Cumulative sum analysis of the learning curve for retrograde intrarenal stone surgery in newbie surgeons.

INTRODUCTION: This study investigated the learning curve of retrograde intrarenal surgery (RIRS) in patients with medium-sized stones using cumulative sum analysis (CUSUM) to evaluate the competence and proficiency of three new surgeons during their first RIRS procedures. MATERIALS AND METHODS: We conducted a retrospective review of 227 patients from 2019 to 2022 at a single institution. The patients were divided into four groups based on the operating surgeon: tutor surgeon (85 patients), newbie surgeon A (21 patients), newbie surgeon B (85 patients), and newbie surgeon C (36 patients). Patients had one or multiple stones with the largest stone diameter fell within the range of 10-30 mm. Fragmentation efficacy was calculated as "removed stone volume (mm3) divided by operative time (minutes)." CUSUM analysis monitored changes in fragmentation efficacy and validated surgical outcomes. RESULTS: No statistically significant differences were observed in the total stone volume, maximum stone size, or total operation time between the three newbie surgeons and the tutor surgeon. The mean fragmentation efficacy value was comparable among the newbie surgeons, but significantly different from that of the tutor surgeon. The minimum acceptable fragmentation efficacy level was set at 25.12 mL/min, based on the tutor's average value. The CUSUM curves for the three surgeons initially remained relatively flat until Cases 12-15, after which they increased and eventually plateaued. Stone-free rates and postoperative complications did not differ significantly among the surgeons. CONCLUSION: Learning curve analysis for the three newbie surgeons indicated that approximately 12-15 cases were required to reach a plateau.

The Prognostic Value of Tumor Cell Clusters in the Fallopian Tube Lumen in Stage I Endometrioid Carcinoma.

The aim of this study was to investigate the pathologic prognostic factors such as tumor cell clusters (TCCs) in the fallopian tube lumen, myometrial invasion patterns, and positive peritoneal cytology (PPC) in women with Stage I endometrial endometrioid carcinoma (EEC). From 2009 to 2020, consecutive patients with Stage I EEC who underwent hysterectomy and bilateral salpingectomy were included. The primary outcome was the recurrence-free survival (RFS) rate, and the clinicopathological factors affecting RFS were analyzed. A total of 765 patients were enrolled. Seventeen patients (2.2%) had TCC in the fallopian tube lumen, and 58 patients showed a microcystic elongated and fragmented pattern (7.6%). PPC was found in 19 patients (2.5%). The median follow-up period was 61.0 months (range: 2.0-149.7). The majority (88.6%) of patients had Stage IA EEC. The 5-year RFS and overall survival rates were 97.5% and 98.5%, respectively. In multivariate analysis for RFS, the significant prognostic factors were lymphovascular invasion (hazard ratio = 4.604; 95% CI: 1.387-15.288; P = 0.013) and grade (grade 2; hazard ratio = 4.949; 95% CI: 1.035-23.654; P = 0.045, and grade 3; hazard ratio = 5.469; 95% CI: 1.435-20.848; P = 0.013). Other pathologic factors including TCC in the fallopian tube lumen, myometrial invasion patterns, PPC, and hormonal status had no prognostic significance. TCC in the fallopian tube lumen, myometrial invasion pattern, PPC, and estrogen and progesterone receptor positivity were not significant prognostic factors in Stage I EEC. In contrast, lymphovascular invasion and grade were significant prognostic factors.

Ibulocydine Inhibits Migration and Invasion of TNBC Cells via MMP-9 Regulation.

Triple-negative breast cancer (TNBC) accounts for approximately 15-20% of all breast cancer types, indicating a poor survival prognosis with a more aggressive biology of metastasis to the lung and a short response duration to available therapies. Ibulocydine (IB) is a novel (cyclin-dependent kinase) CDK7/9 inhibitor prodrug displaying potent anti-cancer effects against various cancer cell types. We performed in vitro and in vivo experiments to determine whether IB inhibits metastasis and eventually overcomes the poor drug response in TNBC. The result showed that IB inhibited the growth of TNBC cells by inducing caspase-mediated apoptosis and blocking metastasis by reducing MMP-9 expression in vitro. Concurrently, in vivo experiments using the metastasis model showed that IB inhibited metastasis of MDA-MB-231-Luc cells to the lung. Collectively, these results demonstrate that IB inhibited the growth of TNBC cells and blocked metastasis by regulating MMP-9 expression, suggesting a novel therapeutic agent for metastatic TNBC.

