A Pooled Analysis of Trastuzumab Deruxtecan in Patients With HER2-Positive Metastatic Breast Cancer With Brain Metastases.

BACKGROUND: This exploratory pooled analysis investigated the efficacy and safety of trastuzumab deruxtecan (T-DXd) versus comparator treatment in patients with HER2-positive metastatic breast cancer (mBC) with brain metastases (BMs) at baseline, categorized according to previous local treatment. PATIENTS AND METHODS: T-DXd data were pooled from DESTINY-Breast01/-02/-03. Comparator data, from patients receiving physician's choice therapy and trastuzumab emtansine, were pooled from DESTINY-Breast02 and -03, respectively. Baseline BM status was assessed according to US Food and Drug Administration criteria. Endpoints included intracranial objective response rate (ORR; complete or partial response in brain) per blinded independent central review (BICR) by RECIST v1.1, time to intracranial response, intracranial duration of response (DoR), central nervous system progression-free survival (CNS-PFS) by BICR, overall survival (OS), and safety. RESULTS: 148 patients who received T-DXd and 83 patients who received comparator treatment had BMs at baseline. In those who were treated with T-DXd, the intracranial ORR of patients with treated/stable and untreated/active BMs was 45.2% and 45.5%, respectively. The median (range) time to intracranial response was 2.8 months (1.1-13.9 months) and 1.5 months (1.2-13.7 months) in patients with treated/stable and untreated/active BMs, respectively. For those with treated/stable BMs, the median (95% CI) intracranial DoR was 12.3 months (9.1-17.9 months), and for those with untreated/active BMs it was 17.5 months (13.6-31.6 months). The median (95% CI) CNS-PFS and OS was 12.3 months (11.1-13.8 months) and not reached (22.1 months-not estimable [NE]) in those with treated/stable BMs, and 18.5 months (13.6-23.3 months) and 30.2 months (21.3 months-NE) in those with untreated/active BMs, respectively. Drug-related TEAEs grade ≥3 were experienced by 43.2% of patients with BMs and 46.4% without BMs with T-DXd. CONCLUSIONS: T-DXd demonstrated meaningful intracranial efficacy and clinical benefit in OS, with an acceptable and manageable safety profile in patients with HER2-positive mBC with treated/stable and untreated/active BMs.

Capivasertib and fulvestrant for patients with hormone receptor-positive advanced breast cancer: characterization, time course, and management of frequent adverse events from the phase III CAPItello-291 study.

BACKGROUND: Capivasertib is a potent, selective pan-AKT inhibitor. In CAPItello-291, the addition of capivasertib to fulvestrant resulted in a statistically significant (P < 0.001) improvement in progression-free survival over fulvestrant monotherapy in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer and disease progression on or after aromatase inhibitor-based therapy. Characterization of the capivasertib-fulvestrant adverse event (AE) profile as managed in CAPItello-291 can inform future management guidance and optimize clinical benefit. PATIENTS AND METHODS: Seven hundred and eight patients were randomized 1 : 1 to capivasertib (400 mg twice daily; 4 days on, 3 days off) or placebo, plus fulvestrant, on a 4-week cycle. Dose reductions/interruptions for capivasertib/placebo were permitted (up to two dose reductions). Safety analyses included exposure, AE, and clinical laboratory data and were conducted in patients who received at least one dose of capivasertib, fulvestrant, or placebo. Frequent AEs associated with phosphoinositide 3-kinase (PI3K)/protein kinase (AKT) pathway inhibition (diarrhea, rash, hyperglycemia) were characterized using group terms. AEs were summarized using descriptive statistics; time-to-event analyses were conducted. RESULTS: Safety analyses included 705 patients: capivasertib-fulvestrant (n = 355) and placebo-fulvestrant (n = 350). Frequent any-grade AEs with capivasertib-fulvestrant were diarrhea (72.4%), rash (38.0%), and nausea (34.6%); frequent grade ≥3 AEs were rash (12.1%), diarrhea (9.3%), and hyperglycemia (2.3%). Diarrhea, rash, and hyperglycemia occurred shortly after starting capivasertib-fulvestrant [median days to onset (interquartile range) of any grade: 8 (2-22), 12 (10-15), and 15 (1-51), respectively], and were managed with supportive medications, dose reductions, interruptions, and/or discontinuation. Discontinuation rates were 2.0%, 4.5%, and 0.3%, respectively. Overall, 13.0% discontinued capivasertib due to AEs. CONCLUSIONS: Frequent AEs associated with PI3K/AKT pathway inhibition occurred early and were manageable. The low rate of treatment discontinuations suggests that, when appropriately managed, these AEs do not pose a challenge to clinical benefit.

