FDG-PET/MRI with high-resolution DWI characterises the distinct phenotypes of endometrial cancer.

AIM: To evaluate the capability of integrated 2-[18F]-fluoro-2-deoxy-d-glucose (FDG)-positron-emission tomography (PET)/magnetic resonance imaging (MRI) to characterise the distinct phenotypes of endometrial cancer. MATERIALS AND METHODS: Thirty-one patients with endometrial cancer (23 with type I, including 17 G1 and six G2 endometrioid adenocarcinomas, and eight with type II, including three G3 endometrioid adenocarcinomas, two carcinosarcomas, and three serous carcinomas) underwent pretreatment FDG-PET/MRI with simultaneous reduced field-of-view diffusion-weighted imaging (DWI). The standardised uptake value (SUV), apparent diffusion coefficient (ADC), and SUV-to-ADC ratio were compared between low-risk (type I and stage I and negative for lymph-vascular space invasion [LVSI]) and high-risk cancers. The diagnostic accuracy for discriminating the cancer phenotypes was evaluated using receiver operating characteristic (ROC) analysis. RESULTS: The SUV was not significantly different between low-risk and high-risk endometrial cancers. High-risk cancers had a significantly lower ADC (756±232×10-6) and a greater SUV-to-ADC ratio (21.7±7.7×109) than low-risk cancers (937±154×10-6, p<0.05 and 13.1±4.1×109, p<0.005, respectively). On comparison of the area under the ROC curves (AUCs), the SUV-to-ADC ratio demonstrated the greatest diagnostic accuracy (ratio 0.83, ADC 0.72, and SUV 0.66). The AUCs for the ratios were significantly higher than those for the SUV values (p<0.05). The optimal SUV-to-ADC cut-off value of 16.9×109 for predicting high-risk cancer revealed a sensitivity of 73%, specificity of 81%, and accuracy of 77%, which was significantly higher than the accuracy for SUV. CONCLUSION: The SUV-to-ADC ratio obtained using integrated FDG-PET/MRI with high-resolution DWI reflects tumour aggressiveness including LVSI, and will be useful for lesion characterisation to decide on an appropriate therapeutic strategy for endometrial cancer.

The ideal strategy for cervical cancer screening in Japan: Result from the Fukui Cervical Cancer Screening Study.

INTRODUCTION: The aims of the Fukui Cervical Cancer Screening (FCCS) study are to determine the frequency of women with high-risk HPV (hrHPV), whether HPV16 or HPV18 (HPV16/18), in the Japanese cancer screening population for the first time and to identify the best strategy for cervical cancer screening in Japan. METHODS: This study enrolled 7584 women aged ≥25 years who were undergoing routine screening. All women underwent LBC and cobas HPV tests. Women with abnormal cytology, whether hrHPV positive or negative; women with hrHPV positivity with either normal or abnormal cytology; and women randomly selected from women with normal cytology and negative hrHPV negative were referred for colposcopy. RESULTS: The prevalences of hrHPV positivity and HPV16/18 positivity were 6.8% and 1.7%, respectively. The baseline data from the FCCS study showed that the combination of HPV tests and cytology was more sensitive than cytology with respect to the detection of intraepithelial neoplasia grade 2 or worse. However, the specificity (94.1%) of the co-testing strategy that required all women with abnormal cytology or hrHPV positivity to be referred for colposcopy was much lower than that (97.8%) of cytology. The sensitivity and specificity of the co-testing strategy that required only women with abnormal cytology or HPV16/18 positivity to undergo colposcopy were 85.5% and 97.0%, respectively. CONCLUSION: The baseline data from the FCCS study suggest that a cervical cancer screening strategy in which only women with abnormal cytology or HPV16/18 positivity undergo colposcopy offers a more balanced sensitivity and specificity than other strategies.

Prognostic value of sequencing-based minimal residual disease detection in patients with multiple myeloma who underwent autologous stem-cell transplantation.

