MR findings of polypoid endometriosis of female genital organs: report of three cases.

Polypoid endometriosis is a benign, rare variant of endometriosis that forms polypoid nodules mimicking malignant tumors. For three cases of polypoid endometriosis of female genital organs, this report presents characteristic MR imaging features reflecting the histopathological findings. The solid and microcystic pattern or the multilocular pattern both reflecting dilated endometrial glands, and characteristic morphology of the nodules, multilobulated or polypoid-shaped, were helpful diagnostic clues present in these three cases. Earlier reported MR findings were also recognized, including signal intensity similar to that of the endometrium on T2-weighted image and contrast enhanced T1-weighted image, hypointense rim on T2-weighted image, lack of diffusion restriction, and hyperintense foci on T1-weighted image. Two cases were diagnosed preoperatively based on MR imaging findings as polypoid endometriosis. Fertility-preserving treatment was administered for one patient. Preoperative inference of polypoid endometriosis from MR imaging can avoid overtreatment and lead to fertility preservation.

Acetaminophen-induced hypotension in sepsis.

BACKGROUND: Acetaminophen-induced hypotension has been reported in critically ill patients; however, it remains unclear whether mannitol, present as a stabilizing compound in acetaminophen formulations, affects hemodynamic changes. The objectives of this study were to clarify the direct effect of acetaminophen on blood pressure by comparing blood pressure changes after acetaminophen and intravenous immunoglobulin (IVIG) administration, both containing mannitol, in patients with sepsis and understand the risk factors for reduced blood pressure following acetaminophen administration. METHODS: This was a retrospective cohort study. Adult patients who were diagnosed with sepsis at Nippon Medical School Hospital, and who were undergoing continuous arterial blood pressure measurement and received intravenous acetaminophen or IVIG, were included. RESULTS: Overall, 185 patients were included, with 92 patients in the IVIG group and 93 in the acetaminophen group. The incidence of hypotension was 36.9% in the IVIG group (34 of 92 patients) and 58.0% in the acetaminophen group (54 of 93 patients) (OR = 8.26, p = 0.004). In a propensity score-matched cohort, 80 matched patients were selected. The incidence of hypotension was 37.5% in the IVIG group (15 of 40 patients) and 67.5% in the acetaminophen group (27 of 40 patients) (OR = 7.21, p = 0.007). CONCLUSIONS: Acetaminophen induced substantially greater hypotension than IVIG in patients with sepsis, with both containing mannitol. Further studies are needed to clarify the effects on hemodynamics of mannitol contained in acetaminophen formulations.

Diagnostic Value of DCE-MRI for Differentiating Malignant Adnexal Masses Compared with Contrast-enhanced-T1WI.

PURPOSE: To compare the diagnostic performance of dynamic contrast-enhanced-MR (DCE-MR) and delayed contrast-enhanced (CE)-MRI added to unenhanced MRI, including diffusion weighted image (DWI) for differentiating malignant adnexal tumors, conducting a retrospective blinded image interpretation study. METHODS: Data of 80 patients suspected of having adnexal tumors by ultrasonography between April 2008 and August 2018 were used for the study. All patients had undergone preoperative MRI and surgical resection at our institution. Four radiologists (two specialized in gynecological radiology and two non-specialized) were enrolled for blinded review of the MR images. A 3-point scale was used: 0 = benign, 1 = indeterminate, and 2 = malignant. Three imaging sets were reviewed: Set A, unenhanced MRI including DWI; Set B, Set A and delayed CE-T1WI; and Set C, Set A and DCE-MRI. Imaging criteria for benign and malignant tumors were given in earlier reports. The diagnostic performance of the three imaging sets of the four readers was calculated. Their areas under the curve (AUCs) were compared using the DeLong method. RESULTS: Accuracies of Set B were 81%-88%. Those of Set C were 81%-85%. The AUCs of Set B were 0.83 and 0.89. Those of Set C were 0.81-0.86. For two readers, Set A showed lower accuracy and AUC than Set B/Set C (less than 0.80), although those were equivalent in other readers. No significant difference in AUCs was found among the three sequence sets. Intrareader agreement was moderate to almost perfect in Sets A and B, and substantial to almost perfect in Set C. CONCLUSION: DCE-MR showed no superiority for differentiating malignant adnexal tumors from benign tumors compared to delayed CE-T1WI with conventional MR and DWI.

