Safety, pharmacokinetics, and efficacy of belantamab mafodotin monotherapy in Japanese patients with relapsed or refractory multiple myeloma: DREAMM-11.

Belantamab mafodotin, a B-cell maturation antigen-targeting antibody-drug conjugate (ADC), was investigated in Japanese patients with relapsed/refractory multiple myeloma in Part 1 of the phase I DREAMM-11 study. Patients who had received ≥ 2 prior lines of therapy including a proteasome inhibitor and immunomodulatory agent were eligible. Eight patients received belantamab mafodotin monotherapy at 2.5 mg/kg (n = 4) or 3.4 mg/kg (n = 4) by intravenous infusion every 3 weeks on day 1 of each cycle until disease progression or unacceptable toxicity. Primary objectives were tolerability and safety, and secondary objectives included pharmacokinetics (PK) and efficacy. The most common Grade ≥ 3 adverse event was thrombocytopenia/platelet count decreased (2.5 mg/kg cohort, 100% [4/4]; 3.4 mg/kg cohort, 75% [3/4]), and no dose-limiting toxicities were observed. Ocular events, including keratopathy findings, were observed in most patients (2.5 mg/kg cohort, 100% [4/4]; 3.4 mg/kg cohort, 75% [3/4]) and were managed with dose modifications. All resolved within the study period. Overall response rates were 50% (2/4) in the 2.5 mg/kg cohort and 25% (1/4) in the 3.4 mg/kg cohort. Although PK profiles in Japanese patients varied, individual exposures overlapped with previous results in Western populations. Belantamab mafodotin monotherapy was generally well-tolerated and demonstrated clinical activity at both doses.

Serum lactate dehydrogenase concentration after transcatheter renal artery embolization correlates with reduction in renal angiomyolipoma volume.

BACKGROUND: The extent of renal angiomyolipoma (AML) volume reduction after renal transcatheter arterial embolization (TAE) varies between patients, with no predictive measure available. PURPOSE: To determine whether the serum lactate dehydrogenase (LDH) concentration shortly after TAE correlates with the extent of tumor shrinkage. MATERIAL AND METHODS: In a cohort of 36 patients undergoing prophylactic renal TAE for unruptured renal AML, we retrospectively acquired data from patient medical records, including serum LDH before and within 7 days after TAE and the tumor volume before and 12-36 months after TAE. The relationship between the serum level of LDH and reduction in tumor volume was evaluated using Spearman correlation analysis. RESULTS: The median LDH concentration was significantly higher after TAE than before (909.0 U/L vs. 186.5 U/L). This early post-TAE serum LDH level and LDH index (post-TAE LDH / pre-TAE LDH) correlated significantly and positively with the absolute decrease in tumor volume (both P < 0.0001). We observed no significant correlation between the relative tumor volume reduction and serum LDH level or LDH index. CONCLUSION: Serum LDH elevation occurs shortly after TAE and correlates with the extent of absolute decrease in AML volume at 12-36 months after TAE. Further large-scale studies are warranted to confirm the predictive role of post-TAE serum LDH level and LDH index in tumor shrinkage in patients with unruptured renal AML.

Use of Non-Contrast-Enhanced MR Angiography to Assess Recanalization after Uterine Artery Embolization.

The purpose of this study was to examine the use of non-contrast-enhanced MR angiography (MRA) for assessing recanalization of uterine arteries (UAs) after uterine artery embolization (UAE) for symptomatic fibroids. Pre-procedural and follow-up unenhanced MRA images of 30 patients were reviewed, and the extent to which the UAs could be visualized was classified on a 4-point scale. An increase in the score between consecutive time points indicates that a previously inconspicuous segment of the UA became visible on follow-up images. Patients were divided into two groups according to the presence (or absence) of recanalization. The median UA visualization score at each follow-up was significantly lower than that at baseline (p < 0.01), but there was no significant difference between the scores of the follow-up images. Recanalization was detected in 63% (19/30) of patients. In these patients, the mean decrease in uterine and largest fibroid volume at 12 months after UAE was inferior to the mean decrease in patients for whom recanalization was not detected. Based on MRA assessment, recanalization after UAE occurred in 63% of patients but did not compromise the reduction in uterine and dominant fibroid volumes within 12 months after UAE.