Targeting phosphomevalonate kinase enhances radiosensitivity via ubiquitination of the replication protein A1 in lung cancer cells.

Radiotherapy (RT) plays an important role in localized lung cancer treatments. Although RT locally targets and controls malignant lesions, RT resistance prevents RT from being an effective treatment for lung cancer. In this study, we identified phosphomevalonate kinase (PMVK) as a novel radiosensitizing target and explored its underlying mechanism. We found that cell viability and survival fraction after RT were significantly decreased by PMVK knockdown in lung cancer cell lines. RT increased apoptosis, DNA damage, and G2/M phase arrest after PMVK knockdown. Also, after PMVK knockdown, radiosensitivity was increased by inhibiting the DNA repair pathway, homologous recombination, via downregulation of replication protein A1 (RPA1). RPA1 downregulation was induced through the ubiquitin-proteasome system. Moreover, a stable shRNA PMVK mouse xenograft model verified the radiosensitizing effects of PMVK in vivo. Furthermore, PMVK expression was increased in lung cancer tissues and significantly correlated with patient survival and recurrence. Our results demonstrate that PMVK knockdown enhances radiosensitivity through an impaired HR repair pathway by RPA1 ubiquitination in lung cancer, suggesting that PMVK knockdown may offer an effective therapeutic strategy to improve the therapeutic efficacy of RT.

ITC-6102RO, a novel B7-H3 antibody-drug conjugate, exhibits potent therapeutic effects against B7-H3 expressing solid tumors.

BACKGROUND: The B7-H3 protein, encoded by the CD276 gene, is a member of the B7 family of proteins and a transmembrane glycoprotein. It is highly expressed in various solid tumors, such as lung and breast cancer, and has been associated with limited expression in normal tissues and poor clinical outcomes across different malignancies. Additionally, B7-H3 plays a crucial role in anticancer immune responses. Antibody-drug conjugates (ADCs) are a promising therapeutic modality, utilizing antibodies targeting tumor antigens to selectively and effectively deliver potent cytotoxic agents to tumors. METHODS: In this study, we demonstrate the potential of a novel B7-H3-targeting ADC, ITC-6102RO, for B7-H3-targeted therapy. ITC-6102RO was developed and conjugated with dHBD, a soluble derivative of pyrrolobenzodiazepine (PBD), using Ortho Hydroxy-Protected Aryl Sulfate (OHPAS) linkers with high biostability. We assessed the cytotoxicity and internalization of ITC-6102RO in B7-H3 overexpressing cell lines in vitro and evaluated its anticancer efficacy and mode of action in B7-H3 overexpressing cell-derived and patient-derived xenograft models in vivo. RESULTS: ITC-6102RO inhibited cell viability in B7-H3-positive lung and breast cancer cell lines, inducing cell cycle arrest in the S phase, DNA damage, and apoptosis in vitro. The binding activity and selectivity of ITC-6102RO with B7-H3 were comparable to those of the unconjugated anti-B7-H3 antibody. Furthermore, ITC-6102RO proved effective in B7-H3-positive JIMT-1 subcutaneously xenografted mice and exhibited a potent antitumor effect on B7-H3-positive lung cancer patient-derived xenograft (PDX) models. The mode of action, including S phase arrest and DNA damage induced by dHBD, was confirmed in JIMT-1 tumor tissues. CONCLUSIONS: Our preclinical data indicate that ITC-6102RO is a promising therapeutic agent for B7-H3-targeted therapy. Moreover, we anticipate that OHPAS linkers will serve as a valuable platform for developing novel ADCs targeting a wide range of targets.

Continuous administration of mirabegron has advantages in inhibition of central sensitization compared with short-term treatment cessation in a mouse model of overactive bladder.

