A case of acquired hemophilia A after pancreaticoduodenectomy for distal cholangiocarcinoma.

Acquired hemophilia A (AHA) is a rare disease that results from factor VIII inhibitors causing abnormal coagulation, and certain cases may develop after highly invasive surgery. The present case study reports on a 68-year-old male patient who developed AHA after undergoing a subtotal stomach-preserving pancreatoduodenectomy for distal cholangiocarcinoma. The patient experienced complications after surgery, requiring reoperation on postoperative day (PD) 5 due to rupture of the Braun's enterostomy. On PD 6, angiography was performed after bleeding was detected in the jejunal limb, but hemostasis occurred spontaneously during the examination. Bleeding was observed again on PD 8 and direct surgical ligation was performed. On PD 14, bleeding recurred in the jejunal limb and angiography was performed to embolize the periphery of the second jejunal artery. During the procedure, the prothrombin time was normal, but only the activated partial thromboplastin time was prolonged. A close examination of the coagulation system revealed a decrease in factor VIII levels and the presence of factor VIII inhibitors, resulting in the diagnosis of AHA. Administration of steroids was initiated on PD 15 and, in addition to daily blood transfusions, activated prothrombin complex concentrate was administered to achieve hemostasis. The patient was discharged from the intensive care unit on PD 36 but later developed an intractable labial fistula due to suture failure at the gastrojejunostomy site. As the use of factor VIII inhibitors continued despite the administration of steroids, cyclophosphamide (CPA) pulse therapy was added at PD 58. However, CPA was ineffective and the administration of rituximab was initiated on PD 98. After 12 courses of rituximab, the patient tested negative for factor VIII inhibitors on PD 219. On PD 289, labial fistula closure was performed with continuous replacement of factor VIII and the patient was discharged on PD 342.

Clinicopathological significance of claspin overexpression and its efficacy as a novel biomarker for the diagnosis of urothelial carcinoma.

We previously reported that claspin is a key regulator in the progression of gastric cancer and renal cell carcinoma. However, the clinicopathological significance of claspin in urothelial carcinoma (UC) has not been investigated. We analyzed the expression and distribution of claspin in UC cases by immunohistochemistry. In the non-neoplastic urothelium, the expression of claspin was either weak or absent, whereas UC tissues showed nuclear staining. The expression of claspin was detected in 58 (42%) of a total of 138 upper tract UC cases treated by radical nephroureterectomy without neoadjuvant chemotherapy. Claspin-positive UC cases were associated with nodular/flat morphology, variant histology, high tumor grade, high pathological T grade, and lymphatic and venous invasion. The expression of claspin was significantly associated with decreased progression-free survival and cancer-specific survival. In addition, claspin was co-expressed with Ki-67, PD-L1, HER2, EGFR, and p53 in consecutive tumor sections of UC. An immunohistochemical analysis of claspin in biopsy specimens revealed that strong to moderate claspin staining was more frequently observed in carcinoma in situ in comparison to dysplasia or the benign urothelium. Furthermore, immunocytochemistry for claspin on urine cytology slides demonstrated that the proportion of claspin-positive cells was significantly greater in high-grade UC than in benign cases. These results suggest that claspin may be a novel prognostic marker and a possible therapeutic target molecule for UC. Moreover, claspin could be a useful diagnostic biomarker of urothelial neoplasia.

Detailed chromosome analysis of wild-type, immortalized fibroblasts with SV40T, E6E7, combinational introduction of cyclin dependent kinase 4, cyclin D1, telomerase reverse transcriptase.

