Evidence-based clinical recommendations for hypofractionated radiotherapy: exploring efficacy and safety - Part 2. Lung (non-small cell lung cancer).

Several recent studies have investigated the use of hypofractionated radiotherapy (HFRT) for various cancers. However, HFRT for non-small cell lung cancer (NSCLC) with or without concurrent chemotherapy is not yet widely used because of concerns about serious side effects and the lack of evidence for improved treatment results. Investigations of HFRT with concurrent chemotherapy in NSCLC have usually been performed in single-arm studies and with a small number of patients, so there are not yet sufficient data. Therefore, the Korean Society for Radiation Oncology Practice Guidelines Committee planned this review article to summarize the evidence on HFRT so far and provide it to radiation oncology clinicians. In summary, HFRT has demonstrated promising results, and the reviewed data support its feasibility and comparable efficacy for the treatment of locally advanced NSCLC. The incidence and severity of esophageal toxicity have been identified as major concerns, particularly when treating large fraction sizes. Strategies, such as esophagus-sparing techniques, image guidance, and dose constraints, may help mitigate this problem and improve treatment tolerability. Continued research and clinical trials are essential to refine treatment strategies, identify optimal patient selection criteria, and enhance therapeutic outcomes.

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.

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.

Healthcare Professionals' Learning Needs and Perspectives on Essential Information in Genetic Cancer Care: A Systematic Review.

BACKGROUND: The increased demand for genetic testing and counseling necessitates healthcare professionals (HCPs) to improve their genetic competency through training programs. This systematic review identified HCPs' learning needs and their perspectives on essential information for families with hereditary cancer. METHODS: This review covered studies published from 2013 to 2024 across five databases. Data were analyzed using a content analysis. RESULTS: Thirteen studies involving 332 HCPs were analyzed. Most studies focused on the learning needs of physicians caring for families affected by Hereditary Breast and Ovarian Cancer in North America and Europe. HCPs required training emphasizing practical counseling skills over the basics of genetics. Learning needs varied by profession: physicians needed training in assessing cancer risk and supporting decision-making in risk management; nurses required information on resources and the genetic care system; genetic counselors sought guidance on family communication and planning. Essential information identified for families included risk-reducing strategies, personalized cancer risk assessment, family implications, psychological issues, (cascade) genetic testing, and social concerns. CONCLUSIONS: The findings have implications for the development of training programs for HCPs, emphasizing the need for tailored training based on professions. Future research should explore the needs of HCPs caring for families with diverse hereditary cancers and cultural backgrounds.

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.

Toxicity Evaluation of Dose-Escalation in Hypofractionated Regional Nodal Irradiation for Breast Cancer: A Retrospective Study.

PURPOSE: Regional nodal irradiation (RNI) to the axilla and supraclavicular area presents distinct toxicities, such as lymphedema and shoulder stiffness, compared with whole-breast irradiation. There is insufficient evidence on the safety of dose-escalation in hypofractionated RNI. We aimed to evaluate and compare toxicity rates in patients with breast cancer who received hypofractionated RNI with and without dose-escalation. METHODS AND MATERIALS: We retrospectively analyzed 381 patients with breast cancer treated with hypofractionated RNI between March 2015 and February 2017. Patients received either the standard-dose to the regional nodal area (43.2 Gy/16 fx; 48.7 Gy3.5 equivalent dose [EQD2], 2 Gy equivalent dose with α/ß= 3.5 Gy) or dose-escalation with a median dose of 54.8 Gy3.5 EQD2 (range, 51.7-60.9 Gy3.5 EQD2), depending on clinical and pathologic nodal stage. Toxicity rates of lymphedema and shoulder stiffness were assessed, and statistical analyses were conducted to identify associated factors. RESULTS: The median follow-up time was 32.3 months (5.7-47.0 months). After radiation therapy, 71 (18.6%) patients developed lymphedema, and 48 (12.6%) developed shoulder stiffness. Patients who received dose-escalation exhibited significantly higher rates of lymphedema (32.1% vs 14.8%; odds ratio, 2.72, P = .0004) and shoulder stiffness (23.8% vs 9.4%; odds ratio, 2.01, P = .0205) compared with the standard-dose group. Moreover, dose-escalation showed a tendency to increase the severity of lymphedema and shoulder stiffness. CONCLUSIONS: Patients who received dose-escalation in hypofractionated RNI face a higher risk of developing lymphedema and shoulder stiffness compared with those who received standard-dose hypofractionated RNI. Therefore, it is crucial to implement close and frequent monitoring for early detection, along with timely rehabilitation interventions for these patients.

