[A Case of Myelodysplastic Syndrome Developed during Chemotherapy for Postoperative Recurrent Ovarian Cancer That Progressed to Acute Myeloid Leukemia].

Recent developments in chemotherapy for gynecologic malignancies have improved treatment results in patients and promoted long-term survival. However, various adverse events caused by long-term chemotherapy are still being observed. Here, we report a case of myelodysplastic syndrome that developed during chemotherapy for recurrent ovarian cancer and progressed to acute myeloid leukemia. However, chemotherapy for ovarian cancer was continued while maintaining the quality of life under certain conditions, such as maintenance of platelet levels in collaboration with a hematologist. A 69- year-old woman(gravida 3, para 2)was diagnosed with stage ⅢC ovarian cancer in our department. After 6 cycles of preoperative chemotherapy with paclitaxel plus carboplatin plus bevacizumab(TC plus Bev), we performed a simple abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy, sigmoid colon resection, and low anterior resection. Postoperatively, 3 cycles of TC plus Bev and 6 cycles of Bev monotherapy were completed for stage ⅢC ovarian cancer (ypT3cNXM0, high-grade serous carcinoma). However, the cancer recurred, and the patient received 3 cycles of gemcitabine plus Bev and 3 cycles of doxorubicin plus Bev. Precursor cells and prolonged neutropenia were observed, and myelodysplastic syndrome was diagnosed. One month later, the condition progressed to acute myeloid leukemia. The patient's neutrophil count recovered spontaneously, and subsequently, 7 cycles of weekly paclitaxel plus Bev therapy were completed along with symptomatic treatment. Unfortunately, she died of septic shock against the background of acute myeloid leukemia. It is important to monitor the appearance of blasts for early detection of therapy-related myelodysplastic syndromes occurring during chemotherapy, as in the case in this report. Additionally, it is important to maintain platelet count and continue chemotherapy for the primary disease.

Pembrolizumab monotherapy in Japanese patients with advanced ovarian cancer: Subgroup analysis from the KEYNOTE-100.

Interim results from the two-cohort, phase 2 KEYNOTE-100 study (NCT02674061) of 376 patients with previously treated advanced recurrent ovarian cancer (ROC) showed that pembrolizumab monotherapy was associated with an objective response rate (ORR) of 8.0% (95% CI, 5.4-11.2). We present outcomes for the Japanese patients (n = 21) enrolled in KEYNOTE-100. Patients with epithelial ROC had received either 1-3 prior chemotherapy lines and had platinum-free interval or treatment-free interval (PFI; TFI) of 3-12 months (cohort A) or 4-6 prior chemotherapy lines and had PFI/TFI of ≥3 months (cohort B). All patients received pembrolizumab 200 mg every 3 weeks as monotherapy for 2 years or until progression, death, unacceptable toxicity or consent withdrawal. Primary objectives were ORR per RECIST v1.1 for each cohort and higher programmed death ligand-1 (PD-L1) tumor expression. The relationship between PD-L1 expression (measured as combined positive score [CPS]) and ORR was assessed. Twenty-one Japanese patients (cohort A, n = 19; cohort B, n = 2) were treated. The median (range) age was 57 (37-78) years; 19 (90.5%) patients had ECOG status of 0 and 16 (76.2%) patients had stage III-IV disease. ORR was 19.0% (95% CI, 5.4-41.9) and seemed to increase with increasing PD-L1 expression. A total of 13 (61.9%) patients had treatment-related adverse events (TRAE), and 5 (23.8%) had grade 3-4 TRAE. There were no treatment-related deaths in this subpopulation. Pembrolizumab monotherapy was associated with antitumor activity in Japanese patients with ROC, with no new safety signals identified in this subpopulation. The data suggested a trend toward higher PD-L1 expression among some patients with higher ORR.

A multi-institutional observational study on the effects of three-dimensional radiotherapy and weekly 40-mg/m2 cisplatin on postoperative uterine cervical cancer patients with high-risk prognostic factors.