Anaemia is independently associated with mortality in patients with hepatocellular carcinoma.

BACKGROUND: Anaemia is frequent in patients with cancer and/or liver cirrhosis and is associated with impaired quality of life. Here, we investigated the impact of anaemia on overall survival (OS) and clinical characteristics in patients with hepatocellular carcinoma (HCC). MATERIALS AND METHODS: HCC patients treated between 1992 and 2018 at the Medical University of Vienna were retrospectively analysed. Anaemia was defined as haemoglobin level <13 g/dl in men and <12 g/dl in women. RESULTS: Of 1262 assessable patients, 555 (44.0%) had anaemia. The main aetiologies of HCC were alcohol-related liver disease (n = 502; 39.8%) and chronic hepatitis C (n = 375; 29.7%). Anaemia was significantly associated with impaired liver function, portal hypertension, more advanced Barcelona Clinic Liver Cancer stage and elevated C-reactive protein (CRP). In univariable analysis, anaemia was significantly associated with shorter median OS [9.5 months, 95% confidence interval (95% CI) 7.3-11.6 months] versus patients without anaemia (21.5 months, 95% CI 18.3-24.7 months) (P < 0.001). In multivariable analysis adjusted for age, Model for End-stage Liver Disease, number of tumour nodules, size of the largest nodule, macrovascular invasion, extrahepatic spread, first treatment line, alpha-fetoprotein and CRP, anaemia remained an independent predictor of mortality (adjusted hazard ratio 1.23, 95% CI 1.06-1.43, P = 0.006). CONCLUSIONS: Anaemia was significantly associated with mortality in HCC patients, independent of established liver- and tumour-related prognostic factors. Whether adequate management of anaemia can improve outcome of HCC patients needs further evaluation.

Trastuzumab deruxtecan versus trastuzumab emtansine in HER2-positive metastatic breast cancer patients with brain metastases from the randomized DESTINY-Breast03 trial.

BACKGROUND: DESTINY-Breast03 is a randomized, multicenter, open-label, phase III study of trastuzumab deruxtecan (T-DXd) versus trastuzumab emtansine (T-DM1) in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (mBC) previously treated with trastuzumab and a taxane. A statistically significant improvement in progression-free survival (PFS) versus T-DM1 was reported in the primary analysis. Here, we report exploratory efficacy data in patients with and without brain metastases (BMs) at baseline. PATIENTS AND METHODS: Patients were randomly assigned 1 : 1 to receive T-DXd 5.4 mg/kg or T-DM1 3.6 mg/kg. Patients with clinically inactive/asymptomatic BMs were eligible. Lesions were measured as per modified RECIST, version 1.1. Outcomes included PFS by blinded independent central review (BICR), objective response rate (ORR), and intracranial ORR as per BICR. RESULTS: As of 21 May 2021, 43/261 patients randomized to T-DXd and 39/263 patients randomized to T-DM1 had BMs at baseline, as per investigator assessment. Among patients with baseline BMs, 20/43 in the T-DXd arm and 19/39 in the T-DM1 arm had not received prior local BM treatment. For patients with BMs, median PFS was 15.0 months [95% confidence interval (CI) 12.5-22.2 months] for T-DXd versus 3.0 months (95% CI 2.8-5.8 months) for T-DM1; hazard ratio (HR) 0.25 (95% CI 0.13-0.45). For patients without BMs, median PFS was not reached (95% CI 22.4 months-not estimable) for T-DXd versus 7.1 months (95% CI 5.6-9.7 months) for T-DM1; HR 0.30 (95% CI 0.22-0.40). Confirmed systemic ORR was 67.4% for T-DXd versus 20.5% for T-DM1 and 82.1% for T-DXd versus 36.6% for T-DM1 for patients with and without BMs, respectively. Intracranial ORR was 65.7% with T-DXd versus 34.3% with T-DM1. CONCLUSIONS: Patients with HER2-positive mBC whose disease progressed after trastuzumab and a taxane achieved a substantial benefit from treatment with T-DXd compared with T-DM1, including those with baseline BMs.