Diagnostic Accuracy of Magnetic Resonance Imaging for International Federation of Gynecology and Obstetrics 2018 IB to IIB Cervical Cancer Staging: Comparison Among Magnetic Resonance Sequences and Pathologies.

OBJECTIVE: This study aimed to investigate the most accurate magnetic resonance (MR) sequence for tumor detection, maximal tumor diameter, and parametrial invasion compared with histopathologic diagnoses. METHODS: Fifty-one patients with International Federation of Gynecology and Obstetrics 2018 IB1 to IIB cervical cancer underwent preoperative MR imaging and surgical resection. Two radiologists independently evaluated the tumor detection, parametrial invasion, and tumor size in each of T2-weighted image, diffusion-weighted image, and contrast-enhanced T1-weighted image. Results obtained for squamous cell carcinoma (SCC) and adenocarcinoma were also compared. RESULTS: Neither the tumor detection rate nor parametrial invasion was found to be significantly different among sequences. Tumor size assessment using MR imaging with pathology showed good correlation: r = 0.63-0.72. The adenocarcinoma size tended to be more underestimated than SCC in comparison with the pathologic specimen. CONCLUSIONS: Cervical cancer staging by MR images showed no significant difference among T2-weighted image, diffusion-weighted image, and contrast-enhanced T1-weighted image. Adenocarcinoma was prone to be measured as smaller than the pathologic specimen compared with SCC.

Diagnostic performance of preoperative MR imaging findings for differentiation of uterine leiomyoma with intraligamentous growth from subserosal leiomyoma.

PURPOSE: To evaluate the diagnostic performance of MRI findings for differentiating uterine leiomyoma with intraligamentous growth, or broad ligament fibroid, from subserosal leiomyoma. METHODS: This study included 37 patients with surgically confirmed uterine smooth muscle tumors (36 leiomyomas and one smooth muscle tumor of uncertain malignant potential) with intraligamentous growth (IL) and size-matched control of 37 patients with subserosal leiomyoma (SS). Two radiologists independently evaluated eight preoperative MRI findings: tumor shape, degeneration, attachment to uterus, ovary elevation, ureter displacement, bladder deformation, rectal displacement, and separation of round ligament (RL) and uterine artery (UA). The diagnostic values of these findings and interobserver agreement were assessed. Receiver-operating characteristic (ROC) analysis of the number of positive MRI findings for diagnosing IL was performed. Clinical outcomes including surgical method, operation time, intraoperative blood loss, perioperative complications, and postoperative hospital stay of the two groups were compared. RESULTS: Significant differences in tumor shape, attachment to uterus, ovary elevation, ureter displacement, and separation of RL and UA were found between IL and SS. Four of these findings, excluding ureter displacement, showed moderate to substantial interobserver agreement. When two or more of these four findings were positive, sensitivity, specificity, and area under the ROC curve were 91%, 77%, 0.90 in reader 1 and 82%, 89%, 0.91 in reader 2. The operation time was significantly longer for IL than for SS. CONCLUSION: Tumor shape, attachment to uterus, ovary elevation, and separation of RL and UA are useful MRI findings for differentiating intraligamentous leiomyoma from subserosal leiomyoma.

One-pot enzymatic synthesis of 2-deoxy-scyllo-inosose from d-glucose and polyphosphate.

2-Deoxy-scyllo-inosose (2DOI, [2S,3R,4S,5R]-2,3,4,5-tetrahydroxycyclohexan-1-one) is a biosynthetic intermediate of 2-deoxystreptamine-containing aminoglycoside antibiotics, including butirosin, kanamycin, and neomycin. In producer microorganisms, 2DOI is constructed from d-glucose 6-phosphate (G6P) by 2-deoxy-scyllo-inosose synthase (DOIS) with the oxidized form of nicotinamide adenine dinucleotide (NAD+). 2DOI is also known as a sustainable biomaterial for production of aromatic compounds and a chiral cyclohexane synthon. In this study, a one-pot enzymatic synthesis of 2DOI from d-glucose and polyphosphate was investigated. First, 3 polyphosphate glucokinases (PPGKs) were examined to produce G6P from d-glucose and polyphosphate. A PPGK derived from Corynebacterium glutamicum (cgPPGK) was found to be suitable for G6P production under ordinary enzymatic conditions. Next, 7 DOISs were examined for the one-pot enzymatic reaction. As a result, cgPPGK and BtrC, the latter of which is a DOIS derived from the butirosin producer Bacillus circulans, achieved nearly full conversion of d-glucose to 2DOI in the presence of polyphosphate.

