PTEN-induced kinase 1 gene single-nucleotide variants as biomarkers in adjuvant chemotherapy for colorectal cancer: a retrospective study.

BACKGROUND: Fluoropyrimidine-based postoperative adjuvant chemotherapy is globally recommended for high-risk stage II and stage III colon cancer. However, adjuvant chemotherapy is often associated with severe adverse events and is not highly effective in preventing recurrence. Therefore, discovery of novel molecular biomarkers of postoperative adjuvant chemotherapy to identify patients at increased risk of recurrent colorectal cancer is warranted. Autophagy (including mitophagy) is activated under chemotherapy-induced stress and contributes to chemotherapy resistance. Expression of autophagy-related genes and their single-nucleotide polymorphisms are reported to be effective predictors of chemotherapy response in some cancers. Our goal was to evaluate the relationship between single-nucleotide variants of autophagy-related genes and recurrence rates in order to identify novel biomarkers that predict the effect of adjuvant chemotherapy in colorectal cancer. METHODS: We analyzed surgical or biopsy specimens from 84 patients who underwent radical surgery followed by fluoropyrimidine-based adjuvant chemotherapy at Saitama Medical University International Medical Center between January and December 2016. Using targeted enrichment sequencing, we identified single-nucleotide variants and insertions/deletions in 50 genes, including autophagy-related genes, and examined their association with colorectal cancer recurrence rates. RESULTS: We detected 560 single-nucleotide variants and insertions/deletions in the target region. The results of Fisher's exact test indicated that the recurrence rate of colorectal cancer after adjuvant chemotherapy was significantly lower in patients with the single-nucleotide variants (c.1018G > A [p < 0.005] or c.1562A > C [p < 0.01]) of the mitophagy-related gene PTEN-induced kinase 1. CONCLUSIONS: The two single-nucleotide variants of PINK1 gene may be biomarkers of non-recurrence in colorectal cancer patients who received postoperative adjuvant chemotherapy.

Primitive Myxoid Mesenchymal Tumor of Infancy With Fatal Hemorrhage In Utero: A Case Report and Literature Review.

Primitive myxoid mesenchymal tumor of infancy (PMMTI) is a rare soft tissue sarcoma in childhood. We present the case of a newborn male who experienced a severe hemorrhage in utero from the tumor on the scalp. He died at the age of 24 hours owing to hemorrhagic shock. The tumor was posthumously diagnosed as PMMTI. A literature search indicated that cases of severe hemorrhage from soft tissue sarcomas in utero or at birth are limited to infantile fibrosarcoma. This is the first case of PMMTI with massive hemorrhage. Clinicians must be aware of hemorrhagic complications of PMMTI.

[Pathological Findings of Chronic Effects Observed in the Kidneys Exposed to Antineoplastic Agents in Two Adolescent Patients].

Cisplatin and ifosfamide are well-known nephrotoxic agents that can cause acute and chronic glomerular and/or tubular toxicity. We examined 2 adolescent patients who were receiving cisplatin and ifosfamide treatments. Pathological findings of patient 1 showed acute tubular necrosis-like patchy injury. Tubulointerstitial nephrosis and glomerular sclerosing were revealed in patient 2. These findings were consistent with the known damages induced by cisplatin and ifosfamide. Proteinuria and mild decline of eGFR were noticed after more than 10 months after the completion of the treatment. It is important to monitor such consequences in long-term follow up. Adult based medical services are required for childhood and adolescent cancer survivors.

Hydrosurgical debridement as an approach to wound healing: an animal thermal burn model.