Cell immortalization enables us to expand the cultured cell infinitely. However, the process of immortalization sometimes changes the nature of the original cell. In this study, we established immortalized embryonic fibroblasts with oncogenic SV40T and human papilla virus-derived E6E7, combinational expression of mutant cyclin-dependent kinase 4 (CDK4), cyclin D1, and telomerase reverse transcriptase (TERT) from identical primary wild-type human embryonic fibroblasts (HE16). After the establishment of immortalized cells, we compared the details of chromosome condition with the G-banding and Q-banding methods. There is no example of detailed analysis so far about chromosome abnormalities, such as trisomy, ring chromosome, reciprocal translocation, and dicentric chromosomes. The detailed chromosome analysis revealed that immortalized cells with SV40T and E6E7 showed intensive chromosome abnormalities, such as gain or loss of the chromosomes all through the genome. Furthermore, we detected that the incidence of chromosome abnormities in the immortalized cell with the combinational introduction of R24C mutant of CDK4, cyclin D1, and TERT is almost identical to that of wild-type cell. Furthermore, short tandem repeat analysis demonstrated that the origin of K4DT cell is primary HE16. These results showed that cellular immortalization with CDK4, cyclin D1, and TERT is more advantageous in keeping the chromosome's original condition than oncogenic immortalization methods.

Histological diversity and molecular characteristics in gastric cancer: relation of cancer stem cell-related molecules and receptor tyrosine kinase molecules to mixed histological type and more histological patterns.

BACKGROUND: Gastric cancers (GCs) are still one of the leading causes of cancer-related mortality. The histological and molecular features of GC may differ widely from area to area within the same tumor. Intratumoral heterogeneity has been considered a major obstacle to an efficient diagnosis and successful molecular treatment. METHODS: We selected and reevaluated 842 GC cases and analyzed the relationship between numbers or composites of histological patterns within tumors, and clinicopathological parameters in mucosal and invasive areas. In addition, we searched for the GC-associated molecules or molecular subtypes marking histological diversities. RESULTS: GC cases with more histological numbers or mixed types in invasive areas showed significantly higher T grade and staging, whereas those in mucosal areas did not show any significant associations. GCs with histological diversities showed poorer prognosis and characteristically expressed cancer stem cell-related molecules (CD44, CD133 or ALDH1) and receptor tyrosine kinase molecules (HER2, EGFR or c-MET) as well as Helicobacter pylori infection. Expressions of CD44, HER2, c-MET, laminin 5·2 or retained E-cadherin in mucosal areas were predictive of more histological numbers and mixed types in invasive areas. In addition, the chromosomal instability subtype of GC showed significant associations with more histological numbers and mixed histological type, whereas the genomic stability subtype of GC showed a significant relationship with pure type. CONCLUSIONS: We displayed the relationship between histological diversity and molecular features in GC, and we hope that the present data can contribute to the early diagnosis and prevention, and effective treatment of GC.

Chronic Kidney Disease, Gut Dysbiosis, and Constipation: A Burdensome Triplet.

Gut dysbiosis has been implicated in the progression of chronic kidney disease (CKD). Alterations in the gut environment induced by uremic toxins, the dietary restriction of fiber-rich foods, and multiple drugs may be involved in CKD-related gut dysbiosis. CKD-related gut dysbiosis is considered to be characterized by the expansion of bacterial species producing precursors of harmful uremic toxins, such as indoxyl sulfate and p-cresyl sulfate, and the contraction of species generating beneficial short-chain fatty acids, such as butyrate. Gut-derived uremic toxins cause oxidative stress and pro-inflammatory responses, whereas butyrate exerts anti-inflammatory effects and contributes to gut epithelial integrity. Gut dysbiosis is associated with the disruption of the gut epithelial barrier, which leads to the translocation of endotoxins. Research on CKD-related gut dysbiosis has mainly focused on chronic inflammation and consequent cardiovascular and renal damage. The pathogenic relationship between CKD-related gut dysbiosis and constipation has not yet been investigated in detail. Constipation is highly prevalent in CKD and affects the quality of life of these patients. Under the pathophysiological state of gut dysbiosis, altered bacterial fermentation products may play a prominent role in intestinal dysmotility. In this review, we outline the factors contributing to constipation, such as the gut microbiota and bacterial fermentation; introduce recent findings on the pathogenic link between CKD-related gut dysbiosis and constipation; and discuss potential interventions. This pathogenic link needs to be elucidated in more detail and may contribute to the development of novel treatment options not only for constipation, but also cardiovascular disease in CKD.