Local control and toxicity outcomes following consolidative radiation therapy in patients with high-risk neuroblastoma: a 20-year experience at a single center.

BACKGROUND: Intensive multimodal treatment can improve survival in patients with high-risk neuroblastoma, and consolidative radiation therapy has contributed to local control. We examined the clinical outcomes of patients who underwent consolidative radiation therapy at our institution. METHODS: We retrospectively reviewed the records of patients with high-risk neuroblastoma who underwent consolidative radiation therapy from March 2001 to March 2021 at Asan Medical Center. Patients underwent multimodal treatment including high-dose chemotherapy, surgery, stem cell transplantation, and maintenance therapy. Radiation (median, 21.0 Gy; range, 14-36) was administered to the primary site and surrounding lymph nodes. RESULTS: This study included 37 patients, and the median age at diagnosis was 2.8 years (range, 1.3-10.0). Four patients exhibited local failure, and 5-year free-from locoregional failure rate was 88.7%, with a median followup period of 5.7 years. The 5-year disease-free survival (DFS) and overall survival (OS) rates were 59.1% and 83.6%, respectively. Univariate analysis revealed that patients with neuron-specific enolase levels > 100 ng/mL had significantly worse DFS and OS (P = 0.036, 0.048), and patients with no residual disease before radiation therapy showed superior OS (P = 0.029). Furthermore, patients with 11q deletion or 17q gain exhibited poor DFS and OS, respectively (P = 0.021, 0.011). Six patients experienced grade 1 acute toxicity. Late toxicity was confirmed in children with long-term survival, predominantly hypothyroidism and hypogonadism, typically < grade 3, possibly attributed to combination treatment. Four patients experienced late toxicity ≥ grade 3 with chronic kidney disease, growth hormone abnormality, ileus, premature epiphyseal closure, and secondary tumor, and recovered by hospitalization or surgical treatment. CONCLUSIONS: In patients with high-risk neuroblastoma, consolidative radiotherapy to the primary tumor site resulted in excellent local control and a tolerable safety profile.

Evidence-based clinical recommendations for hypofractionated radiotherapy: exploring efficacy and safety - Part 1. Brain and head and neck.

Advances in radiotherapy (RT) techniques, including intensity-modulated RT and image-guided RT, have allowed hypofractionation, increasing the fraction size over the conventional dose of 1.8-2.0 Gy. Hypofractionation offers advantages such as shorter treatment times, improved compliance, and under specific conditions, particularly in tumors with a low α/ß ratio, higher efficacy. It was initially explored for use in RT for prostate cancer and adjuvant RT for breast cancer, and its application has been extended to various other malignancies. Hypofractionated RT (HFRT) may also be effective in patients who are unable to undergo conventional treatment owing to poor performance status, comorbidities, or old age. The treatment of brain tumors with HFRT is relatively common because brain stereotactic radiosurgery has been performed for over two decades. However, re-irradiation of recurrent lesions and treatment of elderly or frail patients are areas under investigation. HFRT for head and neck cancer has not been widely used because of concerns regarding late toxicity. Thus, we aimed to provide a comprehensive summary of the current evidence for HFRT for brain tumors and head and neck cancer and to offer practical recommendations to clinicians faced with the challenge of choosing new treatment options.

Real-world outcome of crizotinib for anaplastic lymphoma kinase-positive lung cancer: Multicenter retrospective analysis in South Korea.

