration of trastuzumab therapy for all 27 patients was 5.1 years (0.9–9.3 years).

Conclusion

We found that some patients showed no evidence of disease after the interruption of trastuzumab therapy. Discontinuation of maintenance trastuzumab in this patient population after a limited time should be explored cautiously while awaiting a global collaborative effort for a randomized trial.

     

Relevance of vascular PGI2 synthase to vascular prostacyclin production in Dahl rats susceptible to salt-induced hypertension

To assess the roles of prostacyclin (PGI2) synthase in vascular PGI2 generation, the enzymatic activity was examined in the mesenteric artery of Dahl S rats in the prehypertensive or hypertensive stage. Elevation of blood pressure in Dahl S rats was accompanied by an increase of vascular PGI2 synthase activity. The enzymatic activity was positively correlated to the blood pressure value. Similarly, impaired vascular capacity to generate PGI2, which was observed in prehypertensive Dahl S rats, was restored to the control level of Dahl R rats with the elevation of blood pressure. These data indicate that vascular PGI2 synthase activity is increased with blood pressure elevation, thereby contributing to the restoration of vascular capacity to generate PGI2 in Dahl S rats.     

Bilateral transient radial nerve palsies in an infant after cardiac surgery

PURPOSE: To describe the case of an infant who suffered bilateral transient radial nerve palsies after cardiac surgery. CLINICAL FEATURES: A one-month-old baby was found to have bilateral wrist and finger drop after the removal of splints that has been applied to the right hand for 14 days and to the right hand for six days during perioperative management of Blalock-Taussig shunt surgery. The hand splints had been applied to the forearms with adhesive silky tape to keep peripheral vascular lines in place. The patient also suffered from several episodes of cardiogenic shock, hypoxemia and generalized edema relating to cardiac dysfunction during this fine period. Given the findings of no impairment of median or ulnar nerves and brachioradial muscle, it was suspected that bandaging with adhesive tapes caused peripheral radial nerve damage at the level of posterior interosseus nerve on forearm. Diminished oxygen delivery and edema may additionally have contributed to peripheral nerve ischemia. The aforementioned neurologic symptoms resolved spontaneously after several days. CONCLUSION: Prolonged compression by bandaging of splints on forearm may have resulted in ischemic damage to the posterior interosseus nerve branch combined with extensor carpi radialis longus nerve branch of the radial nerve. We should attempt to reduce the frequency and duration of splinting of the extremities, especially in sedated, paralyzed babies, given the potential risk of compression neuropathy.     

Prolonged hemodynamic maintenance by the combined administration of vasopressin and epinephrine in brain death: a clinical study

The present study attempted long term hemodynamic maintenance in 16 adult brain-dead patients, 14 with head injury and 2 with cerebrovascular accidents. In addition to respiratory and fluid management, 10 were treated with continuous infusion of epinephrine to maintain systolic blood pressure above 90 mm Hg. The remaining 6 patients each received a continuous infusion of synthetic arginine vasopressin (ADH) at a rate of 1 or 2 units/hour (285 +/- 45 microunits/kg/minute) simultaneously with epinephrine. The 10 patients treated with epinephrine alone all succumbed to cardiac arrest within 48 hours of brain death, with a mean survival time of 24.1 +/- 17.2 hours. In the patients who received simultaneous ADH infusion, a minimal dose of epinephrine of no more than 0.5 mg/hr in most instances sufficed to maintain blood pressure. Their mean survival time after brain death was remarkably prolonged to 23.1 +/- 19.1 days. In brain death, ADH plays a critical role in hemodynamic maintenance, and ADH administration permits long term hemodynamic stabilization of brain-death patients, offering increasing opportunities for organ transplantation.     

Hypercalcemia in a Case of Childhood Acute Lymphoblastic Leukemia

Severe hypercalcemia (serum calcium, 4.25–5.25 mmol/l),in association with osteolytic bone lesions, was found in agirl aged 2 yr 7 mo with common acute lymphoblastic leukemia(ALL). Hormonal studies excluded the possibility of the hypercalcemiabeing caused by primary hyperparathyroidism or ectopic parathyroidhormone secretion. Increased plasma prostaglandinE₂ (PGE₂).Jlevels (130 ng/l), probably produced by leukemic cells, wereconsidered to be one of the pathogenic mechanisms responsiblefor the occurrence of hypercalcemia in this patient. Both thehypercalcemia and the abnormal plasma PGE₂ level returned tonormal after chemotherapy.     

A case report of pseudoxanthoma elasticum with upper gastrointestinal hemorrhage

A gastric hemorrhage in a patient with pseudoxanthoma elasticum (PXE) is reported. A 44-year-old woman was admitted to our hospital with hematemesis. Bleeding point was located at upper body of the stomach. As neither endoscopic alcohol injection nor operative hemostasis by over sewing under gastrotomy were unsuccessful, total gastrectomy was performed. Histologic examination of the stomach revealed fragmentation of elastic fiber in the internal lamina of arteriole and degeneration of muscle layer. This change was observed fundamentally in all specimens obtained from different region of the stomach. In addition to describing clinical and pathological feature of this case, the management of gastric hemorrhage in patients with PXE is discussed.     

Chronopharmacological study of bunazosin hydrochloride in healthy subjects

Bunazosin, an alpha-1 adrenoreceptor blocking agent, was given orally to six healthy subjects in the morning or in the evening in order to examine the time-dependent variations in the pharmacological effects of the drug. The study was carried out on four occasions in a placebo controlled cross-over design. No significant change was observed in blood pressure either after the morning or the evening dosage. Finger skin blood flow (FSBF) assessed by laser Doppler flowmetry increased significantly after the morning dosage, but not after the evening trial. The plasma concentration of bunazosin in the morning in general had a tendency to be greater than that in the evening. A significant correlation was observed between the plasma concentrations and the increments in the FSBF. These results indicate that the pharmacological effects of bunazosin are greater following morning dosage. The present study supports the concept that the time-dependent differences in the effect of bunazosin are, at least, caused by the time-dependent changes in plasma drug concentration.     

Compression of body by clothing--increase in urinary norepinephrine excretion caused by foundation garments

The urinary excretions of norepinephrine (NE) and epinephrine (EP) were measured to investigate the physiological effects of girdles worn by women to look attractive. 1) The urinary excretion of NE was remarkably increased by the wearing of a girdle in all the subjects examined, whether living conditions and stimulations were changed or remained unchanged. 2) The urinary excretion of NE was increased by wearing a girdle, regardless of the type of girdle or its intensity of compression. 3) The urinary excretion of NE tended to increase more by the wearing of a bodysuit having a large area of body compression than by the wearing of a girdle having a narrow area of compression. 4) The urinary excretion of NE showed no specific pattern of change, even when the subjects were accustomed to the use of a girdle. These findings may indicate that a girdle of even the best-fitting size exerts a kind of stress on the human body.