AIMS: There is no clear pathophysiologic evidence determining how long overactive bladder (OAB) medication should be continued. We, therefore, investigated the effect of mirabegron using cessation (CES) or continuation (CON) treatment in an OAB animal model. METHODS: Female C57BL/6 mice were divided into four groups (N = 8 each): Sham, OAB, CES, and CON groups. The OAB-like condition was induced by three times weekly intravesical instillations of KCl mixture with hyaluronidase. After the last intravesical instillation for inducing OAB, mirabegron (2 mg/kg/day) was administered in CES and CON groups for 10 and 20 days, respectively. Final experiments were carried out on 20 days from the last intravesical instillation in all groups. After cystometry, mRNA levels of bladder muscarinic, ß-adrenergic, and P2X purinergic receptors were measured to investigate bladder efferent and afferent activity. In addition, mRNA levels of CCL2 and CCR2 in L6-S1 dorsal root ganglia (DRG) were measured to assess afferent sensitization. Immunofluorescent staining of CX3CR1, GFAP, and CCR2 in the L6 spinal cord was also conducted to investigate glial activation and central sensitization. RESULTS: OAB mice showed bladder overactivity evidenced by decreased intercontraction interval (3.56 ± 0.51 vs. 5.76 ± 0.95 min in sham mice), increased non-voiding contractions (0.39 ± 0.11 vs. 0.13 ± 0.07/min in sham mice), and inefficient voiding (72.1 ± 8.6% vs. 87.1 ± 9.5% in sham mice). Increased M2, M3, ß2, ß3, P2X2 , P2X3 , P2X4 , and P2X7 levels in the bladder and increased CCL2 and CCR2 in DRG indicate bladder efferent and afferent hyperexcitability. In addition, CX3CR1, GFAP, and CCR2 in the L6 spinal cord were upregulated in OAB mice. However, the CON group exhibited reduced ß2, ß3, P2X2 , P2X3 , P2X4 , and P2X7 levels in the bladder, reduced CCL2 and CCR2 in DRG, which are markers of afferent hyperexcitability, and reduced immunoreactivities of CX3CR1, GFAP, and CCR2 in the L6 spinal cord, which are markers of the central sensitization. Moreover, the CON group showed better improvements in nonvoiding contractions (0.16 ± 0.09 vs. 0.44 ± 0.17/min) and voiding efficiency (93.9 ± 7.4% vs. 76.5 ± 13.1%) and reductions in bladder ß3 receptors and CCL2 of L6-S1 DRG, and immunoreactivities of CX3CR1 and GFAP in the L6 spinal cord compared to the CES group. CONCLUSIONS: Continuous mirabegron treatment seems to prevent central sensitization and, thus, might be desirable for long-term disease control of OAB.

Active small bowel sparing in intracavitary brachytherapy for cervical cancer.

OBJECTIVE: To propose and evaluate an active method for sparing the small bowel in the treatment field of cervical cancer brachytherapy by prone position procedure. METHODS: The prone position procedure consists of five steps: making bladder empty, prone-positioning a patient on belly board, making the small bowel move to abdomen, filling the bladder with Foley catheter and finally turning the patient into the supine position. The proposed method was applied for the treatment of seven cervical cancer patients. Its effectiveness was evaluated and a correlation between the patient characteristics and the volumetric dose reduction of small bowel was also investigated. Brachytherapy treatment plans were built before and after the proposed method, and their dose-volume histograms were compared for targets and organs-at-risk. In this comparison, all plans were normalized to satisfy the same D90% for high-risk clinical target volume. RESULTS: For the enrolled patients, the average dose of small bowel was significantly reduced from 75.2 ± 4.9 Gy before to 60.2 ± 4.0 Gy after the prone position procedure, while minor dosimetric changes were observed in rectum, sigmoid and bladder. The linear correlation to body mass index, thickness and width of abdominopelvic cavity and bladder volume were 76.2, 69.7, 28.8 and -36.3%, respectively. CONCLUSIONS: The application of prone position procedure could effectively lower the volumetric dose of the small bowel. The dose reduction in the small bowel had a strong correlation with the patient's obesity and abdominal thickness. This means the patients for whom the proposed method would be beneficial can be judiciously selected for safe brachytherapy.

Immunomodulation of HDAC Inhibitor Entinostat Potentiates the Anticancer Effects of Radiation and PD-1 Blockade in the Murine Lewis Lung Carcinoma Model.