Total knee arthroplasty and periprosthetic distal femoral fracture: looking beyond the osteoporosis to previous osteoporotic fracture.

Osteoporosis increases the risk of periprosthetic distal femoral fractures after TKA, especially in patients with a history of osteoporotic fractures. Therefore, careful assessment and proper treatment of osteoporosis need and the importance of taking osteoporotic medication needs to be recognized by the patients following primary TKA. PURPOSE: Osteoporosis is a risk factor for fractures, including those of the hip, vertebrae, and distal radius; however, the association between osteoporosis and periprosthetic fractures after total knee arthroplasty (TKA) has not been much investigated. Therefore, we aimed to investigate the association of the presence of systemic osteoporosis with periprosthetic fractures after TKA. METHODS: This study included 34 patients with periprosthetic fractures following primary TKA and 106 controls matched for age and sex. Bone mineral density was evaluated at the femoral neck, total hip, and lumbar spine using dual X-ray absorptiometry. Medical records were reviewed for age; sex; body mass index; smoking; rheumatoid arthritis, endocrine diseases, and cardiovascular diseases; history of glucocorticoid use; medication for osteoporosis; and history of previous osteoporotic fracture. In addition, anterior femoral notching after TKA was evaluated. Univariable and multivariable logistic regression analysis were used to determine factors associated with periprosthetic fracture. RESULTS: The prevalence of osteoporosis in the fracture group was higher than that in the control group (61.8% vs. 40.6%, p=0.045). The rate of medication for osteoporosis was significantly low in the fracture group (47.6 % vs 76.7%, p=0.026). History of previous osteoporotic fracture (odds ratio [OR], 9.1; p=0.015) and osteoporosis (OR, 3.6; p=0.013) were significant risk factors for periprosthetic fractures after TKA. Medication for osteoporosis could decrease the risk of periprosthetic fracture (OR 0.3; p=0.020). CONCLUSION: Osteoporosis is a major risk factor for periprosthetic distal femoral fractures after TKA. Therefore, careful assessment and proper treatment of osteoporosis need and the importance of taking osteoporotic medication needs to be recognized to the patients following primary TKA, especially in patients with a history of osteoporotic fracture. LEVEL OF EVIDENCE: Prognostic study, level III.

IMpassion132 double-blind randomised phase III trial of chemotherapy with or without atezolizumab for early relapsing unresectable locally advanced or metastatic triple-negative breast cancer.