BACKGROUND: Most patients with multiple myeloma (MM) are considered to be incurable, and relapse owing to minimal residual disease (MRD) is the main cause of death among these patients. Therefore, new technologies to assess deeper response are required. PATIENTS AND METHODS: We retrospectively analyzed 125 patients with MM who underwent high-dose melphalan plus autologous stem-cell transplantation (ASCT) to detect MRD in autograft/bone marrow (BM) cells using a next-generation sequencing (NGS)-based method and allele-specific oligonucleotide-polymerase chain reaction (ASO-PCR). RESULTS: NGS-based method was applicable to 90% and this method had at least one to two logs greater sensitivity compared to ASO-PCR. MRD negative by NGS [MRDNGS(-)] (defined as <10-6) in post-ASCT BM cases (n = 26) showed a significantly better progression-free survival (PFS) (96% at 4 years, P < 0.001) and overall survival (OS) (100% at 4 years, P =0.04) than MRDNGS(+) in post-ASCT BM cases (n = 25). When restricting the analysis to the 39 complete response cases, patients who were MRDNGS(-) (n = 24) showed a significantly better PFS than those that were MRDNGS(+) (n = 15) (P =0.02). Moreover, MRDNGS(-) in post-ASCT BM cases (n = 12) showed significantly a better PFS than MRDNGS(+) cases (n = 7) where MRD was not detected by ASO-PCR (P = 0.001). Patients whose autografts were negative by NGS-based MRD assessment (<10-7) (n = 19) had 92% PFS and 100% OS at 4 years post-ASCT. Conversely, the NGS-based MRD positive patients who received post-ASCT treatment using novel agents (n = 49) had a significantly better PFS (P = 0.001) and tended to have a better OS (P= 0.214) than those that were untreated (n = 33). CONCLUSIONS: Low level MRD detected by NGS-based platform but not ASO-PCR has significant prognostic value when assessing either the autograft product or BM cells post-ASCT.

Acceptance of surrogate end points in clinical trials supporting approval of drugs for cancer treatment by the Japanese regulatory agency.

BACKGROUND: This study investigated the historic use of different end points to support approval of drugs for cancer treatment in Japan. PATIENTS AND METHODS: Anticancer drugs approved between April 2001 and April 2014 were comprehensively investigated using publicly available information. RESULTS: Before the revision of the guideline for oncology drugs in April 2006 in Japan, >80% of end points supporting approval were response rate and overall survival (OS) was not frequent. After the revision of the guideline in Japan, using OS in pivotal clinical trials applied for approval increased to more than approximately one-third of oncology drugs, although trials with an end point of response rate decreased. Regarding drugs for major cancers including non-small-cell lung cancer, gastric cancer, colorectal cancer, and breast cancer, survival was used as an end point in 44.0%, whereas surrogate end points were used in 56.0%. Exploration of potential factors for using surrogate end points other than survival carried out through determinations of odds ratios and 95% confidence intervals identified 'orphan drug designation in Japan' and 'accelerated approval by the U.S. Food and Drug Administration' as significant factors. CONCLUSIONS: The revised guideline for oncology drugs in Japan requires the results of phase 3 studies with survival as an end point at the time of new drug application at least for major cancers. The regulatory agency in Japan also accepts surrogate end points as end points supporting approval besides survival; however, the number of surrogate end points has decreased after the revision of the guideline. We consider that accepting surrogate end points in the Japanese regulatory systems is important to approve oncology drugs quickly in Japan.

Anticancer effects of gemcitabine are enhanced by co-administered iRGD peptide in murine pancreatic cancer models that overexpressed neuropilin-1.

BACKGROUND: Impaired drug transport is an important factor that reduces the efficacy of anticancer agents against pancreatic cancer. Here, we report a novel combination chemotherapy using gemcitabine (GEM) and internalised-RGD (iRGD) peptide, which enhances tumour-specific drug penetration by binding neuropilin-1 (NRP1) receptor. METHODS: A total of five pancreatic cancer murine models (two cell line-based xenografts (CXs) and three tumour grafts (TGs)) were treated with either GEM (100 mg kg(-1), q3d × 4) alone or GEM plus iRGD peptide (8 µmol kg(-1)). Evaluation of NRP1 expression in xenografts and 48 clinical cancer specimens was performed by immunohistochemistry (IHC). RESULTS: We identified a subset of pancreatic cancer models that showed NRP1 overexpression sensitive to iRGD co-administration. Treatment with GEM plus iRGD peptide resulted in a significant tumour reduction compared with GEM monotherapy in CXs, but not remarkable in TGs. Potential targets of iRGD were characterised as cases showing NRP1 overexpression (IHC-2+/3+), and these accounted for 45.8% of the clinical specimens. CONCLUSIONS: Internalised RGD peptide enhances the effects of co-administered drugs in pancreatic cancer models, its efficacy is however only appreciable in those employing cell lines. Therefore, the clinical application needs to be given careful consideration.