OBJECTIVE: This study investigates the advantages of hydrosurgical debridement compared with surgical debridement. METHOD: Thermal skin burns were created on the backs of male Wistar rats. Surgical debridement was used to treat one wound and hydrosurgical debridement (Versajet Hydrosurgery System, Smith&Nephew, UK) used to treat the second wound. Debridement time, blood loss volume, time-to-heal and histologic changes in the wound areas were compared. RESULTS: A total of 23 rats were used in the study. Debridement time and time-to-heal were significantly shorter with hydrosurgical debridement than with surgical debridement (p<0.01 and p<0.05, respectively). Blood loss volume was significantly less with hydrosurgical debridement (p<0.01), and the wound surface area was significantly smaller on days two (p<0.01), four (p<0.05) and seven (p<0.05). Dense inflammatory cell infiltration into dermal muscle was deeper after surgical debridement (p=0.017). Reactive fibrotic tissue at the wound surface was significantly thinner (p<0.001) and the vascular endothelial cell count was significantly higher (p<0.001) after hydrosurgical debridement. CONCLUSION: The hydrosurgical system used appears to provide for minimally invasive debridement that can be performed in a relatively short period of time. Use of the device appears to minimise injury to healthy tissue and ameliorate inflammation, which in turn promotes early wound healing and reduces scar contracture. Hydrosurgical debridement appears to cause less damage to normal tissues. Furthermore, it is easier and requires less time.

Significance of FGF9 gene in resistance to anti-EGFR therapies targeting colorectal cancer: A subset of colorectal cancer patients with FGF9 upregulation may be resistant to anti-EGFR therapies.

Although fibroblast growth factor (FGF) signals are strongly associated with malignancy, limited information is available regarding the role of the FGF9 signal in colorectal cancer (CRC). In this study, we investigated the frequency of FGF9 amplification in CRC clinical specimens and the association between the FGF9 gene and resistance to anti-EGFR therapies. In clinical samples, an FGF9 copy number gain of >5 copies was observed at a frequency of 8/145 (5.5%) and tended to be related to wild-type KRAS (7/96, 7.3%). Furthermore, FGF9 amplification was not observed in any of the samples from the 15 responders to anti-EGFR therapies but was observed in one sample from the seven non-responders with wild-type KRAS, and two samples from non-responders also had high FGF9 mRNA expression levels. FGF9 amplification was validated using a fluorescence in situ hybridization (FISH) analysis, and FGF9-amplified sections showed readily detectable signals originating from FGF9 protein when examined using immunohistochemistry. In both the in vitro and in vivo experiments using FGF9-overexpressing CRC cell lines, FGF9 overexpression induced strong resistance to anti-EGFR therapies via the enforced FGFR signal, and this resistance was cancelled by the application of an FGFR inhibitor. Considering these results, the FGF9 gene may play an important role in resistance to anti-EGFR therapies in patients with CRC, and such resistance might be overcome by combined treatment with an anti-FGFR inhibitor. These findings strongly encourage the development of FGFR-targeted therapy for CRC patients with FGF9 gene upregulation. © 2016 Wiley Periodicals, Inc.

A Rare Case of a Primary Cutaneous Desmoplastic Atypical Granular Cell Tumor.

Granular cell tumors are uncommon neoplasms and a small number of these neoplasms have been reported as showing malignant behavior. Here, we report a rare case of a solitary granular cell tumor that exhibited atypical histology, including an extensive desmoplastic stroma, in a 69-year-old woman. The surgical specimen revealed localized areas of spindling cells, areas of cellular pleomorphism, and p53 overexpression. Based on previously published criteria, we classified this lesion as an atypical granular cell tumor. To date, only very few case reports have documented this desmoplastic variant of granular cell tumor. However, the classifications of benign, atypical, and malignant granular cell tumors are still controversial, owing to an overlap of morphological and immunohistochemical profiles and lack of consistent histological criteria. Additionally, it is unknown whether the histology of the desmoplastic variant in the present case is significant for the classification of granular cell tumors and prediction of patient prognosis. Regardless of these issues, awareness, and close follow-up are required because of potential recurrences of this rare variant of granular cell tumor.

A case of Ménétrier's disease seemingly caused by hilar cholangiocarcinoma.