Comparison of 1.5 T and 3 T non-contrast-enhanced MR angiography for visualization of uterine and ovarian arteries before uterine artery embolization.

OBJECTIVES: This study aimed to compare the performance of non-contrast-enhanced magnetic resonance angiography (NCE-MRA) at 1.5 T and 3 T for the visualization of uterine and ovarian arteries (OAs) before uterine artery embolization (UAE). METHODS: Preprocedural pelvic NCE-MRA images of 85 symptomatic patients undergoing UAE for the treatment of uterine leiomyomas were reviewed by two specialists in pelvic MRI. Left and right uterine arteries (UAs) were judged separately and scored on a 5-point scale. Score 5 was the highest, in which the UA could be visualized inside the musculature, forming a peritumoral plexus. Score 1 was the lowest, where visualization was limited to the descending segment. The detection of enlarged OAs was also compared. The Mann-Whitney U and Fisher exact tests were used for statistical analysis. p < 0.05 was considered to be statistically significant. RESULTS: Of the 170 UAs, 110 were classified at 1.5 T and 60 were classified at 3 T. Median (interquartile range [IQR]) score was 3 (IQR: 2-4) for visualization at 1.5 T vs 5 (IQR: 4-5) for 3 T. The scores for UA visualization were significantly higher at 3 T (p < 0.05). For enlarged OAs, NCE-MRA at 1.5 T and 3 T visualized 7 and 5 enlarged OAs, respectively; there was no significant difference between the two field strengths (p = 0.36). CONCLUSIONS: NCE-MRA performed at 3 T can visualize UAs over a greater range than at 1.5 T. No difference was found regarding the detection of enlarged OAs. KEY POINTS: • Preprocedural MRA can provide interventional radiologists with valuable information, including the origin and course of the uterine arteries and the existence of collateral feeders to the tumor. • This study demonstrates the superiority of non-contrast-enhanced MRA performed at 3 T over that performed at 1.5 T in the visualization of the uterine arteries in patients undergoing uterine artery embolization for the treatment of uterine leiomyomas. • Non-contrast-enhanced MRA is a useful imaging modality for patients with symptomatic leiomyoma undergoing uterine artery embolization in whom contrast administration is unfeasible. If available, it is preferable to perform the examination with a 3 T MR unit rather than a 1.5 T MR unit.

Coculture in vitro with endothelial cells induces cytarabine resistance of acute myeloid leukemia cells in a VEGF-A/VEGFR-2 signaling-independent manner.

An interaction between acute myeloid leukemia (AML) cells and endothelial cells in the bone marrow seems to play a critical role in chemosensitivity on leukemia treatment. The endothelial niche reportedly enhances the paracrine action of the soluble secretory proteins responsible for chemoresistance in a vascular endothelial growth factor A (VEGF-A)/VEGF receptor 2 (VEGFR-2) signaling pathway-dependent manner. To further investigate the contribution of VEGF-A/VEGFR-2 signaling to the chemoresistance of AML cells, a biochemical assay system in which the AML cells were cocultured with human endothelial EA.hy926 cells in a monolayer was developed. By coculture with EA.hy926 cells, this study revealed that the AML cells resisted apoptosis induced by the anticancer drug cytarabine. SU4312, a VEGFR-2 inhibitor, attenuated VEGFR-2 phosphorylation and VEGF-A/VEGFR-2 signaling-dependent endothelial cell migration; thus, this inhibitor was observed to block VEGF-A/VEGFR-2 signaling. Interestingly, this inhibitor did not reverse the chemoresistance. When VEGFR-2 was knocked out in EA.hy926 cells using the CRISPR-Cas9 system, the cytarabine-induced apoptosis of AML cells did not significantly change compared with that of wild-type cells. Thus, coculture-induced chemoresistance appears to be independent of VEGF-A/VEGFR-2 signaling. When the transwell, a coculturing device, separated the AML cells from the EA.hy926 cells in a monolayer, the coculture-induced chemoresistance was inhibited. Given that the migration of VEGF-A/VEGFR-2 signaling-dependent endothelial cells is necessary for the endothelial niche formation in the bone marrow, VEGF-A/VEGFR-2 signaling contributes to chemoresistance by mediating the niche formation process, but not to the chemoresistance of AML cells in the niche.