Diffusion-weighted imaging of uterine adenomyosis: Correlation with clinical backgrounds and comparison with malignant uterine tumors.

AIM: To elucidate correlation between signal intensity on diffusion-weighted images (SI-DWI) and clinical backgrounds for uterine adenomyosis and to compare SI-DWI of adenomyosis and malignant uterine tumors. METHODS: This study examined 46 adenomyosis patients diagnosed using magnetic resonance imaging and 25 patients with surgically confirmed malignant uterine myometrial tumor. First, adenomyosis cases were classified visually into high-intensity and low-intensity groups based on the SI-DWI compared with that of normal uterine myometrium. Secondly, correlation was assessed between SI-DWI of adenomyosis and patient clinical background information such as age, menopausal status, menstrual cycle and dysmenorrhea severity. Third, quantitative comparison was made of low-intensity adenomyosis (LIA), high-intensity adenomyosis (HIA) and malignant tumor groups for the signal intensity ratio (SIR) on DWI and the apparent diffusion coefficient (ADC). Their diagnostic performance was evaluated using logistic regression analysis and receiver operating characteristic (ROC) analysis. RESULTS: The 46 adenomyosis cases were classified as 26 low-intensity and 20 high-intensity cases. Significant correlation was found only for menstrual cycle phases. HIA had significantly lower SIR and higher ADC than malignant tumor. The ADC of HIA was significantly higher than that of LIA. The combination of SIR and ADC showed excellent diagnostic performance (area under ROC curve, 0.99). CONCLUSION: There is a variation in signal intensity on DWI of uterine adenomyosis and it is associated with menstrual cycle phase. Adenomyosis with high signal intensity on DWI can be differentiated from malignant lesions by its lower signal intensity on DWI and higher ADC than that found for malignant uterine tumors, however overlaps exist.

Microcystic, Elongated and Fragmented Pattern Invasion Can Adversely Influence Preoperative Staging for Low-grade Endometrial Carcinoma.

PURPOSE: To investigate the influence of microcystic, elongated and fragmented (MELF) pattern invasion on preoperative evaluation of lymph node (LN) metastasis and myometrial invasion in patients with low-grade endometrial carcinoma. METHODS: The study included 192 consecutive patients with low-grade endometrial carcinoma who underwent preoperative computed tomography (CT) and magnetic resonance imaging (MRI), followed by surgery. One hundred sixty one of 192 patients underwent LN dissection and were analyzed for LN metastasis. All patients were analyzed for myometrial invasion. Presence of enlarged LN was evaluated by using size criteria on CT. Depth of myometrial invasion was evaluated on MRI using T2-weighted imaging, diffusion-weighted imaging and contrast-enhanced T1-weighted imaging comprehensively. Sensitivity and specificity for LN metastasis and deep myometrial invasion were evaluated for MELF group and non-MELF group. The difference of sensitivity between two groups was compared using Chi-square and Fisher's exact test. RESULTS: MELF pattern invasion was identified in 43/192 patients (22%). LN metastases were observed in 18/39 patients in MELF group and 6/122 patients in non-MELF group for pelvic LN and 11/29 patients in MELF group and 4/57 patients in non-MELF group for para-aortic LN. Sensitivity for the detection of pelvic LN metastasis in MELF group was significantly lower than in non-MELF group (16.7% vs 66.7%). As for the assessment of the deep myometiral invasion, pathological deep myometrial invasion were found in 31/43 patients in MELF group and 32/149 patients in non-MELF group. Sensitivity in MELF group showed lower values than in non-MELF group (54.8% vs 78.1% for reader 1, 54.8% vs 62.5% for reader 2), although there was no statistically significant difference (P = 0.09 for reader 1 and P = 0.72 for reader 2). CONCLUSION: In case of low-grade endometrial carcinoma with MELF pattern invasion, preoperative staging by CT and MRI have a risk for underestimation.