Claspin overexpression is associated with high-grade histology and poor prognosis in renal cell carcinoma.

Renal cell carcinoma (RCC) is one of the most common human cancers. We previously reported that claspin is a key regulator in the progression of gastric cancer, and it likely plays an important role in cancer stem cells of gastric cancer. However, the significance of claspin in RCC has not been examined. First, we analyzed the expression and distribution of claspin in 95 RCC cases by immunohistochemistry. In the nonneoplastic kidney, the staining of claspin was either weak or absent, whereas RCC tissue showed nuclear staining. In total, claspin expression was detected in 45 (47%) of 95 RCC cases. The claspin staining appeared relatively stronger in high nuclear grade RCC than in low nuclear grade RCC. Claspin-positive RCC cases were associated with higher T grade, tumor stage, nuclear grade, vein invasion, and poorer prognosis. CLSPN siRNA treatment decreased RCC cell proliferation. The levels of phosphorylated Erk and Akt were lower in CLSPN siRNA-transfected RCC cells than in control cells. In addition, claspin was coexpressed with CD44, epidermal growth factor receptor, p53, and programmed death ligand-1. These results suggest that claspin plays an important role in tumor progression in RCC and might be a prognostic marker and novel therapeutic target molecule.

Clinicopathological significance of claspin overexpression and its association with spheroid formation in gastric cancer.

Gastric cancer (GC) is one of the leading causes of cancer-related death worldwide. Spheroid colony formation is a useful method to identify cancer stem cells (CSCs). The aim of this study was to identify a novel prognostic marker or therapeutic target for GC using a method to identify CSCs. We analyzed the microarray data in spheroid body-forming and parental cells and focused on the CLSPN gene because it is overexpressed in the spheroid body-forming cells in both the GC cell lines MKN-45 and MKN-74. Quantitative reverse-transcription polymerase chain reaction analysis revealed that CLSPN messenger RNA expression was up-regulated in GC cell lines MKN-45, MKN-74, and TMK-1. Immunohistochemistry of claspin showed that 94 (47%) of 203 GC cases were positive. Claspin-positive GC cases were associated with higher T and N grades, tumor stage, lymphatic invasion, and poor prognosis. In addition, claspin expression was coexpressed with CD44, human epidermal growth factor receptor type 2, and p53. CLSPN small interfering RNA treatment decreased GC cell proliferation and invasion. These results indicate that the expression of claspin might be a key regulator in the progression of GC and might play an important role in CSCs of GC.

Endoscopic submucosal dissection followed by chemoradiotherapy for superficial esophageal cancer: choice of new approach.

BACKGROUND: The standard treatment for superficial esophageal cancer (SEC) involving muscularis mucosal (T1a-MM) or submucosal (T1b) invasion has been the surgical resection of the esophagus. However, esophagectomy with extended lymph node dissection is highly invasive. Recent reports have shown that endoscopic submucosal dissection (ESD) followed by chemoradiotherapy (CRT) has promising results and might become a new therapeutic approach. This retrospective study aimed to elucidate the efficacy and safety of this new treatment. METHODS: Patients with clinical stage T1b tumor without apparent metastasis treated with ESD followed by CRT from 2014 to 2017 (the CRT group) were included. The outcomes on disease-free survival (DFS) of this group were compared with those of consecutive patients in a historical control group who underwent ESD followed by esophagectomy (the esophagectomy group) between 2008 and 2015. RESULTS: Of 32 patients analyzed, 16 were in the CRT group and 16 with similar stage cancer were in the esophagectomy group. Radiotherapy was completed in all patients, and the incidence of grade ≥ 3 nonhematologic adverse events was 6%. The 2-year overall survival rates were 100%, and locoregional control was achieved in all patients in the CRT group, and the 2-year DFS rates were 88 and 100% for the CRT and esophagectomy groups, respectively, without significant differences. CONCLUSIONS: Our data confirmed our new approach as being safe and effective for locoregional control and may provide a nonsurgical treatment option for patients with clinical stage T1b tumors.