Efficacy and safety of prophylactic superselective embolization for angiomyolipoma at the renal hilum.

OBJECTIVE: This study investigated the efficacy and safety of superselective transcatheter arterial embolization for angiomyolipoma at the renal hilum. METHODS: Between August 2012 and January 2015, 13 patients with 16 angiomyolipomas at the renal hilum underwent initial, prophylactic, superselective transcatheter arterial embolization. The patients were followed by computed tomography or magnetic resonance imaging, and volume-reduction ratios after embolization were measured. RESULTS: The mean or median post-embolization volume reduction ratios were 23% (follow-up duration, 1-2 months), 55% (3-6 months), 55% (7-12 months), 66% (1-2 years), 67% (2-3 years), and 54% (>3 years). After initial embolization, none of the 16 tumors bled or required surgery; two (13%) tumors recurred; and three (19%) tumors received repeat embolization. Estimated glomerular filtration rates were not decreased at medians of 7 days (near the time of discharge) and 39 days (first clinical follow-up) post-procedure, compared with baseline. Except for post-embolization syndrome, no procedure-related complications occurred. CONCLUSIONS: Superselective embolization for renal hilar angiomyolipoma is safe and kidney-preserving, with good tumor volume reduction and bleeding prevention.

Prognostic Significance of Aberrant Claudin-6 Expression in Endometrial Cancer.

BACKGROUND: Among the claudin (CLDN) family, CLDN6 exhibits aberrant expression in various cancers, but its biological relevance has not yet been established. We generated a monoclonal antibody (mAb) against human CLDN6 and verified its specificity. By immunohistochemical staining and semi-quantification, we evaluated the relationship between CLDN6 expression and clinicopathological parameters in tissues from 173 cases of endometrial cancer. RESULTS: The established mAb selectively recognized CLDN6 protein. Ten of the 173 cases (5.8%) showed high CLDN6 expression (score 3+), whereas 19 (11.0%), 18 (10.4%) and 126 (72.4%) cases revealed low CLDN6 expression (score 2+, 1+ and 0, respectively). In addition, intratumor heterogeneity of CLDN6 expression was observed even in the cases with high CLDN6 expression. The 5-year survival rates in the high and low CLDN6 groups was approximately 30% and 90%, respectively. Among the clinicopathological factors, the high CLDN6 expression was significantly associated with surgical stage III/IV, histological grade 3, lymphovascular space involvement, lymph node metastasis and distant metastasis. Furthermore, the high CLDN6 expression was an independent prognostic marker for overall survival of endometrial cancer patients (hazard ratio 3.50, p = 0.014). CONCLUSIONS: It can be concluded that aberrant CLDN6 expression is useful to predict poor outcome for endometrial cancer and might be a promising therapeutic target.

Can we predict the existence of extrarenal feeders to renal angiomyolipomas?