BACKGROUND: The aim of this study was to evaluate the effects of treatment with both three-dimensional radiotherapy (3DRT) and weekly 40-mg/m2 cisplatin on postoperative uterine cervical cancer patients with high-risk prognostic factors. METHODS: We conducted a retrospective multi-institutional chart review of postoperative uterine cervical cancer patients with high-risk prognostic factors who had been treated with both 3DRT and weekly 40-mg/m2 cisplatin from 2007 to 2012. Each participating hospital provided detailed information regarding patient characteristics, treatment outcomes, and treatment complications. RESULTS: The eligible 96 patients were analyzed. The median follow-up period was 61 months. The 3-year relapse-free survival, overall survival (OS), and locoregional relapse-free survival (LRFS) rates were 76%, 90%, and 88%, respectively. In multivariate analysis, the histological finding of either adenocarcinoma or adenosquamous carcinoma was a significant risk factor for both OS and LRFS. The percentage of patients with grade ≥ 3 acute hematologic toxicity, acute lower gastrointestinal toxicity (GIT), and late lower GIT were 45%, 19%, and 17%, respectively. CONCLUSIONS: The outcomes of concurrent chemoradiotherapy (CCRT) using weekly 40-mg/m2 cisplatin are similar to those in the previous studies that used several chemotherapy regimens. However, postoperative CCRT using 3DRT had a high level of late GIT.

Two cases of uterine malignant lymphoma diagnosed by needle biopsy.

The incidence of primary malignant lymphoma arising in the female genital tract is extremely rare and constitutes approximately 0.05% of malignant tumors. Uterine malignant lymphoma develops in the endometrial stroma, causing minimal necrosis. It is therefore difficult to diagnose malignant lymphoma, as it does not involve genital bleeding or epithelial defects. We have performed transcervical needle biopsies from deep in the myometrium, with the purpose of diagnosing uterine muscle layer lesions, such as leiomyosarcoma, but this is an unusual method. In this report, we suggest that transcervical needle biopsy is useful in the diagnosis of uterine malignant lymphoma.

[Transvaginal ultrasound-guided core needle biopsy for residual potentially malignant ovarian tumors in cases with severe peritoneal adhesion and frozen pelvis requiring polysurgery].

A multiparous woman in her 40s had advanced peritoneal adhesions and frozen pelvis from 3 previous surgeries. Endometrial ovarian cysts also remained. After the last surgery, imaging showed cysts with a septum and enhanced moieties in the Douglas pouch. Highly invasive surgery was anticipated, and the patient underwent a transvaginal ultrasound-guided core needle biopsy(TVCNB, 16-gauge needle)with full awareness of the risks involved. The histopathological diagnosis was adenocarcinoma. We inserted a ureteral stent and performed an S-shaped colon resection and standard ovarian cancer surgery after preoperative chemotherapy. TVCNB in this case was less invasive and easier to perform than other exploratory procedures, and has a low risk of iatrogenic intraperitoneal dissemination even if the tumor is malignant. Chemotherapy can be administered before surgery if malignancy is detected. In summary, TVCNB is a useful alternative method for conducting exploratory operations.

[Sustained remission over 10 years after rituximab-monotherapy in a patient with primary duodenal follicular lymphoma].

A 79-year-old man received gastrointestinal endoscopy for reexamination of a gastric submucosal tumor in May 2002 and whitish granular mucosa was found near the ampulla of Vater of the duodenum, though biopsy specimens showed only lymphocyte infiltrations. In December 2002, a second gastrointestinal endoscopy revealed an irregular granular elevated lesion around the ampulla of Vater and biopsy specimens showed pathological findings of follicular lymphoma. No other abnormal findings raising suspicion of tumor formation were observed on systemic examinations and the diagnosis of duodenal follicular lymphoma was confirmed. Systemic chemotherapy using rituximab at 375 mg/m(2) weekly for 4 consecutive weeks was started in January 2003. Six months later, endoscopic findings of the lesions revealed nearly normal mucosa around the ampulla of Vater, though histologically the biopsy specimens showed residual lymphoma cells. The same rituximab therapy as before was started in November. There has been no evidence of recurrence and a prolonged, more than 10 years, complete remission has been achieved.

Abnormal cross-talk between mutant presenilin 1 (I143T, G384A) and glycosphingolipid biosynthesis.