Transverse uterine fundal incision for placenta praevia with accreta, involving the entire anterior uterine wall: a case series.

OBJECTIVE: To determine the feasibility and safety of transverse fundal incision with manual placental removal in women with placenta praevia and possible placenta accreta. DESIGN: Case series. SETTING: Four level-three Japanese obstetric centres. POPULATION: Thirty-four women with prior caesarean section and placenta praevia that widely covers the anterior uterine wall, in whom placenta accreta cannot be ruled out. METHODS: A transverse fundal incision was performed at the time of caesarean section and manual placental removal was attempted under direct observation. MAIN OUTCOME MEASURE: Operative fluid loss. RESULTS: The total volume of fluid lost during our operative procedure compares favourably with the volume lost during our routine transverse lower-segment caesarean sections performed in patients without placenta praevia or accreta. The average fluid loss was 1370 g. No patients required transfer to intensive care, and there were no cases of fetal anaemia. CONCLUSIONS: This procedure has the potential to reduce the heavy bleeding that arises from caesarean deliveries in women with placenta praevia and placenta accreta.

Double-network acrylamide hydrogel compositions adapted to achieve cartilage-like dynamic stiffness.

Since articular cartilage has a limited potential for spontaneous healing, various techniques are employed to repair cartilage lesions. Acrylate-based double-network (DN) hydrogels containing ~90% water have shown promising properties as repair materials for skeletal system soft tissues. Although their mechanical properties approach those of native cartilage, the critical factor-stiffness-of DN-gels does not equal the stiffness of articular cartilage. This study investigated whether revised PAMPS/PAAm compositions with lower water content result in stiffness parameters closer to cartilage. DN-gels containing 61, 86 and 90% water were evaluated using two non-destructive, mm-scale indentation test modes: fast-impact (FI) and slow-sinusoidal (SS) deformation. Deformation resistance (dynamic modulus) and energy handling (loss angle) were determined. The dynamic modulus increased with decreasing water content in both testing modes. In the 61% water DN-gel, the modulus resembled that of cartilage (FI-mode: DN-gel = 12, cartilage = 17; SS-mode: DN-gel = 4, cartilage = 1.7 MPa). Loss angle increased with decreasing water content in fast-impact, but not in slow-sinusoidal deformation. However, loss angle was still much lower than cartilage (FI: DN-gel = 5, cartilage = 11; SS: DN-gel = 10, cartilage = 32°), indicating somewhat less ability to dissipate energy. Overall, results show that it is possible to adapt DN-gel composition to produce dynamic stiffness properties close to normal articular cartilage.

[Lung adenocarcinoma with mixed subtypes which had been followed up for 5-years].

A 63-year-old female was admitted to our hospital for investigation of serum elevation of carcinoembryonic antigen (CEA). She underwent high anterior resection for a rectal cancer 5-years ago. Chest computed tomography (CT) obtained 5-years ago showed a nodule in the right S10, measuring 1.3 x 0.8 cm in size. The nodule was assessed as benign. Chest CT on admission showed the enlarged nodule with a pleural indentation, measuring 2.2 x 1.6 cm in size. Definitive diagnosis could not be established. Since it was difficult to exclude the possibility of malignancy, video-assisted partial resection was performed. Histological examination of the nodule revealed primary adenocarcinoma in frozen sections. Lobectomy with lymph node dissection was performed. The ultimate diagnosis was adenocarcinoma with mixed subtypes. The tumor was classified as stage IA with T1bN0M0. We reported this case because it was a rare slow-growing adenocarcinoma that had a 5-years clinical history before operation.

Invasion of carcinoma cells into reconstituted type I collagen gels: visual real-time analysis by time-lapse microscopy.