MR findings of uterine PEComa in patients with tuberous sclerosis: report of two cases.

Tuberous sclerosis complex (TSC), a rare autosomal dominant neurocutaneous disorder, is characterized by the presence of benign congenital tumors in multiple organs. Neoplasms with perivascular epithelioid cell differentiation (PEComas), including angiomyolipoma (AML) and lymphangioleiomyomatosis (LAM), can occur in association with TSC. This report describes two cases of uterine PEComas presenting characteristic MR imaging features reflecting pathological findings. From MR images, both cases showed single or multiple large, irregularly shaped or lobulated hemorrhagic lesions within the myometrium. They differed from typical adenomyotic cysts in their large size and irregular margins. Histopathologic analysis revealed that the hemorrhage was caused by adenomyosis and tumor cells that proliferated in surrounding stroma of the hemorrhagic lesions, compatible with PEComas. Microscopic observation revealed an infiltrative growth pattern of PEComas, with small nodules formed. The tumor lesions, however, were difficult to detect on MR images. The myometrium showed normal appearance on both T1-weighted and T2-weighted images in both cases. We speculate that PEComas may infiltrate extensively into the myometrium even when the myometrium shows almost normal radiologic appearance.

Ribosomal Synthesis of Backbone-Cyclic Peptides Compatible with In Vitro Display.

Backbone-cyclic peptides are an attractive class for therapeutic development. However, in vitro display technologies coupled with ribosomal synthesis are intrinsically inapplicable to such "phenotypes" because of loss of the C-terminal peptide region linking to "genotype". Here, we report a methodology enabling the display of backbone-cyclic peptides. To achieve this, genetic code reprogramming was utilized to implement a rearrangement strategy involving the ribosomal incorporation of a designer initiator containing a thiazolidine-protected cysteine and 2-chloroacetoamide (ClAc) side chain, followed by an α-thio acid and cysteine at downstream positions. Upon expression of the linear peptide, spontaneous thioester rearrangement occurs between the α-thioester and the thiol group of the cysteine, liberating the α-thio group and resulting in cross-linking to the upstream ClAc side-chain group. Then selective deprotection of the thiazolidine-protected cysteine immediately promotes intramolecular native chemical ligation, as demonstrated for various sequences and ring sizes. In this approach, the backbone-cyclic peptides retain their C-terminal peptide regions via the side-chain thioether covalent linkage, making them compatible with in vitro display.

Pharmacokinetic and pharmacodynamic studies of pregabalin suppositories based on pharmacological research.

OBJECTIVES: As commercially available pregabalin preparations are limited to oral administration, it is impossible to use it as an adjuvant analgesic for neuropathic cancer-related pain in terminally ill cancer patients with oral feeding difficulties. The objective of this study was to develop a pregabalin suppository to be available at hospitals. METHODS: Pregabalin suppositories were prepared using bases comprising six different compositions of Witepsol H-15, Witepsol S-55, and Witepsol E-75. The suppository release test and stability test were performed in vitro. The pharmacokinetics and pharmacodynamics of the suppositories were assessed in rats. KEY FINDINGS: In the in vitro releasing test, the pregabalin suppositories with H-15, H-15 : S-55 = 1 : 1, H-15 : S-55 = 2 : 1, H-15 : S-55 = 1 : 2 released approximately 100% of the pregabalin within 180 min. Among these pregabalin suppositories, only the suppository with H-15 : S-55 = 2 : 1 demonstrated an equivalent AUC0-∞ with the oral administration group. Consistent with the results of the pharmacokinetic study, the pregabalin suppository with H-15 : S-55 = 2 : 1 exhibited antinociceptive effects. In addition, the pregabalin suppository with H-15 : S-55 = 2 : 1 was stable for 12 weeks when refrigerated with light shielding. CONCLUSIONS: The pregabalin suppositories prepared in this study may be applicable for pain control for terminally cancer ill patients with oral feeding difficulties.

Pregabalin prescription for terminally ill cancer patients receiving specialist palliative care in an acute hospital.