Although the combination of radiotherapy and immunotherapy has proven to be effective in lung cancer treatment, it may not be sufficient to fully activate the antitumor immune response. Here, we investigated whether entinostat, a histone deacetylase inhibitor, could improve the efficacy of radiotherapy and anti-PD-1 in a murine syngeneic LL/2 tumor model. A total of 12 Gy of X-rays administered in two fractions significantly delayed tumor growth in mice, which was further enhanced by oral entinostat administration. Flow cytometry-aided immune cell profiling revealed that entinostat increased radiation-induced infiltration of myeloid-derived suppressor cells and CD8+ T cells with decreased regulatory T-cells (Tregs). Transcriptomics-based immune phenotype prediction showed that entinostat potentiated radiation-activated pathways, such as JAK/STAT3/interferon-gamma (IFN-γ) and PD-1/PD-L1 signaling. Entinostat augmented the antitumor efficacy of radiation and anti-PD-1, which may be related to an increase in IFN-γ-producing CD8+ T-cells with a decrease in Treg cells. Comparative transcriptomic profiling predicted that entinostat increased the number of dendritic cells, B cells, and T cells in tumors treated with radiation and anti-PD-1 by inducing MHC-II genes. In conclusion, our findings provided insights into how entinostat improves the efficacy of ionizing radiation plus anti-PD-1 therapy and offered clues for developing new strategies for clinical trials.

Acute exacerbation of fibrotic hypersensitivity pneumonitis: incidence and outcomes.

BACKGROUND: Patients with fibrotic hypersensitivity pneumonitis (HP) show variable clinical courses, and some experience rapid deterioration (RD), including acute exacerbation (AE). However, little is known about AE in fibrotic HP. Here, we retrospectively examined the incidence, risk factors, and outcomes of AE in fibrotic HP. METHODS: The incidence rates of AE were calculated in 101 patients with biopsy-proven HP. AE was defined as the worsening of dyspnoea within 30 days, with new bilateral lung infiltration and no evidence of infection or other causes of dyspnoea. RESULTS: During follow-up (median: 30 months), 18 (17.8%) patients experienced AE. The 1, 3, and 5 year incidence rates of AE were 6.0, 13.6, and 22.8%, respectively. Lower diffusing capacity of the lung for carbon monoxide (DLCO) and a radiologic usual interstitial pneumonia (UIP)-like pattern were risk factors for AE. In-hospital mortality after AE was 44.4%. Median survival from diagnosis was significantly shorter in patients with AE (26.0 months) than in those with no-AE RD (55.0 months; p = 0.008) or no RD (not reached; p < 0.001). AE remained a significant predictor of all-cause mortality (hazard ratio, 8.641; 95% confidence interval, 3.388-22.040; p < 0.001) after adjustment for age, body mass index, lung function, lymphocyte levels in bronchoalveolar lavage fluid, and the presence of a UIP-like pattern. CONCLUSIONS: AE was not uncommon among patients with fibrotic HP and significantly affected prognosis. A lower DLCO value and radiologic UIP-like pattern at diagnosis were associated with the development AE in patients with fibrotic HP.

Prevention of radiotherapy induced enteropathy by probiotics (PREP): protocol for a double-blind randomized placebo-controlled trial.

BACKGROUND: Radiation induced enteropathy is a common complication of radiotherapy for pelvic tumors and adversely affects patient quality of life. Probiotics are thought to restore bowel microflora to optimal levels and reinforce intestinal barrier capacity. Although probiotics are effective in the treatment of radiation induced enteropathy, less is known about their efficacy to prevent radiation induced enteropathy. METHODS: This double-blind randomized placebo-controlled study will investigate the efficacy of probiotics to prevent radiation-induced enteropathy in patients with gynecologic or urologic cancer who received pelvic radiotherapy. The study is designed to enroll 248 eligible patients, who will be randomized 1:1 to a probiotic or placebo group. Toxicities will be evaluated using Common Terminology Criteria for Adverse Events (CTCAE) v5.0. DISCUSSION: The primary aim of this study is to provide high level evidence for the ability of probiotics to prevent acute radiation induced enteropathy. The secondary aims are to determine the effects of probiotics on the incidence of chronic radiation induced enteropathy and the safety of probiotics in patients with gynecologic or urologic cancer. TRIAL REGISTRATION: ClinicalTrials.gov ( NCT03978949 , Registered on 7 June 2019).