Stromal-epithelial interactions play a critical role in promoting tumorigenesis and invasion. To obtain detailed information on cancer cell behaviors on the stroma and kinetics of cell migration, which cannot be observed by conventionally-used Boyden chamber assays, this study was aimed at analyzing the cell invasion process in vitro using time-lapse microscopic observation. Serum-free conditions and reconstituted type I collagen gels which provided a basal membrane-stroma-like microenvironment were used to first establish a basal condition. Time-lapse microscopic observation for 30 h of cell invasion into the collagen gel revealed kinetic parameters and individualistic behavior of cancer cells. Of breast cancer MDA-MB-231 or MCF-7 cells and colon cancer LS180 or HT29 cells examined, MDA-MB-231 cells most rapidly disappeared from the collagen gel surface under basal conditions. Estrogen-dependent MCF-7 cells disappeared at a rate approximately two times slower than that of MDA-MB-231 cells under serum- and phenol red-free conditions. By the addition of 10 nM ß-estradiol to the basal medium, MCF-7 cell invasion was facilitated to a rate similar to that of MDA-MB-231 cells. Microscopic analyses of collagen gel-sections demonstrated that most of the MDA-MB-231 and MCF-7 cells remained within 60 µm from the gel top under basal conditions, which is consistent with the observation obtained using Boyden chambers that no cells could cross the collagen I gel barrier unless 1% fetal calf serum was added to basal conditions. In summary, this study demonstrated future applicability of this method to understand the initial phase of cancer cell invasion processes.

[Detection of the point of communication by pneumoperitoneum at the surgery for pleuroperitoneal communication].

A 53-year-old male was admitted to our hospital because of dyspnea. Chest radiograph showed a massive right-sided hydrothorax. He was suffering from chronic renal failure and had undergone continuous ambulatory peritoneal dialysis (CAPD) for 8 months. The diagnosis of pleuroperitoneal communication (PPC) was made using injection of indigocarmine into the peritoneal cavity with subsequent pleural detection by thoracocentesis. Injection of contrast media into the peritoneal cavity showed a dome shaped radio-opaque shadow which is located on the diaphragmatic dome followed by the movement of contrast media into the thoracic cavity. Video-assisted thoracic surgery (VATS) was performed under general anesthesia. To identify the point of communication, the method of detecting air leakage was employed. A bleb like lesion on which the hole existed was observed at the center of the diaphragm, and air leakage was identified by filling the thoracic cavity with saline. The pressure in the peritoneal cavity was maintained at 10 mmHg by continuous CO2 inflation. Direct closure was performed to repair the PPC, which succesfully stopped the air leakage. CAPD could be restarted immediately after surgery. No recurrence of hydrothorax has been detected for more than 14 months after surgery.

Antifouling activity of synthetic polymer gels against cyprids of the barnacle (Balanus amphitrite) in vitro.

Barnacle (Balanus amphitrite) settlement on synthetic hydrogels with various chemical structures was tested in laboratory assays. The results demonstrated that cyprids settle less or not at all on hydrogels and PDMS elastomer compared with the polystyrene control. The low settlement on gels is most likely due to the 'easy release' of initially attached cyprids from the gel surfaces. This low adhesion of cyprids is independent of surface hydrophilicity or hydrophobicity, and of surface charge. The results also revealed that hydrogels can be categorized into two groups. One group showed an extremely strong antifouling (AF) performance that was independent of the elasticity (E) or swelling degree (q) of the gels. The second group showed relatively less strong AF performance that was E- or q-dependent. In the latter case, E, rather than the q, may be the more important factor for cyprid settlement.

Antifouling properties of tough gels against barnacles in a long-term marine environment experiment.

In the marine environment, the antifouling (AF) properties of various kinds of hydrogels against sessile marine organisms (algae, sea squirts, barnacles) were tested in a long-term experiment. The results demonstrate that most hydrogels can endure at least 2 months in the marine environment. In particular, mechanically tough PAMPS/PAAm DN and PVA gels exhibited AF activity against marine sessile organisms, especially barnacles, for as long as 330 days. The AF ability of hydrogels toward barnacles is explained in terms of an 'easy-release' mechanism in which the high water content and the elastic modulus of the gel are two important parameters.

Does eicosapentaenoic acid (EPA) inhibit cerebral vasospasm in patients after aneurysmal subarachnoid hemorrhage?