Mutations in the presenilin 1 (PS1) gene are associated with early onset familial Alzheimer's disease (FAD). In this study, we found that the expression of mutant-PS1 in stable transfectants of SH-SY5Y neuroblastoma cells results in a reduction of the biosynthesis and steady-state levels of glucosylceramide. As an in vivo corroboration of these data, there was a significant reduction of brain glucosylceramide and gangliosides in an animal model of FAD. In mutant-PS1-transfectants (I143T, G384A), immunocytochemistry disclosed a remarkable reduction of glucosylceramide synthase (GlcT-1)-like immunoreactivity in the cells when compared with those of mock- and wild-PS1 transfectants. Immunoprecipitation of GlcT-1 protein from mutant-PS1 transfectants demonstrated a marked reduction in GlcT-1 protein, but there was no reduction in the levels of GlcT-1 mRNA. Both coprecipitation and γ-secretase inhibition experiments suggest that mutant-PS1 seems to form a complex with GlcT-1 protein and to be involved in GlcT-1 degradation, which was never found in other cell types. Thus, mutations in the PS1 gene result in profound glycosphingolipids abnormalities by abnormal molecular interaction with GlcT-1.

Clinical management of atypical polypoid adenomyoma of the uterus. A clinicopathological review of 29 cases.

OBJECTIVE: The clinical management of atypical polypoid adenomyoma (APAM) of the uterus remains to be established. We collected APAM cases, reviewed the clinicopathological features, and discussed the clinical management. METHODS: Twenty-nine patients with APAM were identified by searching the tumor registry of the Japan Clinical Oncology Group (JCOG). Clinical information and histological specimens were obtained from 13 institutional members of the JCOG, and a central pathological review was performed. RESULTS: The mean age of the patients was 38 years (range, 22-58). Squamous metaplasia was present in 19 cases (65.5%), and well-differentiated endometrioid adenocarcinoma coexisted in 5 cases (17.2%). Primary treatment consisted of dilatation and curettage in 9 patients (31.0%), vaginal resection in 2 patients (6.9%), hysteroscopic transcervical resection (TCR) using hysteroscopy in 10 patients (34.5%), and hysterectomy in 8 patients (27.6%). There were recurrences in 5 (23.8%) of the 21 cases in which fertility was preserved, and the recurrent rate was 10% (1/10) in patients those were treated with TCR and 36.4% (4/11) in those the other treatment options were selected. All patients were alive after primary treatment (a mean follow-up period was 39.6 months; range, 1-202). CONCLUSION: The clinical outcome of APAM is benign. However, differential diagnosis should be performed because of its histological similarity to invasive endometrial carcinoma and the possibility of coexistence with other endometrial neoplasms. TCR is a recommended diagnostic and treatment option for patients who desire to preserve fertility.

Neurotrophin levels in cerebrospinal fluid of adult patients with meningitis and encephalitis.

BACKGROUND: The data on cerebrospinal fluid (CSF) levels of neurotrophins (NTs) in patients with meningoencephalitis are scarce, especially in adult patients. METHODS: We measured CSF levels of NTs such as nerve growth factor (NGF), brain-derived neurotrophic factor, and neurotrophin-3 (NT-3) in adult patients with various meningitis (n = 10) and encephalitis (n = 10) in both acute phase and recovery phase and adult control subjects (n = 21) by the enzyme-linked immunosorbent assay for NTs. RESULTS: Data show that NGF and NT-3 CSF levels were markedly elevated in the patient group in the acute phase compared with non-neurological controls (p < 0.001 and p < 0.05, respectively) and later returned to the levels of controls. Most intriguingly, we only recognized a significant correlation between NGF and NT-3 CSF levels in the patients in the acute phase. CONCLUSION: Such strong correlation of NGF and NT-3 CSF levels strongly suggests that in adult patients, some common regulatory mechanism(s) might be present among various kinds of NTs to cope with central nervous system infection.

A scoring system for histopathologic and immunohistochemical evaluations of uterine leiomyosarcomas.