Serial changes of CT findings in patients with chronic hypersensitivity pneumonitis: imaging trajectories and predictors of fibrotic progression and acute exacerbation.

OBJECTIVES: To evaluate the longitudinal changes of chest CT findings in patients with chronic hypersensitivity pneumonitis (HP) and identify risk factors for fibrotic progression and acute exacerbation (AE). METHODS: This retrospective study included patients with chronic HP with follow-up CT. Baseline and serial follow-up CT were evaluated semi-quantitatively. Fibrosis score was defined as the sum of the area with reticulation and honeycombing. The modified CT pattern of Fleischner Society idiopathic pulmonary fibrosis diagnostic guidelines was evaluated. Cox proportional hazards regression was performed to determine significant variables associated with fibrotic progression and AEs. RESULTS: Of 91 patients, mean age was 59.1 years and 61.5% were women. The median follow-up period was 4.9 years. Seventy-nine patients (86.8%) showed fibrotic progression with persistent areas of mosaic attenuation, finally replaced by fibrosis, and 20 (22.0%) developed AE. Baseline fibrosis score and CT pattern of usual interstitial pneumonia (UIP)/probable UIP were independent risk factors for predicting fibrotic progression (hazard ratio [HR] = 1.05, 95% confidence interval [CI] = 1.02-1.09, p < 0.001, for fibrosis score; HR = 2.50, CI = 1.50-4.16, p < 0.001, for CT pattern) and AEs (HR = 1.07, CI = 1.01-1.13, p = 0.019, for fibrosis score; HR = 5.47, CI = 1.23-24.45, p = 0.026, for CT pattern) after adjusting clinical covariables. CONCLUSION: Fibrotic progression and AE were identified in 86.8% and 22.0% of patients with chronic HP. Fibrosis score and CT pattern of UIP/probable UIP on baseline chest CT may predict fibrotic progression and AE. KEY POINTS: • Most patients (87%) showed fibrotic progression on long-term follow-up with persistent areas of mosaic attenuation that were finally replaced by fibrosis at a later stage. • One-fifth of patients (22%) experienced acute exacerbation associated with worse prognosis. • Fibrosis score (sum of reticulation and honeycombing) and CT pattern of UIP/probable UIP on baseline CT were independent predictors for predicting fibrotic progression and acute exacerbation.

Prognostic Implication of Diagnostic Confidence Level in Patients with Fibrotic Hypersensitivity Pneumonitis.

BACKGROUND: Hypersensitivity pneumonitis (HP) has various clinical courses and outcomes, but the prognostic factors are not well-defined. Vasakova et al. [Am J Respir Crit Care Med. 2017 Sep;196(6):680-9] have proposed a diagnostic algorithm that categorized suspected patients according to the level of confidence in the diagnosis. This study aimed to investigate whether the confidence level of clinical diagnosis has prognostic implication in patients with fibrotic HP. METHODS: This study included 101 biopsy-proven fibrotic HP patients diagnosed between 2002 and 2017. The patients were retrospectively classified into confident, probable, possible, and unlikely chronic HP, according to the confidence level in the diagnostic criteria/algorithm. The survival and forced vital capacity (FVC) changes were compared between the groups. Risk factors for mortality were analysed using a Cox proportional hazard model. RESULTS: The median follow-up duration was 67.6 months. The mean age was 60.4 years, and percentages of women were 60.4%. When classified based on the diagnostic criteria/algorithm, possible HP was the most common (51.5%), followed by probable (26.7%), confident (9.9%), and unlikely HP (6.9%). Distinctive survival curves were found according to the diagnostic confidence level, showing the worst outcome in unlikely chronic HP (median survival, 30.2 months). In a multivariable Cox analysis, unlikely HP was a significant predictor of poor survival (hazard ratio, 4.652; 95% confidence interval, 1.231-17.586; p = 0.023), after adjustment for age, body mass index, FVC, and diffusing capacity. CONCLUSIONS: The diagnostic confidence level may predict clinical outcomes in patients with HP. Unlikely HP was shown to have a significantly poorer survival than other diagnostic confidence levels.

Reduction of superficial radiation dose with bolus in passive scattering proton beam therapy.