A 54-year-old man presented to our department with abdominal discomfort and anorexia and was diagnosed as having Ménétrier's disease (MD) with hilar cholangiocarcinoma. Based on his clinical examination, there was no evidence of Helicobacter pylori or cytomegalovirus (CMV) infection. Although we administered proton pump inhibitor and high-calorie enteral nutrition, hypoproteinemia did not improve, and the refractory protein-losing enteropathy persisted. However, interestingly, MD improved immediately after resection of the hilar cholangiocarcinoma. Generally, the etiology of MD is unknown, but H. pylori and CMV infections have been implicated. To our knowledge, there has been no previous report indicating that a malignant tumor could be involved in the etiology of MD. Thus, we report an extremely rare case of MD which is seemingly caused by malignancy.

Applicability of the FDA-approved Immunohistochemical Panel for Identification of MMRd Phenotype in Uterine Endometrioid Carcinoma.

Recently, the US Food and Drug Administration (FDA) approved the Ventana MMR RxDx Panel as the first immunohistochemical companion diagnostic test for identification of tumors with mismatch repair (MMR) status. The aim of this study was to investigate the accuracy of this test in comparison with polymerase chain reaction (PCR)-based microsatellite instability (MSI) analysis. We assessed the MMR/MSI concordance rate in 140 cases of endometrioid carcinoma. MMR status was evaluated by immunohistochemistry (MMR-IHC), and MSI status was evaluated by PCR-based analysis (MSI-PCR). Potential molecular mechanisms responsible for MSH6 staining variations were also analyzed. Immunohistochemistry showed that 34 tumors (24.3%) were MMRd; these included 26 with combined MLH1/PMS2 loss, 2 with combined MSH2/MSH6 loss, and 6 with isolated MSH6 loss. Heterogeneous MSH6 loss was found in 10 tumors and was recognized only in tumors with combined MLH1/PMS2 loss. Eight of 10 tumors with heterogeneous MSH6 loss harbored MSH6 C8 tract instability, suggesting a secondary somatic event after MLH1/PMS2 loss. MSI-PCR revealed that 102 tumors were MSS, 4 were MSI-low, and 34 were MSI-high. Consequently, MMR-IHC and MSI-PCR showed perfect concordance (kappa=0.080, P <0.0001). However, 10 of the 34 MSI-high tumors, including the 6 tumors with isolated MSH6 loss, showed only minimal microsatellite shift by MSI-PCR, which may have been erroneously interpreted as MSS or MSI-low. On the basis of these findings, we consider that the FDA-approved immunohistochemical panel can detect MMR variations consistently and is more accurate than MSI-PCR for determining the applicability of immune checkpoint inhibitors for treatment of endometrioid carcinomas.

Migration rate of proximal adductor canal block catheters placed parallel versus perpendicular to the nerve after total knee arthroplasty: a randomized controlled study.

BACKGROUND: Perineural catheters placed parallel to the nerve course are reported to have lower migration rates than those placed perpendicular to it. However, catheter migration rates for a continuous adductor canal block (ACB) remain unknown. This study compared postoperative migration rates of proximal ACB catheters placed parallel and perpendicular to the saphenous nerve. METHODS: Seventy participants scheduled for unilateral primary total knee arthroplasty were randomly assigned for parallel or perpendicular placement of the ACB catheter. The primary outcome was the migration rate of the ACB catheter on postoperative day (POD) 2. Catheter migration was defined as being unable to confirm saline administration via the catheter around the saphenous nerve at the mid-thigh level under ultrasound guidance. Secondary outcomes included active and passive range of motion (ROM) of the knee on postoperative rehabilitation. RESULTS: Sixty-seven participants were included in the final analyses. The catheter migrated significantly less often in the parallel group (5 of 34 (14.7%)) than in the perpendicular group (24 of 33 (72.7%)) (p<0.001). The mean (SD) active and passive knee flexion ROM (degrees) improved significantly in the parallel than in the perpendicular group (POD 1: active, 88.4 (13.2) vs 80.0 (12.4), p=0.011; passive, 95.6 (12.8) vs 85.7 (13.6), p=0.004; POD 2: active, 88.7 (13.4) vs 82.2 (11.5), p=0.036; passive, 97.2 (12.8) vs 91.0 (12.0), p=0.045). CONCLUSION: Parallel placement of the ACB catheter provided a lower postoperative catheter migration rate than perpendicular placement of the ACB catheter along with corresponding improvements in ROM and secondary analgesic outcomes. TRIAL REGISTRATION NUMBER: UMIN000045374.