BACKGROUND: Cerebral vasospasm following subarachnoid hemorrhage (SAH) is a significant cause of morbidity and mortality and recent studies indicate that Rho-kinase plays an important role in the occurrence of such cerebral vasospasm. Eicosapentaenoic acid (EPA), an n-3 polyunsaturated fatty acid, inhibits sphingosylphosphorylcholine (SPC)-induced Rho-kinase activation in vitro, so this study examined whether EPA prevented cerebral vasospasm occurrence after SAH in patients. METHODS: The trial population was 101 patients with SAH subjected to craniotomy and clip application. EPA was orally administered at a daily dose of 1800 mg EPA from day 4 to day 14 to 73 patients; the other 28 constituted the control group, receiving no EPA. RESULTS: EPA significantly curtailed both the occurrence of symptomatic vasospasm (14% EPA group, 36% control, P = 0.019) and of cerebral infarction because of cerebral vasospasm (4% EPA group, 29% control, P = 0.001). Moreover, the percentage of patients with a clinically good outcome was significantly higher in the EPA group (85%, P = 0.022) than in control (64%); there were no deaths in the EPA group but three (11%) in control (P = 0.020). CONCLUSION: These findings suggest EPA inhibits symptomatic cerebral vasospasm and cerebral infarction after SAH and also improves clinical prognosis.

Novel technique for estimating cerebrovascular permeability demonstrates capsazepine protection following ischemia-reperfusion.

OBJECTIVE: There has been some discussion as to whether the pial vasculature behaves in the same way as the blood-brain barrier as a whole. Recent studies have shown that capsazepine protects these vessels from the effects of ischemia-reperfusion. We have now used a new method to examine this protection in the whole brain. METHODS: Horseradish peroxidase concentrations were measured in brain sections and plasma, following starch microsphere induced ischemia, which lasted from 20 to 60 minutes, with 30 minutes reperfusion. The PS product was calculated from the Crone-Renkin equation. RESULTS: Permeability increase, which depended on duration of ischemia, was considerably greater in the pia than the parenchyma. The increase was also greater in tissue surrounding large radial venules of the cortex. Single vessel studies showed that these differences mirror those between small and large pial venules. Capsazepine treatment protected the parenchymal blood-brain barrier by limiting the post-ischemic permeability increase to about one third, but had no effect on the pia or radial vessel permeability. CONCLUSIONS: Permeability has been estimated in tissue sections with good spatial resolution using this new technique, which has demonstrated that the TRPV1 receptor plays an important role in the whole brain, not confined to small pial venules.

DARPP-32 expression arises after a phase of dysplasia in oesophageal squamous cell carcinoma.

This is the first report to correlate DARPP-32 immunoreactivity (dopamine and cAMP-regulated phosphoprotein, M(r) 32 000) to clinicopathological status in human cancer. DARPP-32 is recognised as a neuronal protein. A recent study demonstrated that DARPP-32, and a truncated isoform t-DARPP, are overexpressed in gastric carcinoma during the process of carcinogenesis. The biological function of DARPP-32, however, is still unclear. The purpose of this study was to clarify the roles of DARPP-32 and t-DARPP in oesophageal squamous cell carcinoma (OSCC). Initially, we investigated DARPP-32 and t-DARPP expression in OSCC cell lines by Reverse transcription-polymerase chain reaction and Western blot. DARPP-32 expression was observed in four out of seven (57.1%) cell lines, but t-DARPP expression was not observed in any cell lines. In oesophageal tissue sample, DARPP-32 expression was observed in four out of seven (57.1%) tumour tissues, while t-DARPP was not observed in any tissues. Subsequently, DARPP expression was assessed by immunohistochemistry, using a polyclonal antibody, in tissue sections from 122 patients with primary OSCC. DARPP immunoreactivity was not observed in any normal oesophageal mucous membranes. On the other hand, positive DARPP immunostaining was detected in 37 patients (30.3%) and correlated inversely with pathologic stage (P=0.0284), pT (P=0.0438), pN (P=0.0303) and tumour size (P=0.012). The overall survival rate was worse in patients with DARPP-negative tumours than in patients with DARPP-positive tumours (P=0.0453). Interestingly, DARPP expression was observed in only one out of 45 cases of dysplasia. These observations suggest that DARPP-32 (rather than t-DARPP) expression arises after a phase of dysplasia in OSCC, and that tumours expressing DARPP-32 progress less rapidly than DARPP-32-negative tumours.