Author Correction: Comparison of Image-Guided Intensity-Modulated Radiotherapy and Low-dose Rate Brachytherapy with or without External Beam Radiotherapy in Patients with Localized Prostate Cancer.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Comparison of radiation dermatitis between hypofractionated and conventionally fractionated postoperative radiotherapy: objective, longitudinal assessment of skin color.

This study aimed to quantitatively compare radiation dermatitis due to hypofractionated (Hypo) and conventionally fractionated (Conv) external-beam radiotherapy in patients who underwent postoperative radiotherapy after breast-conserving surgery. Skin color changes, in terms of L* (brightness, white-black), a* (red-green), and b* (yellow-blue) values, due to external-beam radiotherapy were examined at alternate fractions using an objective method. Twenty-six patients were included in the Hypo group (42.56 Gy/16 fractions) and 46 in the Conv group (50 Gy/25 fractions). Radiotherapy decreased the L* value (darker) and increased the a* value (redder) gradually. These color alterations progressed linearly according to elapsed fractions and were similar between Hypo and Conv per fraction. The Hypo group showed significantly milder alterations in L* and a* values than the Conv group. The maximal dosage was significantly correlated to alterations in L* and a* values. Common Terminology Criteria for Adverse Events v4 assessment did not show a statistically significant difference between the Hypo (Grade 0:1:2 = 2:24:1) and Conv (1:39:6, p = 0.25) groups. The results of our objective analysis revealed that patients undergoing Hypo show milder color alteration than those undergoing Conv and that the maximal dosage is a useful predicator of color alteration.

Comparison of Image-Guided Intensity-Modulated Radiotherapy and Low-dose Rate Brachytherapy with or without External Beam Radiotherapy in Patients with Localized Prostate Cancer.

To compare the outcome of low-dose rate brachytherapy (LDR-BT) and image-guided intensity-modulated radiotherapy (IG-IMRT) for localized prostate cancer, we examined 488 LDR-BT and 269 IG-IMRT patients. IG-IMRT treated older and advanced disease with more hormonal therapy than LDR-BT, which excluded T3b-T4 tumor and initial PSA > 50 ng/ml. The actuarial five-year biochemical failure-free survival rate was 88.7% and 96.7% (p = 0.0003) in IG-IMRT and LDR-BT, respectively; it was 88.2% (85.1% for IG-IMRT and 94.9% for LDR-BT, p = 0.0578) for the high-risk group, 95.2% (91.6% and 97.0%, p = 0.3361) for the intermediate IG-IMRT and 96.8% (95.7% and 97%, p = 0.8625) for the low-risk group. Inverse probability of treatment weighting (IPTW) involving propensity scores was used to reduce background selection bias. IPTW showed a statistically significant difference between LDR-BT and IG-IMRT in high risk (p = 0.0009) and high risk excluding T3-4/initial PSA > 50 ng/ml group (p = 0.0073). IG-IMRT showed more gastrointestinal toxicity (p = 0.0023) and less genitourinary toxicity (p < 0.0001) than LDR-BT. LDR-BT and IG-IMRT showed equivocal outcome in low- and intermediate-risk groups. For selected high-risk patients, LDR-BT showed more potential to improve PSA control rate than IG-IMRT.

Active Bone Marrow With Focal FDG Accumulation Mimicking Bone Metastasis With a Case of Early Esophageal Cancer.

A 68-year-old man underwent F-FDG PET/CT for the staging of esophageal carcinoma discovered by a medical checkup. Increased focal accumulation in some vertebrae, right humerus, and right femoral bone was noted on FDG-PET, whereas CT showed relatively high attenuation, and MRI showed hypointense lesions on T1- and T2-weighted imaging. A bone biopsy revealed mildly hypercellular bone marrow in the thoracic spine with FDG accumulation and markedly hypocellular bone marrow in the pelvic bone without an increased uptake. InCl scintigraphy showed a similar distribution and confirmed the diagnosis of bone marrow reconversion.

Small amounts of ethanol attenuate folic acid stability in acidic beverages during storage.