PURPOSE: In passive scattering proton beam therapy, scattered protons from the snout and aperture increase the superficial dose, however, treatment planning systems (TPSs) based on analytic algorithms (such as proton convolution superposition) are often inaccurate in this aspect. This additional dose can cause permanent alopecia or severe radiation dermatitis. This study aimed to evaluate the effect of bolus on the superficial radiation dose in passive scattering proton beam therapy. METHODS: We drew a clinical target volume (CTV) and a scalp-p (phantom), and created plans using a TPS for a solid water phantom with and without bolus. We calculated the dose distribution in the established plans independently with Monte Carlo (MC) simulation and measured the actual dose distribution with an array of ion chambers and radiochromic films. To assess the clinical impact of bolus on scalp dose, we conducted independent dose verification using MC simulation in a clinical case. RESULTS: In the solid water phantom without bolus, the calculated scalp-p volume receiving 190 cGy was 20% with TPS but 80% with MC simulation when the CTV received 200 cGy. With 2 cm bolus, this decreased from 80% to 10% in MC simulation. With the measurements, average superficial dose to the scalp-p was reduced by 5.2% when 2 cm bolus was applied. In the clinical case, the scalp-c (clinical) volume receiving 3000 cGy decreased from 74% to 63% when 2 cm bolus was applied. CONCLUSION: This study revealed that bolus can reduce radiation dose at the superficial body area and alleviate toxicity in passive scattering proton beam therapy.

Evaluation of the dosimetric effect of scattered protons in clinical practice in passive scattering proton therapy.

The present study verified and evaluated the dosimetric effects of protons scattered from a snout and an aperture in clinical practice, when a range compensator was included. The dose distribution calculated by a treatment planning system (TPS) was compared with the measured dose distribution and the dose distribution calculated by Monte Carlo simulation at several depths. The difference between the measured and calculated results was analyzed using Monte Carlo simulation with filtration of scattering in the snout and aperture. The dependence of the effects of scattered protons on snout size, beam range, and minimum thickness of the range compensator was also investigated using the Monte Carlo simulation. The simulated and measured results showed that the additional dose compared with the results calculated by the TPS at shallow depths was mainly due to protons scattered by the snout and aperture. This additional dose was filtered by the structure of the range compensator so that it was observed under the thin region of the range compensator. The maximum difference was measured at a depth of 16 mm (8.25%), with the difference decreasing with depth. Analysis of protons contributing to the additional dose showed that the contribution of protons scattered from the snout was greater than that of protons scattered from the aperture when a narrow snout was used. In the Monte Carlo simulation, this effect of scattered protons was reduced when wider snouts and longer-range proton beams were used. This effect was also reduced when thicker range compensator bases were used, even with a narrow snout. This study verified the effect of scattered protons even when a range compensator was included and emphasized the importance of snout-scattered protons when a narrow snout is used for small fields. It indicated that this additional dose can be reduced by wider snouts, longer range proton beams, and thicker range compensator bases. These results provide a better understanding of the additional dose from scattered protons in clinical practice.

Impact of intracavitary brachytherapy technique (2D versus 3D) on outcomes of cervical cancer: a systematic review and meta-analysis.

PURPOSE: To perform a systematic review and meta-analysis of the impact of brachytherapy (BT) technique (two-dimensional [2D] or three-dimensional image-guided [3D]) on outcomes of cervical cancer patients. METHODS: PubMed and EMBASE databases were searched up to April 16, 2019, for studies which evaluated the effect of 3D-BT compared to 2D-BT in cervical cancer. Endpoints included cumulative incidence of severe toxicity, locoregional recurrence-free survival (LRRFS), progression-free survival (PFS), and overall survival (OS). Hazard ratios (HRs) were pooled in the meta-analysis using the random-effects model. RESULTS: Six studies of eight cohorts were included in the quantitative synthesis. The pooled HR regarding toxicity was evaluated in five cohorts in three studies, and the HR of 3D-BT compared to 2D-BT was 0.54 (95% confidence interval [CI] 0.37-0.77). All six studies were included for the synthesis for LRRFS, and the pooled HR favors 3D-BT (0.61 [95% CI 0.40-0.93]). For PFS, three studies were included for analysis and 3D-BT was superior to 2D-BT (HR = 0.75 [95% CI 0.59-0.96]). Five studies were included for the pooled HR regarding OS, and pooled HR of 3D-BT compared to 2D-BT was 0.65 (95% CI 0.40-1.06). CONCLUSION: 3D-BT might reduce severe toxicity and improve LRRFS and PFS in patients with cervical cancer. 3D-BT should be considered for standard management of cervical cancer, and efforts for adopting this procedure in Korea should be pursued.