Cyclic stretch induces upregulation of endothelin-1 with keratinocytes in vitro: possible role in mechanical stress-induced hyperpigmentation.

The aim of this study was to investigate the possible pathological relation between mechanical stress and hyperpigmentation. We did this by investigating the influence of cyclic stretch on the expression of keratinocyte- and fibroblast-derived melanogenetic paracrine cytokines in vitro. Using primary human keratinocytes and fibroblasts, alterations of mRNA expression of melanogenetic paracrine cytokines due to cyclic stretch were investigated using a real-time polymerase chain reaction (PCR). The cytokines included basic fibroblast growth factor (bFGF), stem cell factor (SCF), granulocyte/macrophage colony-stimulating factor, interleukin-1α, and endothelin-1 (ET-1) for keratinocytes and bFGF, SCF, and hepatocyte growth factor for fibroblasts. The dose dependence of keratinocyte-derived ET-1 upregulation was further investigated using real-time PCR and an enzyme-linked immunosorbent assay. We also investigated the effects of cyclic stretch on the proliferation and differentiation of keratinocytes. Among the melanogenetic paracrine cytokines investigated, keratinocyte-derived ET-1 was consistently upregulated in all four cell lines. The degree of upregulation increased with the degree of the length and frequency of the stretch; in contrast, cell number and differentiation markers showed no obvious alterations with cyclic stretch. Keratinocyte-derived ET-1 upregulation possibly plays a significant role in the pathogenesis of pigmented disorders, such as friction melanosis, caused by mechanical stress.

Function of EWS-POU5F1 in sarcomagenesis and tumor cell maintenance.

POU5F1 is a transcription factor essential for the self-renewal activity and pluripotency of embryonic stem cells and germ cells. We have previously reported that POU5F1 is fused to EWSR1 in a case of undifferentiated sarcoma with chromosomal translocation t(6;22)(p21;q12). In addition, the EWS-POU5F1 chimeras have been recently identified in human neoplasms of the skin and salivary glands. To clarify the roles of the EWS-POU5F1 chimera in tumorigenesis and tumor cell maintenance, we used small-interfering RNA-mediated gene silencing. Knockdown of EWS-POU5F1 in the t(6;22) sarcoma-derived GBS6 cell line resulted in a significant decrease of cell proliferation because of G1 cell cycle arrest associated with p27(Kip1) up-regulation. Moreover, senescence-like morphological changes accompanied by actin polymerization were observed. In contrast, EWS-POU5F1 down-regulation markedly increased the cell migration and invasion as well as activation of metalloproteinase 2 and metalloproteinase 14. The results indicate that the proliferative activity of cancer cells and cell motility are discrete processes in multistep carcinogenesis. These findings reveal the functional role of the sarcoma-related chimeric protein as well as POU5F1 in the development and progression of human neoplasms.

Tissue reactions to cog structure and pure gold in lifting threads: a histological study in rats.