BACKGROUND: Immune checkpoint inhibitors improve the efficacy of first-line chemotherapy for patients with programmed death-ligand 1 (PD-L1)-positive unresectable locally advanced/metastatic triple-negative breast cancer (aTNBC), but randomised data in rapidly relapsing aTNBC are scarce. PATIENTS AND METHODS: IMpassion132 (NCT03371017) enrolled patients with aTNBC relapsing <12 months after last chemotherapy dose (anthracycline and taxane required) or surgery for early TNBC. PD-L1 status was centrally assessed using SP142 before randomisation. Initially patients were enrolled irrespective of PD-L1 status. From August 2019, enrolment was restricted to PD-L1-positive (tumour immune cell ≥1%) aTNBC. Patients were randomised 1:1 to placebo or atezolizumab 1200 mg every 21 days with investigator-selected chemotherapy until disease progression or unacceptable toxicity. Stratification factors were chemotherapy regimen (carboplatin plus gemcitabine or capecitabine monotherapy), visceral (lung and/or liver) metastases and (initially) PD-L1 status. The primary endpoint was overall survival (OS), tested hierarchically in patients with PD-L1-positive tumours and then, if positive, in the modified intent-to-treat (mITT) population (all-comer patients randomised pre-August 2019). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR) and safety. RESULTS: Among 354 patients with rapidly relapsing PD-L1-positive aTNBC, 68% had a disease-free interval of <6 months and 73% received carboplatin/gemcitabine. The OS hazard ratio was 0.93 (95% confidence interval 0.73-1.20, P = 0.59; median 11.2 months with placebo versus 12.1 months with atezolizumab). mITT and subgroup results were consistent. Median PFS was 4 months across treatment arms and populations. ORRs were 28% with placebo versus 40% with atezolizumab. Adverse events (predominantly haematological) were similar between arms and as expected with atezolizumab plus carboplatin/gemcitabine or capecitabine following recent chemotherapy exposure. CONCLUSIONS: OS, which is dismal in patients with TNBC relapsing within <12 months, was not improved by adding atezolizumab to chemotherapy. A biology-based definition of intrinsic resistance to immunotherapy in aTNBC is urgently needed to develop novel therapies for these patients in next-generation clinical trials.

Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with early breast cancer.

The European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with early breast cancer were updated and published online in 2023, and adapted, according to previously established standard methodology, to produce the Pan-Asian adapted (PAGA) ESMO consensus guidelines for the management of Asian patients with early breast cancer. The adapted guidelines presented in this manuscript represent the consensus opinions reached by a panel of Asian experts in the treatment of patients with breast cancer representing the oncological societies of China (CSCO), Indonesia (ISHMO), India (ISMPO), Japan (JSMO), Korea (KSMO), Malaysia (MOS), the Philippines (PSMO), Singapore (SSO), Taiwan (TOS) and Thailand (TSCO), co-ordinated by ESMO and KSMO. The voting was based on scientific evidence and was independent of the current treatment practices, drug access restrictions and reimbursement decisions in the different Asian regions represented by the 10 oncological societies. The latter are discussed separately in the manuscript. The aim is to provide guidance for the optimisation and harmonisation of the management of patients with early breast cancer across the different regions of Asia, drawing on the evidence provided by both Western and Asian trials, whilst respecting the differences in screening practices, molecular profiling, as well as the age and stage at presentation. Attention is drawn to the disparity in the drug approvals and reimbursement strategies, between the different regions of Asia.

Event-free survival by residual cancer burden with pembrolizumab in early-stage TNBC: exploratory analysis from KEYNOTE-522.