OBJECTIVES: To identify factors predicting the presence of extrarenal feeders to renal angiomyolipomas (AMLs) METHODS: This is a retrospective study of 44 patients with 58 renal AMLs embolized in our department. Arteriography obtained during embolization and CT angiography obtained before and after embolization were reviewed to characterize AMLs with and without extrarenal feeders. Tumor characteristics were compared between the two groups. Simple logistic regression and ROC curve analysis were performed. P < 0.05 was considered to be statistically significant. RESULTS: Of the 58 AMLs reviewed, 29% had extrarenal arteries and 71% did not. AMLs with extrarenal feeders were significantly larger than those without, in terms of volume (median, 368 mL versus 109 mL, p < 0.0002) and the largest diameter (mean, 12.0 cm versus 7.7 cm, p < 0.0001). Patient age, presence of tuberous sclerosis complex or sporadic lymphangioleiomyomatosis, and tumor location did not differ between the groups. The largest diameter and volume had similar predictive values for the presence of extrarenal feeders (AUC, 0.83 versus 0.82, p = 0.673). Extrarenal feeders were present in 0%, 21%, and 79% of the AMLs ≤ 6.5 cm, AMLs 6.6-10.5 cm, and AMLs > 10.5 cm, respectively. CONCLUSIONS: AML size correlates with the presence of extrarenal feeders, with the largest diameter and volume being significant predictors. AMLs > 10.5 cm had a high chance of extrarenal feeders, making it mandatory to search for feeders to them in order to avoid incomplete embolization; AMLs ≤ 6.5 cm did not have extrarenal feeders, making a search for them unnecessary in these cases. KEY POINTS: • The presence of extrarenal feeders to renal angiomyolipoma is associated with tumor size, but not with patient age, concomitant disease, or tumor location. • The largest diameter and volume predict the presence of extrarenal feeders to AML, with similar predictive values. • AMLs > 10.5 cm have a high chance (79%) of extrarenal feeders, making it mandatory to search for feeders to them in order to avoid incomplete embolization; AMLs ≤ 6.5 cm do not have extrarenal feeders, making a search for them unnecessary in these cases.

Postembolization Intratumoral Chronic Bleeding, without the Classic CT Feature of Active Extravasation, in Tuberous Sclerosis Complex-Related Renal Angiomyolipoma: Two Case Reports.

Two patients with tuberous sclerosis complex each had multiple bilateral renal angiomyolipomas. After undergoing embolization for a ruptured angiomyolipoma, patient 1 experienced long-lasting abdominal fullness; contrast-enhanced computed tomography (CECT) revealed a large chronic hematoma without contrast extravasation. Patient 2 underwent embolization for the largest right renal angiomyolipoma which contained a chronic hematoma. 2 weeks later, the symptom of abdominal fullness presented, and CECT revealed that the preexisting hematoma had enlarged without contrast extravasation. In both cases, a second embolization of the angiomyolipomas resulted in shrinking of the intratumoral hematomas and alleviation of the associated symptoms. Therefore, chronic postembolization intratumoral bleeding from renal angiomyolipoma may present as a persistently large or growing hematoma with an associated symptom of abdominal fullness but without the typical CECT feature of active extravasation.

Superselective Transcatheter Arterial Embolization for Large Unruptured Renal Angiomyolipoma in Lymphangioleiomyomatosis.

PURPOSE: To retrospectively evaluate therapeutic performance and complications of superselective transcatheter arterial embolization (TAE) for unruptured renal angiomyolipoma (AML) in patients with lymphangioleiomyomatosis (LAM) and to investigate the correlation between percentage reduction in tumor volume and intratumoral fat content. MATERIALS AND METHODS: Superselective TAE was performed in 14 consecutive patients with 15 large unruptured renal AMLs associated with LAM (mean age, 38 y; range, 21-57 y). Patients had renal AML with aneurysms ≥ 5 mm in diameter, tumor-related abdominal symptoms, or both. In all cases, embolization of 1 tumor was achieved in a single session by using multiporous gelatin sponge particles (GSPs) with additional metallic coils in all but 1 case. Tumor volume and fat content percentage were measured on CT or MR imaging before and after superselective TAE (median, 11 months; range, 6-14 months). RESULTS: Residual tumor staining declined by > 90% after all TAE sessions except 2, with embolization of all treated aneurysms. No nontarget embolization or severe complications were encountered. Mean percentage reduction in tumor volume after superselective TAE was 69% (range, 21%-95%). Percentage tumor volume reduction was negatively correlated with fat content before embolization (P < .01). CONCLUSIONS: Superselective TAE with multiporous GSPs and metallic coils for large unruptured renal AML in patients with LAM is useful for reducing tumor volume and treating intratumoral aneurysms without major pulmonary or renal complications. Extent of tumor reduction may be influenced by fat content before embolization.