BACKGROUND: Thread lifting has become popular as a minimally-invasive suspension procedure, but there is little basic and clinical evidence in the literature on the long-term effects. OBJECTIVES: The authors investigate the effects of two types of lifting threads in a rat model over the course of seven months. METHODS: The dorsal skin of 18 Wistar rats was implanted with a 20-mm fragment of one of three types of thread: nonabsorbable monofilament cog, pure gold (24 karat) with no cog, and pure gold-coated cog. Six rats were in each group. Tissue samples were harvested and histologically evaluated at one, three, and seven months. RESULTS: Histological assessment indicated (1) acute tissue reactions to the regular cog thread involving myofibroblasts and (2) delayed tissue reactions to the pure gold thread involving giant cells. The gold-coated cog thread showed a combination of the histological reactions associated with the cog thread and the pure gold thread, including faint early reactions, strong delayed reactions, and long-lasting capsule formation. Notably, the gold coating gradually came loose from the thread surface, suggesting that the release of tiny gold particles may promote longer-lasting tissue reactions. CONCLUSIONS: The combination of cog structure and pure gold coating was evaluated for the first time in this study and results suggest that the gold-coated cog thread has clinical potential.

Development of white globe appearance lesions in the noncancerous stomach after vonoprazan administration: a report of two cases with a literature review.

White globe appearance has recently been identified as a novel endoscopic marker useful in the diagnosis of early gastric cancer. Recently, this lesion has also been reported in the noncancerous stomach, including cases with autoimmune atrophic gastritis, although the clinical significance remains unclear. We present the details of a 68-year-old woman who began vonoprazan therapy for severe gastroesophageal reflux disease causing esophageal stricture. On follow-up endoscopy 1 year after beginning vonoprazan, multiple white globe appearance lesions developed in all sections of her stomach, except for the antrum. We also detected lesions during a yearly follow-up in the noncancerous stomach of a 70-year-old man who had received vonoprazan for 3 years. Lesions in both cases constituted cystic gland dilatations containing eosinophilic material. There was no evidence of accompanying autoimmune atrophic gastritis in either patient. This report is the first to our knowledge describing newly developed white globe appearance lesions in the noncancerous stomach during follow-up in two cases who received vonoprazan. Our findings suggest that these lesions in the noncancerous stomach might be associated with vonoprazan treatment. We investigated the two cases endoscopically and histologically, and we report our findings with a literature review.

Marked reduction in the number of white globe appearance lesions in the noncancerous stomach after exchanging vonoprazan for esomeprazole treatment: a follow-up case report.

Recently, an association has been suggested between development of white globe appearance lesions in the noncancerous stomach and treatment with a potassium-competitive acid blocker or a proton pump inhibitor. We previously reported two cases with development of white globe appearance lesions after vonoprazan treatment, suggesting a similar association. Here, we present the follow-up report of one of those two cases, concerning a 68-year-old woman who developed multiple white globe appearance lesions 1 year after starting vonoprazan treatment for severe gastroesophageal reflux disease leading to esophageal stricture. The patient refused to continue vonoprazan treatment after the lesions developed, and esomeprazole was initiated instead. Three months later, most of the white globe appearance lesions had disappeared, without worsening of her gastroesophageal reflux disease. Histologically, mucosal structural changes induced by vonoprazan, such as parietal cell protrusion with oxyntic gland dilatation, remained unchanged, whereas the gastric glands became less packed and a small calcification in the concentrated eosinophilic material was observed in a remaining white globe appearance cyst after esomeprazole treatment. Here, we discuss possible pathogenic mechanisms of these dramatic gastric mucosal changes observed in the present case, based on our endoscopic and histological findings.

Continuous pericapsular nerve group block for postoperative pain management in total hip arthroplasty: report of two cases.

BACKGROUND: Total hip arthroplasty (THA) is one of the surgical procedures associated with severe postoperative pain. Appropriate postoperative pain management is effective for promoting early ambulation and reducing the length of hospital stay. Effects of conventional pain management strategies, such as femoral nerve block and fascia iliaca block, are inadequate in some cases. CASE PRESENTATION: THA was planned for 2 patients with osteoarthritis. In addition to general anesthesia, continuous pericapsular nerve group (PENG) block and lateral femoral cutaneous nerve (LFCN) block were performed for postoperative pain management. Numerical rating scale (NRS) scores measured at rest and upon movement were low at 2, 12, 24, and 48 h postoperatively, suggesting that the treatments were effective for managing postoperative pain. The Bromage score at postoperative days (POD) 1 and 2 was 0. CONCLUSION: Continuous PENG block and LFCN block were effective for postoperative pain management in patients who underwent THA. PENG block did not cause postoperative motor blockade.