Significance of the number of high-risk factors in patients with cervical cancer treated with radical hysterectomy and concurrent chemoradiotherapy.

OBJECTIVE: The purpose of this study was to evaluate the impact of high-risk factors on the survival of patients with cervical cancer treated with surgery followed by adjuvant chemoradiotherapy. METHODS: From 2000 to 2014, medical records of 897 patients with International Federation of Gynecology and Obstetrics stage IB-IIA disease treated with surgery were retrospectively reviewed. Among them, 483 patients with high-risk factors, including pelvic lymph node metastasis, parametrial invasion, or resection margin involvement, were analyzed. RESULTS: The median follow-up time was 57 months (range, 6-205 months). For patients with single and multiple high-risk factors, the 5-year DFS rates were 80.4% and 65.7%, respectively (p < 0.001), and 5-year OS rates were 87.3% and 75.1%, respectively (p = 0.001). Distant metastasis was the most common pattern of recurrence (86.1%). Furthermore, distant metastasis-free survival significantly differed with the number of high-risk factors present (single 82.7% vs. multiple 68.8%, p < 0.001). In the multivariate analysis, while parametrial invasion and resection margin involvement showed no association, the adenocarcinoma histology, pelvic lymph node metastasis, higher metastatic lymph node ratio, and multiple high-risk factors were independent prognosticators associated with poor DFS and OS. CONCLUSIONS: Patients with early-stage cervical cancer having multiple high-risk factors, adenocarcinoma histologic type, and pelvic lymph node metastasis accompanied by a higher lymph node ratio after surgery are more likely to have occult distant metastasis. Further, consolidation with systemic chemotherapy after adjuvant therapy might be considered to improve the survival outcome in this patient population.

WDR11-mediated Hedgehog signalling defects underlie a new ciliopathy related to Kallmann syndrome.

WDR11 has been implicated in congenital hypogonadotropic hypogonadism (CHH) and Kallmann syndrome (KS), human developmental genetic disorders defined by delayed puberty and infertility. However, WDR11's role in development is poorly understood. Here, we report that WDR11 modulates the Hedgehog (Hh) signalling pathway and is essential for ciliogenesis. Disruption of WDR11 expression in mouse and zebrafish results in phenotypic characteristics associated with defective Hh signalling, accompanied by dysgenesis of ciliated tissues. Wdr11-null mice also exhibit early-onset obesity. We find that WDR11 shuttles from the cilium to the nucleus in response to Hh signalling. WDR11 regulates the proteolytic processing of GLI3 and cooperates with the transcription factor EMX1 in the induction of downstream Hh pathway gene expression and gonadotrophin-releasing hormone production. The CHH/KS-associated human mutations result in loss of function of WDR11. Treatment with the Hh agonist purmorphamine partially rescues the WDR11 haploinsufficiency phenotypes. Our study reveals a novel class of ciliopathy caused by WDR11 mutations and suggests that CHH/KS may be a part of the human ciliopathy spectrum.

Significance of para-aortic lymph node evaluation in patients with FIGO IIIC1 cervical cancer.

OBJECTIVE: This study investigated the effect of para-aortic lymph node sampling or dissection in recently revised International Federation of Gynecology and Obstetrics IIIC1p cervical cancer treated with primary surgery and adjuvant radiation therapy with concurrent chemotherapy. METHODS: We retrospectively reviewed the records of 343 patients with early-stage cervical cancer and pathologically proven pelvic lymph node metastasis following curative surgery from 2001 to 2014. No patient had imaging evidence of para-aortic lymph node involvement, and all patients received adjuvant concurrent chemotherapy with or without concurrent chemotherapy. We investigated the significance of para-aortic lymph node sampling or dissection on disease-free survival and overall survival. RESULTS: After median follow-up of 58.3 months, 5-year disease-free survival and overall survival in all patients were 69.9 and 80.2%, respectively. Disease-free survival and overall survival did not differ between the para-aortic lymph node dissection group and the No para-aortic lymph node dissection group (P = 0.700 and P = 0.605). However, patients with para-aortic lymph node-positive disease had poorer disease-free survival and overall survival compared with those with para-aortic lymph node-negative disease (P < 0.001 and P < 0.001). CONCLUSIONS: This study found no survival benefit of para-aortic lymph node evaluation among patients with International Federation of Gynecology and Obstetrics IIIC1p cervical cancer who were clinically para-aortic lymph node-negative. Although para-aortic lymph node metastasis is a poor prognosticator, the benefit of para-aortic lymph node dissection in terms of survival needs further investigation.