Uterine leiomyosarcomas (LMS) are difficult to distinguish from benign leiomyomas without surgery. In this study we performed transcervical needle biopsy on 475 patients, 8 LMS patients and 467 patients with non-sarcomas (non-LMS) in a high-risk group for LMS, and evaluated whether examinations performed with Ki-67 and CD34 immunohistochemical analyses in addition to the standard hematoxylin-eosin (H&E)-stained sections would improve preoperative diagnostic precision of the uterine smooth muscle tumors. Histopathologic analysis included three factors: degree of cytologic atypia, mitotic index and coagulative tumor cell necrosis (CTCN). We also evaluated cell proliferation with Ki-67 expression. In cases of suspected CTCN, we examined CD34 expression and counted positive blood vessels in the necrotic area. Three of the 8 LMS cases satisfied the diagnostic criteria of LMS by histopathologic evaluation with H&E-stained sections. We made a score list based on these analyses; scores for LMS specimens ranged from 6-14 points; non-LMS specimens scored 0-2 points. At the cut-off score of 6 points, the positive predictive value to distinguish LMS from non-LMS was 100%, showing that this scoring system, is a useful method for preoperative differentiation between LMS and non-LMS tumors.

Is it safe to continue antithrombotic agents before prostate biopsy?

BACKGROUND: Whether antithrombotic agents should be stopped before prostate biopsy is unsettled. We investigated the impact of antithrombotic agents on bleeding complications after prostate biopsy. MATERIALS AND METHODS: Among the patients who underwent transrectal ultrasound-guided prostate biopsy from June 2006 to December 2013 at Ebina General Hospital, Kanagawa, Japan, 1817 cases were retrospectively assessed. Patients were divided into two groups: those not taking antithrombotic agents (control group) and those taking them (experimental group). The frequency and severity of bleeding complications after the procedure were compared. The severity of bleeding events was graded using the Common Terminology Criteria for Advanced Events vol. 4.0. RESULTS: Hemorrhagic complications were classified into grades 1 to 3. Patients with complications of Grade 2 and above needed treatment. As for the Grade 1 event, there were no differences between two groups. The frequency of more than Grade 2 bleeding events was 1.7% and 3.5% in the control and experimental group, respectively; the odds ratio was 2.18 (P = 0.039). Grade 3 events occurred in seven patients of the control group (0.5%) and four patients of the experimental group (1.2%). CONCLUSIONS: The present study showed that continuation of antithrombotic agents increased the frequency of hemorrhagic complications requiring intervention. It suggests that attention should be paid to the patients taking antithrombotic agents before prostate biopsy.

Robust 3D image reconstruction of pancreatic cancer tumors from histopathological images with different stains and its quantitative performance evaluation.

PURPOSE: Histopathological imaging is widely used for the analysis and diagnosis of multiple diseases. Several methods have been proposed for the 3D reconstruction of pathological images, captured from thin sections of a given specimen, which get nonlinearly deformed due to the preparation process. The majority of the available methods for registering such images use the degree of matching of adjacent images as the criteria for registration, which can result in unnatural deformations of the anatomical structures. Moreover, most methods assume that the same staining is used for all images, when in fact multiple staining is usually applied in order to enhance different structures in the images. METHODS: This paper proposes a non-rigid 3D reconstruction method based on the assumption that internal structures on the original tissue must be smooth and continuous. Landmarks are detected along anatomical structures using template matching based on normalized cross-correlation (NCC), forming jagged shape trajectories that traverse several slices. The registration process smooths out these trajectories and deforms the images accordingly. Artifacts are automatically handled by using the confidence of the NCC in order to reject unreliable landmarks. RESULTS: The proposed method was applied to a large series of histological sections from the pancreas of a KPC mouse. Some portions were dyed primarily with HE stain, while others were dyed alternately with HE, CK19, MT and Ki67 stains. A new evaluation method is proposed to quantitatively evaluate the smoothness and isotropy of the obtained reconstructions, both for single and multiple staining. CONCLUSIONS: The experimental results show that the proposed method produces smooth and nearly isotropic 3D reconstructions of pathological images with either single or multiple stains. From these reconstructions, microanatomical structures enhanced by different stains can be simultaneously observed.

Super-Resolution of Magnetic Resonance Images via Convex Optimization with Local and Global Prior Regularization and Spectrum Fitting.