BACKGROUND: About 3%-5% of non-small cell lung cancer (NSCLC) presents positive anaplastic lymphoma kinase (ALK). Recently, several target agents have been approved as a treatment for ALK-positive NSCLC. This study aimed to analyze the real-world efficacy and outcome when administered crizotinib, the first approved target agent for ALK-positive NSCLC, according to first- or late-line treatment. METHODS: A total of 290 patients with ALK-positive advanced NSCLC who were treated with crizotinib in 15 institutions in South Korea from January 2009 to December 2018 were enrolled. RESULTS: The median age of patients was 57.0 years, and 50.3% were male. The median follow-up duration was 29.3 months. Among them, 113 patients received crizotinib as first-line therapy. The objective response rate (ORR) was 60.1% (57.0% for first-line recipients, 61.8% for second-/later-line). Median (95% CI) progression-free survival (PFS) was 13.7 (11.6-17.0) months. For first-line recipients, overall survival (OS) was 26.3 (17.6-35.0) months. No significant difference in ORR, PFS and OS, according to the setting of crizotinib initiation, was observed. In a multivariate Cox regression analysis, old age, male gender, initially metastatic, and number of metastatic organs were associated with poor PFS and OS. The most common adverse events were nausea and vomiting, and severe adverse event leading to dose adjustment was hepatotoxicity. CONCLUSIONS: ORR, PFS, OS, and adverse event profiles were comparable to previous clinical trials. Our findings could aid in the efficient management of ALK-positive lung cancer patients.

The Real-World Outcome of First Line Atezolizumab in Extensive-Stage Small Cell Lung Cancer: A Multicenter Prospective Cohort Study.

PURPOSE: The addition of immune checkpoint inhibitors to chemotherapy has improved survival outcomes in patients with extensive-stage small cell lung cancer (ES-SCLC). However, their real-world effectiveness remains unknown. Therefore, we investigated the effectiveness of atezolizumab plus chemotherapy in ES-SCLC in actual clinical settings. MATERIALS AND METHODS: In this multicenter prospective cohort study, patients with ES-SCLC receiving or scheduled to receive atezolizumab in combination with etoposide and carboplatin were enrolled between June 2021 and August 2022. The primary outcomes were progression-free survival (PFS) and the 1-year overall survival (OS) rate. RESULTS: A total of 100 patients with ES-SCLC were enrolled from seven centers. Median age was 69 years, and 6% had an Eastern Cooperative Oncology Group performance status (ECOG PS) ≥ 2. The median PFS was 6.0 months, the 1-year OS rate was 62.2%, and the median OS was 13.5 months. An ECOG PS of 2-3 and progressive disease as the best response were poor prognostic factors for PFS, while an ECOG PS of 2-3 and brain metastasis were associated with poor prognosis for OS. In addition, consolidative thoracic radiotherapy was found to be an independent favorable prognostic factor for OS (hazard ratio, 0.336; p=0.021). Grade ≥ 3 treatment-related adverse events were observed in 7% of patients, with treatment-related deaths occurring in 2% of patients. CONCLUSION: We provided evidence of the favorable real-world effectiveness and safety of atezolizumab plus chemotherapy in ES-SCLC patients, including in the elderly and those with poor ECOG PS. Additional consolidative thoracic radiotherapy may also benefit ES-SCLC patients.

Application of surface-guided radiation therapy in prostate cancer: comparative analysis of differences with skin marking-guided patient setup.