Long-term results and management of ureteral transitional cell carcinoma using the holmium: YAG laser via rigid-ureteroscopy.

The standard operative procedure for ureteral transitional cell carcinoma is nephrouterectomy with partial cystectomy at the affected ureteral orifice. However, nephron-sparing surgery and endoscopic surgery and management have become common practice for low-grade and low-stage cases. We investigated the follow-up results of patients who underwent endoscopic surgery using the holmium:YAG laser, and evaluated its treatment effect. The patients were 4 men and 3 women aged from 68 to 87 years (mean: 74.7 years). Two were imperative cases and 5 were elective cases. The tumor size ranged from 8 to 25 mm (mean: 15.4 mm). Hydronephrosis was not found in any case, and urinary cytology was negative in all cases. Biopsy revealed 5 cases of grade 1, and 2 of grade 2. A Versa Pulse Select 80 laser generator, a 365-microm slim line laser fiber, and a rigid ureteroscope with 8F-point diameter were used. A 6F double J catheter was placed postoperatively for 3 weeks. Pulse energy was set at 0.5-1.0 J (mean: 0.8 J) with a frequency of 10 Hz. The total amount of energy was 0.9-11.22 KJ (mean: 2.89 KJ) and the operation time including ureteral stent placement was 20-97 min (mean: 66 min). Neither urinary tract perforation nor ureteral stricture associated with laser irradiation was observed. The postoperative follow-up period ranged from 23-88 months (mean: 67.8 months). Patients underwent urinary cytological examination once a month, and cystoscopy, retrograde pyelography and urethroscopy once every 3 months for 2 years, then once every 6 months thereafter. One patient developed tumor recurrence 23 months after surgery and received another laser treatment, but no recurrence has been observed in the other 6 patients (85.7%). Transurethral endoscopic surgery and management using the holmium:YAG laser is safe and effective nephron-sparing surgery for ureteral transitional cell carcinoma, and good long-term treatment results can be expected even in elective cases if the indications are carefully selected.

[Bonding of resin cement to bleached dental enamel].

PURPOSE: The effects of bleaching times, types of etching agent and storage period of bleached bovine tooth on the shear bond strength of resin cement to the enamel were examined. MATERIALS AND METHODS: Bovine teeth were repeatedly bleached 0, 1, 3, and 5 times then stored in 37 degrees C water for 1 week. The effect of bleaching number of the bovine tooth on the bond strength of resin cement to the enamel was investigated using 40% phosphoric acid (EG) etching technique. Next, the effects of types of etching agent and of storage period of bleached bovine tooth with three times in 37 degrees C water on the bond strength were studied using 10% citric acid-3% ferric chloride (10-3) or 10% citric acid (10-0) solution. RESULTS: The bleaching of bovine tooth allowed for a dramatic decrease in the bond strength from 18.3 MPa to 9.8 MPa (1 time), and 3.9 MPa (3 times), even though the bovine enamel was etched by EG. However, when 10-3 or 10-0 solution was applied to the three times bleached enamel, bond strengths were 13.9 and 10.0 MPa, respectively. Furthermore, prolonging of the storage period of the three times bleached bovine tooth in water to 2 months resulted in a increase in the bond strength from 3.9 to 10.1 MPa, even if bovine enamel was etched by EG, and close to that obtained from the 10-3 etching. CONCLUSION: To obtain the expected bond strength to bleached enamel, it is better to wait for 2 months for a restoration and use the 10-3 etching.