Given a low-resolution image, there are many challenges to obtain a super-resolved, high-resolution image. Many of those approaches try to simultaneously upsample and deblur an image in signal domain. However, the nature of the super-resolution is to restore high-frequency components in frequency domain rather than upsampling in signal domain. In that sense, there is a close relationship between super-resolution of an image and extrapolation of the spectrum. In this study, we propose a novel framework for super-resolution, where the high-frequency components are theoretically restored with respect to the frequency fidelities. This framework helps to introduce multiple simultaneous regularizers in both signal and frequency domains. Furthermore, we propose a new super-resolution model where frequency fidelity, low-rank (LR) prior, low total variation (TV) prior, and boundary prior are considered at once. The proposed method is formulated as a convex optimization problem which can be solved by the alternating direction method of multipliers. The proposed method is the generalized form of the multiple super-resolution methods such as TV super-resolution, LR and TV super-resolution, and the Gerchberg method. Experimental results show the utility of the proposed method comparing with some existing methods using both simulational and practical images.

Examination of the use of needle biopsy to perform laparoscopic surgery safely on uterine smooth muscle tumors.

The warning statement issued by the United States Food and Drug Administration against the use of laparoscopic power morcellators prompted a discussion about the methods of preoperative diagnosis of uterine myometrial lesions. Since 1994, transcervical needle biopsies have been performed to differentiate between uterine leiomyomas and leiomyosarcomas. Needle biopsies are also useful for performing laparoscopic surgery on uterine smooth muscle tumors with histopathological safety. In the present study, data from hematoxylin and eosin (HE)-stained specimens obtained by transcervical needle biopsies from 331 patients with smooth muscle tumors and high intensity regions on T1 weighted images (WI) and/or T2WI from magnetic resonance imaging (MRI) scans were retrospectively examined. From a total of 10 patients with moderate or severe cytological atypia, 4 exhibited smooth muscle tumors of uncertain malignant potential and 6 exhibited leiomyosarcomas. The final diagnosis in 3 patients with ≥10 mitotic figures/high-power field was leiomyosarcoma. A total of 5 patients with coagulative tumor cell necrosis exhibited final diagnoses of leiomyosarcoma. Patients without cytological atypia, mitotic figures or coagulative tumor cell necrosis were not diagnosed with either leiomyosarcomas or smooth muscle tumors of uncertain malignant potential. The present study revealed that laparoscopic surgery is safe when HE-stained specimens obtained by transcervical needle biopsy from areas of high intensity on an MRI scan are negative for all three criteria assessed-cytological atypia, mitotic figures and coagulative tumor cell necrosis.

Comparison of osteopontin expression in endometrioid endometrial cancer and ovarian endometrioid cancer.

This study compared the DNA, RNA, and protein levels of osteopontin (OPN) in endometrioid endometrial cancer (EEC) and ovarian endometrioid cancer (OEC). In total, 63 cancer cases (EEC: 33, OEC: 30) were included. Of these, 47 (EEC: 26, OEC: 21) were examined by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and 48 (EEC: 25, OEC: 23) were examined by quantitative PCR. OPN expression was detected in 15 (50.0%) of 30 EECs and in 14 (50.0%) of 28 OECs. There was no significant difference in the percentage of positive cytoplasmic OPN staining between the EECs and OECs (12.8 vs 10.4; p = 0.6811). The correlation between relative mRNA and protein expression levels was significant in both the EECs and OECs; however, the correlation between relative DNA and mRNA levels was not significant. There was no significant difference in OPN expression between the EECs and OECs.

Endometrial thickness in Japanese women with hypertension or/and type 2 diabetes mellitus.

OBJECTIVES: The purpose of this study was: (a) to examine whether the endometrium of postmenopausal women with hypertension (HT) and/or type 2 diabetes mellitus (DM) was thicker than that of healthy controls (HC) and (b) whether endometrial thickness (ET) was associated with endometrial cancer risk factors. STUDY DESIGN: A total of 242 postmenopausal women were included in this study. Thirty women with type 2 DM, 49 women with HT, 23 women with DM and HT and 140 HCs were studied. Clinical evaluation of all women was done using TVS and endometrial cytology. RESULTS: In the 140 HCs, the mean ET of nulliparous women was larger than multiparous women (3.0 mm versus 1.6 mm, p = 0.017). However, there was no significant relationship between ET and other clinical parameters such as a history of sterility or BMI. There was no significant difference in ET amongst the four groups. The relationship between ET, age, pregnancy history, menopause age, BMI and presence of DM or HT were analyzed using stepwise multivariate analysis. There was no significant relationship between these risk factors and ET (p = 0.063). CONCLUSIONS: The risk factors such as age, pregnancy history, menopause age, BMI and presence of DM or HT were not related to ET in Japanese women.