PURPOSE: Surface-guided radiation therapy is an image-guided method using optical surface imaging that has recently been adopted for patient setup and motion monitoring during treatment. We aimed to determine whether the surface guide setup is accurate and efficient compared to the skin-marking guide in prostate cancer treatment. MATERIALS AND METHODS: The skin-marking setup was performed, and vertical, longitudinal, and lateral couch values (labeled as "M") were recorded. Subsequently, the surface-guided setup was conducted, and couch values (labeled as "S") were recorded. After performing cone-beam computed tomography (CBCT), the final couch values was recorded (labeled as "C"), and the shift value was calculated (labeled as "Gap (M-S)," "Gap (M-C)," "Gap (S-C)") and then compared. Additionally, the setup times for the skin marking and surface guides were also compared. RESULTS: One hundred and twenty-five patients were analyzed, totaling 2,735 treatment fractions. Gap (M-S) showed minimal differences in the vertical, longitudinal, and lateral averages (-0.03 cm, 0.07 cm, and 0.06 cm, respectively). Gap (M-C) and Gap (S-C) exhibited a mean difference of 0.04 cm (p = 0.03) in the vertical direction, a mean difference of 0.35 cm (p = 0.52) in the longitudinal direction, and a mean difference of 0.11 cm (p = 0.91) in the lateral direction. There was no correlation between shift values and patient characteristics. The average setup time of the skin-marking guide was 6.72 minutes, and 7.53 minutes for the surface guide. CONCLUSION: There was no statistically significant difference between the surface and skin-marking guides regarding final CBCT shift values and no correlation between translational shift values and patient characteristics. We also observed minimal difference in setup time between the two methods. Therefore, the surface guide can be considered an accurate and time-efficient alternative to skin-marking guides.

Corrigendum: Correction of the Figure. Trends of stratified prostate cancer risk in a single Korean province from 2003 to 2021: A multicenter study conducted using regional training hospital data.

This corrects the article on p. 140 in vol. 64, PMID: 36882172.

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.

Surveillance of Symptom Burden Using the Patient-Reported Outcome Version of the Common Terminology Criteria for Adverse Events in Patients With Various Types of Cancers During Chemoradiation Therapy: Real-World Study.

BACKGROUND: Over 90% of patients with cancer experience 1 or more symptoms caused directly by cancer or its treatment. These symptoms negatively impact on the completion of planned treatment as well as patients' health-related quality of life (HRQoL). It often results in serious complications and even life-threatening outcomes. Thus, it has been recommended that surveillance of symptom burden should be performed and managed during cancer treatment. However, differences in symptom profiles in various patients with cancer have not been fully elucidated for use in performing surveillance in the real world. OBJECTIVE: This study aims to evaluate the burden of symptoms in patients with various types of cancers during chemotherapy or radiation therapy using the PRO-CTCAE (Patient-Reported Outcome Version of the Common Terminology Criteria for Adverse Events) and its impact on quality of life. METHODS: We performed a cross-sectional study of patients undergoing outpatient-based chemotherapy, radiation therapy, or both at the National Cancer Center at Goyang or at the Samsung Medical Center in Seoul, Korea between December 2017 and January 2018. To evaluate cancer-specific symptom burden, we developed 10 subsets for using the PRO-CTCAE-Korean. To measure HRQoL, we used the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). Participants answered questions prior to their clinic appointments on tablets. Multivariable linear regression was used to analyze symptoms based on cancer type and to evaluate the association between the PRO-CTCAE items and the EORTC QLQ-C30 summary score. RESULTS: The mean age (SD) of the patients was 55.0 (11.9) years, and 39.94% (540/1352) were male. Overall, symptoms in the gastrointestinal category were the most dominant in all cancers. Fatigue (1034/1352, 76.48%), decreased appetite (884/1352, 65.38%), and numbness and tingling (778/1352, 57.54%) were the most frequently reported. Patients reported more local symptoms caused by a specific cancer. In terms of nonsite-specific symptoms, patients commonly reported concentration (587/1352, 43.42%), anxiety (647/1352, 47.86%), and general pain (605/1352, 44.75%). More than 50% of patients with colorectal (69/127, 54.3%), gynecologic (63/112, 56.3%), breast (252/411, 61.3%), and lung cancers (121/234, 51.7%) experienced decreased libido, whereas 67/112 (59.8%) patients with gynecologic cancer and lymphoma/myeloma reported pain during sexual intercourse. Patients with breast, gastric, and liver cancers were more likely to have the hand-foot syndrome. Worsening PRO-CTCAE scores were associated with poor HRQoL (eg, fatigue: coefficient -8.15; 95% CI -9.32 to -6.97), difficulty in achieving and maintaining erection (coefficient -8.07; 95% CI -14.52 to -1.61), poor concentration (coefficient -7.54; 95% CI -9.06 to -6.01), and dizziness (coefficient -7.24; 95% CI -8.92 to -5.55). CONCLUSIONS: The frequency and severity of symptoms differed by cancer types. Higher symptom burden was associated with poor HRQoL, which suggests the importance of appropriate surveillance of PRO symptoms during cancer treatment. Considering patients had comprehensive symptoms, it is necessary to include a holistic approach in the symptom monitoring and management strategies based on comprehensive patient-reported outcome measurements.