The value of the portable fibrinogen measuring device-a case report of severe postpartum hemorrhage with obstetric disseminated intravascular coagulation.

BACKGROUND: Fibrinogen concentration is an important indicator of the treatment for obstetric disseminated intravascular coagulation (DIC). We present how using the fibrinogen measuring device could solve problems in the treatment of postpartum hemorrhage with complicated DIC. CASE PRESENTATION: A 32-year-old woman with monochorionic diamniotic twins at 22 weeks of pregnancy was diagnosed with placental abruption and underwent emergent cesarean section. The estimated blood loss was 8375 g. She was transferred to our hospital for further treatment. Compressive uterine sutures and balloon tamponade were performed. We transfused fibrinogen and fresh frozen plasma actively during the operation to maintain plasma fibrinogen above 200 mg/dL by using a point-of-care fibrinogen measuring device. In spite of massive hemorrhage exceeding 10 L, she was extubated at the end of the operation and discharged on the 7th day after the operation. CONCLUSION: The portable fibrinogen measuring device was useful for point-of-care assessment of obstetric DIC.

A desmoplastic fibroblastoma that developed in the anterior mediastinum: a case report.

BACKGROUND: Desmoplastic fibroblastoma (also known as collagenous fibroma) is a benign, slowly growing soft-tissue tumor. Most desmoplastic fibroblastomas develop in the limbs, neck, or trunk. A mediastinal origin is quite rare. CASE PRESENTATION: A 32-year-old Asian female was referred to us for the diagnosis and treatment of an anterior mediastinal tumor. The tumor was 80 mm in the largest diameter and was located on the pericardium. No invasion was evident. She underwent resection of the tumor via video-assisted thoracoscopic resection. The tumor was totally encapsulated, and its pedicle was on the pericardium. The resected specimen was very rigid, making it difficult to remove from the intercostal space. Histologically, the tumor was composed of a paucicellular dense collagenous tissue. Mitosis was rarely observed, and cellular atypia was not evident, suggesting that the tumor was benign. We diagnosed the tumor as a desmoplastic fibroblastoma by morphology and immunohistochemistry. CONCLUSIONS: Desmoplastic fibroblastoma of the mediastinum is an extremely rare disease. Preoperative diagnosis is difficult. Early surgical resection is suitable for diagnosis and treatment planning.

Tumor Growth Suppression With Novel Intra-arterial Chemotherapy Using Epirubicin-entrapped Water-in-oil-in-water Emulsion In Vivo.

BACKGROUND/AIM: A mixture of anticancer agents and iodized poppy seed oil (IPSO) has been widely used for intra-arterial chemotherapy of hepatocellular carcinoma. However, the anticancer agents can easily separate from IPSO, so the therapeutic potential is limited. We developed epirubicin-entrapped water-in-oil-in-water emulsion (WOW-Epi) using a double-membrane emulsification technique. MATERIALS AND METHODS: We delivered WOW-Epi through a hepatic arterial injection to VX2 hepatic tumor rabbit model (1.2 mg/kg). RESULTS: VX2 tumor growth was selectively suppressed in the WOW-Epi-treated group compared with the control treated groups. The accumulation of WOW in nearby cancer cells was confirmed via electron-microscopy. Endocytosis seemed to be the mechanism underlying the uptake of WOW. CONCLUSION: WOW-Epi led to tumour growth suppression in vivo. WOW does not cause toxicity to arterial vessels. WOW-Epi will be hopefully used for repeated intra-arterial chemotherapy to HCC patients in the near future.