Folic acid (FA) is an essential compound involved in important biochemical processes and is used to fortify various food products. FA in fortified acidic beverages decomposes during storage due to H+ attack. FA stability in acidic beverages is a serious problem as food fortification should guarantee labeled FA concentrations until the expiry date. In this study, we investigated the influence of ethanol (EtOH) on FA depletion using a model acidic beverage and observed that small amounts of EtOH, derived from added flavor, promoted FA depletion. FA depletion was promoted by only small amounts of EtOH, but not by acetonitrile. This suggested that FA decomposition might be accelerated by EtOH, which surrounds FA molecules in solution due to selective solvation. In the development of FA-fortified beverages, EtOH content should be decreased or removed altogether, to prevent accelerating FA decomposition.

Long-term Outcomes of a Dose-reduction Trial to Decrease Late Gastrointestinal Toxicity in Patients with Prostate Cancer Receiving Soft Tissue-matched Image-guided Intensity-modulated Radiotherapy.

BACKGROUND/AIM: We experienced an unexpected high incidence of gastrointestinal (GI) toxicity in patients undergoing image-guided intensity-modulated radiotherapy (IG-IMRT) using helical tomotherapy in our initial 2.2 Gy/fraction schedule for prostate cancer; hence, a dose-reduction trial from 2.2 Gy to 2 Gy/fraction was conducted using modified planning target volume (PTV) contouring. PATIENTS AND METHODS: We compared 130 patients treated using 2.2 Gy/fraction (Group A) and 144 treated using the 2 Gy/fraction (Group B) with modified PTV (excluding rectal volume) with a median follow-up period of 62 months. Prescribed dose was 72.6-74.8 Gy in 33-34 fractions (Group A) and 72-74 Gy in 36-37 fractions (Group B). RESULTS: Patients in Group B had a reduced rectal and bladder V10-V70 and were irradiated at the maximal dose. Their cumulative incidence of grade ≤2 GI toxicity at 5 years improved from 10.1% [95% confidence interval (CI), 4.9-15.3%] to 1.4% (0-3.3%). Grade 2≤ urinary toxicity also decreased from 5.5% (1.5-9.4%) in Group A to 1.4% (0-3.3%, p=0.0167) in Group B. The biochemical failure-free 5-year survival rate was 89.1% (95%CI=83.6-95.4%) and 87.5% (82.0-92.9%, p=0.75) in groups A and B, respectively. CONCLUSION: The reduced dose fraction schedule decreased the incidence of late GI toxicity without compromising prostate-specific antigen control. Careful target volume definition and fraction size are important even for IG-IMRT.

Palliative Reirradiation for Painful Bone Metastases: Clinical Cases and Literature Review.

Reirradiation to previously irradiated peripheral bone metastases for pain has been shown to be safe and effective, but no specific trial has been completed to define the indications for reirradiation of patients with recurrent symptoms of metastatic bone disease. Thus, we aimed to assess the effectiveness and prognostic factors of reirradiation for painful bone metastases. To do so, we reviewed the cases of 14 patients with painful bone metastases who had undergone reirradiation at our hospital. A favorable pain response after reirradiation was achieved in 50% (7/14) of the patients. An interval from initial radiotherapy >6 months was a significant prog nostic factor for pain response (p = 0.03). Performance status was correlated with pain response, with borderline significance (p = 0.06). No severe adverse events were reported. We conclude that reirradiation of painful bone metastases is effective in providing pain relief, especially for patients with a long interval from initial radiation and good performance status.

Clinical Usefulness of the Platelet-to Lymphocyte Ratio in Patients with Angiosarcoma of the Face and Scalp.