BACKGROUND: KEYNOTE-522 demonstrated statistically significant improvements in pathological complete response (pCR) with neoadjuvant pembrolizumab plus chemotherapy and event-free survival (EFS) with neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab in patients with high-risk, early-stage triple-negative breast cancer (TNBC). Prior studies have shown the prognostic value of the residual cancer burden (RCB) index to quantify the extent of residual disease after neoadjuvant chemotherapy. In this preplanned exploratory analysis, we assessed RCB distribution and EFS within RCB categories by treatment group. PATIENTS AND METHODS: A total of 1174 patients with stage T1c/N1-2 or T2-4/N0-2 TNBC were randomized 2 : 1 to pembrolizumab 200 mg or placebo every 3 weeks given with four cycles of paclitaxel + carboplatin, followed by four cycles of doxorubicin or epirubicin + cyclophosphamide. After surgery, patients received pembrolizumab or placebo for nine cycles or until recurrence or unacceptable toxicity. Primary endpoints are pCR and EFS. RCB is a prespecified exploratory endpoint. The association between EFS and RCB was assessed using a Cox regression model. RESULTS: Pembrolizumab shifted patients into lower RCB categories across the entire spectrum compared with placebo. There were more patients in the pembrolizumab group with RCB-0 (pCR), and fewer patients in the pembrolizumab group with RCB-1, RCB-2, and RCB-3. The corresponding hazard ratios (95% confidence intervals) for EFS were 0.70 (0.38-1.31), 0.92 (0.39-2.20), 0.52 (0.32-0.82), and 1.24 (0.69-2.23). The most common first EFS events were distant recurrences, with fewer in the pembrolizumab group across all RCB categories. Among patients with RCB-0/1, more than half [21/38 (55.3%)] of all events were central nervous system recurrences, with 13/22 (59.1%) in the pembrolizumab group and 8/16 (50.0%) in the placebo group. CONCLUSIONS: Addition of pembrolizumab to chemotherapy resulted in fewer EFS events in the RCB-0, RCB-1, and RCB-2 categories, with the greatest benefit in RCB-2. These findings demonstrate that pembrolizumab not only increased pCR rates, but also improved EFS among most patients who do not have a pCR.

Trastuzumab deruxtecan in previously treated patients with HER2-positive metastatic breast cancer: updated survival results from a phase II trial (DESTINY-Breast01).

BACKGROUND: Primary analysis of the multicenter, open-label, single-arm, phase II DESTINY-Breast01 trial (median follow-up 11.1 months) demonstrated durable antitumor activity with trastuzumab deruxtecan (T-DXd) in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (mBC) previously treated with trastuzumab emtansine (T-DM1). We report updated cumulative survival outcomes with a median follow-up of 26.5 months (data cut-off 26 March 2021). PATIENTS AND METHODS: Patients with HER2-positive mBC resistant or refractory to T-DM1 received T-DXd 5.4 mg/kg intravenously every 3 weeks until disease progression, unacceptable adverse events, or withdrawal of consent. The primary endpoint was confirmed objective response rate (ORR) by independent central review (ICR). Secondary endpoints included overall survival (OS), duration of response (DoR), progression-free survival (PFS), and safety. RESULTS: The ORR by ICR was 62.0% [95% confidence interval (CI) 54.5% to 69.0%] in patients who received T-DXd 5.4 mg/kg every 3 weeks (n = 184). Median OS was 29.1 months (95% CI 24.6-36.1 months). Median PFS and DoR were 19.4 months (95% CI 14.1-25.0 months) and 18.2 months (95% CI 15.0 months-not evaluable), respectively. Drug-related treatment-emergent adverse events (TEAEs) were observed in 183 patients (99.5%), and 99 patients (53.8%) had one or more grade ≥3 TEAEs. Adjudicated drug-related interstitial lung disease/pneumonitis occurred in 15.8% of patients (n = 29), of which 2.7% (n = 5) were grade 5. CONCLUSIONS: These updated results provide further evidence of sustained antitumor activity of T-DXd with a consistent safety profile in heavily pretreated patients with HER2-positive mBC.

Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, staging and treatment of patients with metastatic breast cancer.

The most recent version of the European Society for Medical Oncology (ESMO) Clinical Practice Guidelines for the diagnosis, staging and treatment of patients with metastatic breast cancer (MBC) was published in 2021. A special, hybrid guidelines meeting was convened by ESMO and the Korean Society of Medical Oncology (KSMO) in collaboration with nine other Asian national oncology societies in May 2022 in order to adapt the ESMO 2021 guidelines to take into account the differences associated with the treatment of MBC in Asia. These guidelines represent the consensus opinions reached by a panel of Asian experts in the treatment of patients with MBC representing the oncological societies of China (CSCO), India (ISMPO), Indonesia (ISHMO), Japan (JSMO), Korea (KSMO), Malaysia (MOS), the Philippines (PSMO), Singapore (SSO), Taiwan (TOS) and Thailand (TSCO). The voting was based on the best available scientific evidence and was independent of drug access or practice restrictions in the different Asian countries. The latter were discussed when appropriate. The aim of these guidelines is to provide guidance for the harmonisation of the management of patients with MBC across the different regions of Asia, drawing from data provided by global and Asian trials whilst at the same time integrating the differences in genetics, demographics and scientific evidence, together with restricted access to certain therapeutic strategies.