BACKGROUND: Pregabalin is recommended as an adjuvant analgesic for neuropathic cancer-related pain, and may be taken at all steps of the World Health Organization analgesic ladder. However, unlike opioids, pregabalin treatments are limited to an oral administration route. If patients have oral feeding difficulties, it is not possible to administer any drug as an adjuvant analgesic for neuropathic cancer-related pain. Therefore, the aim of the present study was to clarify the problems of pain control after pregabalin discontinuation in terminally ill cancer patients. METHODS: Our subjects comprised cancer patients who died during their hospital stay and were referred between April 2013 and October 2015 to the palliative care team of the 899-bed Cancer Hospital at the Nippon Medical School Hospital in Japan. The medical records of each patient were retrospectively reviewed, and patient characteristics were recorded. RESULTS: We obtained data on 183 patients during the study period. Thirty-eight (20.8 %) patients were treated with pregabalin. Thirty-three (86.8 %) out of 38 patients were prescribed pregabalin for neuropathic cancer-related pain. The incidence of bony metastases was significantly higher in patients administered pregabalin than in those not taking the drug (non-pregabalin group 32.4 % vs pregabalin group 57.9 %). Pregabalin was ultimately discontinued in all patients, with the main reason being oral feeding difficulties (81.6 %). After the discontinuation of pregabalin, the amount of opioid drugs administered was increased in 56.5 % of patients with oral feeding difficulties. CONCLUSION: Our results demonstrated that the amount of opioid drugs administered was increased in more than 50 % of patients following the discontinuation of pregabalin, and was repeatedly increased for some patients. A new administration route is required for cancer patients unable to take oral medication. TRIAL REGISTRATION: UMIN000022507. May 28, 2016 retrospectively registered.

[Basic Studies on the Stability of Flavored Oral Solutions of Rebamipide].

Stomatitis frequently occurs during chemotherapy and radiotherapy for cancer. Because of its pharmacological properties including anti-inflammatory activity and stimulatory effects on endogenous prostaglandin synthesis, rebamipide has been suggested as a potentially effective treatment against stomatitis. In the present study we tested the stability of oral rebamipide solutions prepared in our hospital pharmacy using sodium alginate as a thickener to increase retention of this agent in the oral cavity, and the addition of different flavoring mixtures intended for use in enteral diets to reduce the bitterness of rebamipide and sodium alginate. Samples of oral rebamipide solution prepared with 13 kinds of flavoring and sodium alginate were evaluated in terms of their appearance, redispersibility, pH, viscosity, and rebamipide content immediately after preparation and 1, 3, 7, and 10 days after storage at room temperature under ambient light or in a cool, dark place. After 10 days of storage, favorable stability was observed in four sample solutions supplemented with green apple, pineapple, yogurt, and tomato flavoring mixtures intended for use in Elental(®) diets. These oral solutions may have potential clinical application.

Dissolution profile of 24 levofloxacin (100 mg) tablets.

Although there are 23 generic levofloxacin (100 mg) tablets (LVFX tablets) and 1 brand name LVFX tablet (supply now discontinued) in Japan, there have been no reports that have evaluated and compared the dissolution profiles of LVFX tablets using the same dissolution method. We studied the dissolution profile of LVFX tablets by the Paddle method, a standard dissolution test method. Among 23 generic LVFX tablets, 2 LVFX tablets had lower dissolution rates and 14 had higher dissolution rates than the brand name LVFX tablet. It is suggested that LVFX tablets have different dissolution profiles, which could cause different pharmacokinetic profiles.

A retrospective study of risk factors for infection in cancer patients receiving specialist palliative care.

Preventing infectious diseases in patients with cancer receiving palliative care is extremely important. However, little is known about the factors causing infection in these patients. The aim of this study was to clarify the factors contributing to infection in patients with cancer receiving palliative care. The medical records of each patient were reviewed, and patient characteristics were recorded. Factors that correlated significantly with infection, as revealed by univariate analysis, were performance status, the fall risk assessment score, and venous catheters. Our present study provides further evidence that the fall risk assessment score is a risk factor for infection. Critical infections might be prevented in patients with cancer receiving palliative care by monitoring the above 3 factors.