Angiosarcoma of the face and scalp (ASFS) is an extremely aggressive tumor that frequently metastasizes, often leading to death. The neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) are inflammatory markers that predict outcome of various cancers. We aimed to examine the relationship between pretreatment inflammatory markers and ASFS outcome. We included 17 patients with ASFS and a control group of 56 age- and gender-matched healthy individuals. Total white blood counts, neutrophil, lymphocyte, monocyte, and platelet counts were recorded; NLR, PLR, and LMR were calculated. Kaplan-Meier curves were used to calculate overall survival (OS) and distant metastasis-free survival (DMFS). Optimal cut-off values for each inflammatory marker were calculated using receiver operating curve analysis. Median follow-up was 22 months (range, 6-75). There was a statistically significant difference in absolute neutrophil counts and NLR between patient and control groups. Two-year OS and DMFS rates were 41% and 35%, respectively. In patients with tumors < 10 cm, PLR was highly correlated with DMFS, with the 2-year DMFS for those with a high PLR being 50% compared with 100% for those with a low PLR (p = 0.06). This study suggests that PLR is superior to NLR and LMR, and is a clinically useful marker in patients with ASFS with small tumors.

Interfractional Rectal Displacement Requiring Repeated Precaution Did Not Correlate to Biochemical Control and Rectal Toxicity in Patients with Prostate Cancer Treated with Image-guided Intensity-modulated Radiation Therapy.

AIM: To investigate the correlation between frequency of action level of interfractional rectal displacement requiring repeated precaution in patients with prostate cancer and late toxicity from image-guided intensity-modulated radiation therapy (IG-IMRT) using helical tomotherapy. PATIENTS AND METHODS: We examined 264 patients who underwent IG-IMRT during 2007-2011. Megavoltage computed tomographic (MVCT) images were acquired before radiation therapy and was examined with soft-tissue matching by comparing treatment planning images within 9,345 fractions. Displacement of the anterior rectal region larger than 5 mm, requiring repeated precaution, was defined as the level of rectal displacement requiring action (ARD). RESULTS: ARD was identified in 815 (7.7%) out of 9,345 fractions and at least once in 82% (216/264) of patients. The highest incidence of ARD (11%) was found during the initial week of treatment (first five and next five fractions), after which the incidence decreased to 6% (p<0.0001). Patients with lean body (lower body mass index (BMI) tended to have a higher incidence of ARD. We identified 16 (6%) cases of gastrointestinal toxicity and 12 (4.5%) genitourinary toxicities as a late adverse reaction (3 months or later after IG-IMRT). There was no correlation between ARD and late toxicity. Prostate-specific antigen (PSA) control was also similar (p=0.12) between those with ARD (96% at 5 year) and those without ARD (88%). CONCLUSION: ARD occurred predominantly in lean patients, during the initial week of treatment and became less likely over time. ARD was not correlated to late toxicity and PSA control, therefore, IG-IMRT technique was able to adequately control error due to interfractional prostate and rectal motion.

Local field radiotherapy without elective nodal irradiation for postoperative loco-regional recurrence of esophageal cancer.

BACKGROUND: Radiotherapy is an effective treatment for the postoperative loco-regional recurrence of esophageal cancer; however, the optimal treatment field remains controversial. This study aims to evaluate the outcome of local field radiotherapy without elective nodal irradiation for postoperative loco-regional recurrence of esophageal cancer. METHODS: We retrospectively investigated 35 patients treated for a postoperative loco-regional recurrence of esophageal cancer with local field radiotherapy between December 2008 and March 2016. The median irradiation dose was 60 Gy (range: 50-67.5 Gy). Thirty-one (88.6%) patients received concurrent chemotherapy. RESULTS: The median follow-up period was 18 months (range: 5-94 months). The 2-year overall survival was 55.7%, with a median survival time of 29.9 months. In the univariate analysis, the maximal diameter ≤20 mm (P = 0.0383), solitary lesion (P = 0.0352), and the complete remission after treatment (P = 0.00411) had a significantly better prognosis. A total of 27 of 35 patients (77.1%) had progressive disease (loco-regional failure [n = 9], distant metastasis [n = 7], and both loco-regional failure and distant metastasis [n = 11]). No patients had Grade 3 or greater mucositis. CONCLUSION: Local field radiotherapy is a considerable treatment option for postoperative loco-regional recurrence of esophageal cancer.