Effect of addition of bevacizumab to chemoradiotherapy in newly diagnosed stage IVB cervical cancer: a single institution experience in Korea.

OBJECTIVE: The aim of this study was to compare the clinical outcomes of chemoradiotherapy with or without bevacizumab in patients with newly diagnosed International Federation of Gynecology and Obstetrics (FIGO) stage IVB cervical cancer. METHODS: 41 patients with stage IVB cervical cancer who underwent chemoradiotherapy between August 2015 and December 2017 were retrospectively analyzed. This study included 11 patients who received bevacizumab before or after radiotherapy (group A) and 30 patients who received conventional chemoradiotherapy without bevacizumab (group B). We excluded the following patients: those with dual primary cancers; those whose pathologic diagnosis was neither squamous cell carcinoma nor adenocarcinoma; those who did not undergo radiotherapy; or those from whom follow-up data could not be collected. We analyzed the treatment responses, toxicities, progression-free survival, and overall survival rates. RESULTS: A total of 41 patients were included in the analysis. The median follow-up was 19 months (range 3-108). The response rates at 3 months after treatment were 90.9% in group A and 83.3% in group B (p=0.54). After completing all treatments, the complete response rates were 81.8% in group A and 47% in group B (p=0.04). Grade ≥3 gastrointestinal toxicities, including bleeding, fistula, perforation, and obstruction, were more frequent in group A (54.5%) than in group B (6.7%) (p=0.003). The 12 month progression-free survival and overall survival rates were similar in both arms (12 month progression-free survival: 45.5% vs 46.7%, respectively, p=0.22; 12 month overall survival: 81.8% vs 72.9%, respectively, p=0.57). Patients with node-only metastasis had better 12 month progression-free survival in group B than in group A (59.1% vs 42.9%, respectively, p=0.04). However, the responses to both treatments did not differ in patients with organ metastasis. CONCLUSIONS: Bevacizumab for stage IVB cervical cancer is associated with higher complete response rates. However, patients treated with bevacizumab experienced more bowel toxicities. Bevacizumab did not improve progression-free survival among patients with node-only metastasis.

Risk assessment of phthalates in pharmaceuticals.

Phthalates are used for industrial plasticizers to impart flexibility and durability to polyvinyl chloride. Despite widespread use of phthalates, reported endocrine-disrupting properties raise safety concerns for consumers. Since phthalates are permitted as excipients in controlled-release capsules and enteric coatings, patients taking drugs containing these chemicals may potentially be at some health risk. In this study, 102 distinct pharmaceutical products were analyzed by gas chromatography/mass spectrometry to determine phthalate content and maximal phthalate exposure rate was calculated. In 102 drug samples, di(2-ethylhexyl) phthalate (DEHP), dibutyl phthalate (DBP), and diethyl phthalate (DEP) were detected in 9.8, 27.45, and 5.88% of cases, respectively. The highest level of DEP was found in extended-release (ER) capsules with concentrations ranging from 935.5 to 1535.37 ppb. The highest levels of DBP (1.32-7.07 ppb) were detected in tablets, whereas highest level (7.07 ppb) of DEHP was found in suspension preparations. The phthalate hazard index (HI) (human exposure tolerable daily intake) was calculated for each sample, but no sample exhibited an HI value exceeding 1; the minimum value taken to indicate a serious health risk. Thus, no apparent serious health risk from phthalate exposure arises from taking these medications. The low HI values suggest that phthalate contamination in pharmaceuticals may not pose an apparent significant risk to humans. However, the sources of phthalate present in pharmaceutical products still needs to be investigated and verified through on-site inspections in manufacturing processes in order to minimize human exposure. It is recommended that measures be taken to prevent phthalate contamination in pharmaceuticals.