Trends of stratified prostate cancer risk in a single Korean province from 2003 to 2021: A multicenter study conducted using regional training hospital data.

PURPOSE: To identify changes in prostate cancer (PCa) risk-stratification during the last two decades in Korea, where the social perception of PCa was limited due to a relatively low incidence but has recently been triggered by the rapidly increasing incidence of benign prostate hyperplasia. MATERIALS AND METHODS: Retrospective data of patients who had received a diagnosis of PCa in a single Korean province (Daegu-Gyeongsangbuk) at all seven training hospitals in the years 2003, 2007, 2011, 2015, 2019, and 2021 were subjected to analysis. Changes in PCa risk-stratification were investigated with respect to serum prostate-specific antigen (PSA), Gleason score (GS), and clinical stage. RESULTS: Of the 3,393 study subjects that received a diagnosis of PCa, 64.1% had high-risk disease, 23.0% intermediate, and 12.9% low-risk disease. The proportion diagnosed with high-risk disease was 54.8% in 2003, 30.6% in 2019, but then increased to 35.1% in 2021. The proportion of patients with high PSA (>20 ng/mL) steadily decreased from 59.4% in 2003 to 29.6% in 2021, whereas the proportion with a high GS (>8) increased from 32.8% in 2011 to 34.0% in 2021, and the proportion with advanced stage disease (over cT2c) increased from 26.5% in 2011 to 37.1% in 2021. CONCLUSIONS: In this retrospective study, conducted in a single Korean province, high-risk PCa accounted for the largest proportion of newly registered Korean PCa patients during the last two decades and increased in the early 2020s. This outcome supports the adoption of nationwide PSA screening, regardless of current Western guidelines.

The Updated World Health Organization Classification Better Predicts Survival in Patients With Endocervical Adenocarcinoma (KROG 20-07).

PURPOSE: The 2020 World Health Organization classification divided endocervical adenocarcinoma (ADC) into human papillomavirus-associated (HPVA) and human papillomavirus-independent (HPVI) ADCs. This multi-institutional study aimed to investigate the clinical features and prognosis of patients with endocervical ADC based on the updated World Health Organization classification. METHODS AND MATERIALS: We retrospectively reviewed the 365 patients with endocervical ADC who underwent radical hysterectomy from 7 institutions. Tumor characteristics, patterns of failure, and survival outcomes were compared between HPVA and HPVI ADCs. RESULTS: Two hundred seventy-five (75.3%) and 90 (24.7%) patients had HPVA and HPVI ADC diagnoses, respectively. In all cases, the 5-year disease-free survival (DFS) and overall survival (OS) rates were 58.2% and 71.3%, respectively. HPVI ADC showed higher rates of local recurrence (25.6% vs 10.9%) and distant metastasis (33.3% vs 17.5%) than HPVA ADC. Multivariate survival analysis revealed that HPVI ADC showed significantly worse DFS (hazard ratio [HR], 1.919; 95% confidence interval [CI], 1.324-2.781; P < .001), distant metastasis-free survival (HR, 2.100; 95% CI, 1.397-3.156; P < .001), and OS (HR, 2.481; 95% CI, 1.586-3.881; P < .001) than HPVA ADC. Patients with gastric- and serous-type HPVI ADC had significantly worse OS than those with other HPVI ADCs (P = .020). Similarly, invasive stratified mucin-producing-type HPVA ADC showed significantly worse OS than other HPVA ADCs (P < .001). CONCLUSIONS: We demonstrated that HPVI ADC exhibited inferior DFS and OS and higher rates of local and distant recurrence compared with HPVA ADC. Gastric- and serous-type HPVI ADCs and invasive stratified mucin-producing-type HPVA ADC showed worse OS than other types of HPVI and HPVA ADCs, respectively. Our observation of significant differences in prognoses according to the histologic types needs to be validated in larger cohorts of patients with endocervical ADC.