[Bilateral adrenal lymphoma with adrenal insufficiency: a case report].

A 65 year-old man visited the outpatient clinic of internal medicine complaining of fever and upper abdominal pain. Bilateral adrenal tumors were detected by CT scan and ultrasonography without any hormonal abnormalities. The diagnosis was bilateral primary non-functioning adrenal tumors because there was no tumor except adrenals with the detailed examinations. Then we are informed about the patient and he was transferred for the surgery. Cortisol was administrated because adrenal insufficiency was observed before surgery. Right adrenalectomy was performed after the recovery of patient status with cortisol. The pathological diagnosis was malignant lymphoma (diffuse large, B cell type). The patient was getting worse and dead 15 days after the surgery.

Shrinkage effect of gonadotropin releasing hormone agonist treatment on uterine leiomyomas and t(12;14).

Specific chromosomal abnormalities, e.g. del(7q), t(12;14), 12 trisomy, and the rearrangement of 6p, are seen in approximately 30% of uterine leiomyomas. We investigated the association between the shrinkage effect of GnRH agonist on uterine leiomyomas and t(12;14), the second most frequent chromosomal abnormality in myomas. This study involved 42 women with uterine leiomyomas treated with a gonadotropin releasing hormone (GnRH) agonist before surgery. The volume of the largest myoma nodule was measured by MRI before and at 12 weeks after the beginning of GnRH agonist treatment, and the percentage change in volume was calculated. A specific chromosomal abnormality, t(12;14), was examined on thin sections of frozen leiomyomas by fluorescence in situ hybridization with chromosome-specific probes. Of the 42 tumors, 8 (19%) showed translocation. The mean (+/- SD) percentages change in volume of the largest myomas without and with translocation were -32+/-24 and 23+/-60%, respectively (p=0.006). The myomas showing translocation had significantly less reduction in size with GnRH treatment than did those without translocation. No myoma with trisomy 12 was found. On the basis of our results, we assumed that uterine leiomyomas showing t(12;14) are not so dependent on ovarian hormones for growth.

Telomerase activity in needle biopsied uterine myoma-like tumors: differential diagnosis between uterine sarcomas and leiomyomas.

Preoperative differential diagnoses between uterine sarcomas and leiomyomas are difficult. As telomerase activation is thought to be essential for the immortality of malignant cells, it is considered a potentially useful diagnostic marker. The aim of the present study was to evaluate the potential diagnostic use of measuring telomerase activity in needle biopsy samples to distinguish uterine sarcoma from leiomyoma. Sixty-two patients with suspected uterine sarcomas based on clinical findings or magnetic resonance imaging findings, and who were scheduled for surgery, underwent transcervical ultrasound-guided needle biopsy. Three samples were obtained per patient for histopathological examination and telomerase activity measurement. Telomerase activity was measured using the telomeric repeat amplification protocol and correlated with final histopathological findings of surgical specimens. Of the 62 patients, 6 leiomyosarcomas and 1 endometrial stromal sarcoma (high grade) were diagnosed by histopathology. In 6 of the 7 samples from uterine sarcomas, relatively high telomerase activity (22-102 units) was detected, whereas only low telomerase activity (11-18 units) existed in 3 of the remaining 55 samples from benign or borderline uterine smooth muscle tumors. At a cut-off value of 20 units, sensitivity, specificity, positive predictive, and negative predictive values for detecting uterine sarcoma were 86% (95% confidence interval, 59-100%), 100% (94-100%), 100% (54-100%) and 98% (95-100%), respectively. The results indicated that telomerase activity in needle biopsy samples is a useful diagnostic marker to distinguish uterine sarcoma from leiomyoma.