Pattern of practice for postoperative management of endometrial cancer in Korea: a survey by the Korean Gynecologic Oncology Group and the Korean Radiation Oncology Group (KGOG 2028-KROG 2104).

OBJECTIVE: This study aimed to investigate the current status of postoperative management of uterine endometrial cancer (EC) in Korea. METHODS: A mail survey was administered to members of the Korean Gynecologic Oncology Group and Korean Radiation Oncology Group. A total of 38 gynecologic cancer surgeons (GYNs) and 31 radiation oncologists (RO) in 43 institutions was responded. The questionnaire consisted of general questions for clinical decision and clinical case questions. The GYN and RO responses were compared using chi-square statistics. RESULTS: The 2 expert groups had similar responses for clinical decision based on the results of the Gynecologic Oncology Group (GOG)-249 and Postoperative Radiation Therapy for Endometrial Carcinoma-III trials in the early-stage EC. In contrast, the responses based on GOG-258 results differed, as GYNs most frequently opted for sequential chemotherapy (CTx) and radiotherapy (RT), while ROs preferred concurrent chemoradiotherapy in locally advanced stage (p<0.05). Based on the GOG-258, GYNs preferred CTx alone for adjuvant treatment of serous or clear cell adenocarcinoma histology, whereas ROs advocated for combined CTx and RT (sequential or concurrent). Among the clinical case questions, GYNs were more likely than ROs to choose CTx alone rather than the combination of CTx and RT (sequential or concurrent) as the answers to case questions representing patients with locally advanced stage or unfavorable histology (all p<0.05). CONCLUSION: The present study showed several different opinions of GYNs and ROs regarding adjuvant treatment for EC, particularly for adjuvant RT in advanced stage or unfavorable histology.

NCK-associated protein 1 regulates metastasis and is a novel prognostic marker for colorectal cancer.

Metastatic colorectal cancer (CRC) remains a substantial problem for mortality and requires screening and early detection efforts to increase survival. Epithelial-mesenchymal transition (EMT) and circulation of tumor cells in the blood play important roles in metastasis. To identify a novel target for metastasis of CRC, we conducted a gene microarray analysis using extracted RNA from the blood of preclinical models. We found that NCK-associated protein 1 (NCKAP1) was significantly increased in the blood RNA of patient-derived xenograft (PDX) models of colon cancer. In the NCKAP1 gene knockdown-induced human colon cancer cell lines HCT116 and HT29, there was a reduced wound healing area and significant inhibition of migration and invasion. As the result of marker screening for cytoskeleton and cellular interactions, CRC treated with siRNA of NCKAP1 exhibited significant induction of CDH1 and phalloidin expression, which indicates enhanced adherent cell junctions and cytoskeleton. In HCT116 cells with a mesenchymal state induced by TGFß1, metastasis was inhibited by NCKAP1 gene knockdown through the inhibition of migration, and there was increased CTNNB1 expression and decreased FN expression. We established metastasis models for colon cancer to liver transition by intrasplenic injection shRNA of NCKAP1-transfected HCT116 cells or by implanting tumor tissue generated with the cells on cecal pouch. In metastasis xenograft models, tumor growth and liver metastasis were markedly reduced. Taken together, these data demonstrate that NCKAP1 is a novel gene regulating EMT that can contribute to developing a diagnostic marker for the progression of metastasis and new therapeutics for metastatic CRC treatment.

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.