Hydrogen production from hazardous petroleum sludge gasification over nickel-loaded porous ZSM-5 and Al2O3 catalysts under air condition.

In this study, the potential of petroleum sludge (PS) for hydrogen production via the gasification process was evaluated. For this purpose, nickel (Ni)-loaded ZSM-5 and γ-Al2O3 (Ni-ZS and Ni-Al) catalysts were prepared and employed for PS gasification in air condition. The effects of different supports, Ni loading content, and reaction temperatures on the production of hydrogen-rich syngas along with the stability and reusability of the best catalyst were investigated. Applying 5%Ni-ZS obtained more gas yield (68.09 wt%) and hydrogen selectivity (25.04 vol%) compared to those obtained by 5%Ni-Al mostly owing to weak metal-support interactions which led to the dominance of well-dispersed metallic Ni. At various Ni loading percentages, 10%Ni-ZS showed the highest catalytic efficiency, which increased both gas yield (70.92 wt%) and hydrogen selectivity (30.74 vol%). However, excessive Ni content (especially 20%) significantly reduced the gas yield and hydrogen selectivity because of limited accessibility of support's active sites, poor dispersion of Ni, and inappropriate acidity. Increasing the temperature promoted the gas yield and produced hydrogen, where the highest gas yield (73.18 wt%) and hydrogen selectivity (33.15 vol%) were obtained at 850 °C due to the endothermic nature of gasification reactions. The 10%Ni-ZS catalyst showed proper stability during three consecutive experiments at 850 °C. The spent catalyst was successfully regenerated without a significant reduction in activity or selectivity.

Association between obsessive-compulsive disorder and the risk of schizophrenia using the Korean National Health Insurance Service-National Sample Cohort: a retrospective cohort study.

AIMS: Obsessive-compulsive disorder (OCD) and schizophrenia are often reported as co-morbid conditions. However, the evidence of an association between OCD and the risk of schizophrenia is limited. This study investigated the risk of schizophrenia in patients newly diagnosed with OCD using a nationally representative sample cohort in South Korea. METHODS: Data were obtained from the 2002-2013 Korean National Health Insurance Service-National Sample Cohort of the National Health Insurance Service. Using propensity score matching, 2509 patients with OCD and a control group of 7527 patients were included in the analysis. Chi-squared tests were used to investigate and compare the general characteristics of the study population. The risk of schizophrenia was analysed using the Cox proportional hazard model. RESULTS: The incidence rate was 45.79/10 000 person-year for patients with OCD and 4.19/10 000 person-year for patients without OCD. Patients with OCD had a higher risk of schizophrenia compared to the control group after adjusting for covariates (hazard ratio = 10.46, 95% confidence interval = 6.07-18.00). CONCLUSIONS: This study identified an association between the diagnosis of OCD and the risk of schizophrenia in a South Korean national representative cohort. Further research using a prospective design to clarify the causality of OCD in schizophrenia in a controlled environment should be conducted to validate these findings.

A New Approach to Quantify and Grade Radiation Dermatitis Using Deep-Learning Segmentation in Skin Photographs.

AIMS: Objective evaluation of radiation dermatitis is important for analysing the correlation between the severity of radiation dermatitis and dose distribution in clinical practice and for reliable reporting in clinical trials. We developed a novel radiation dermatitis segmentation system based on convolutional neural networks (CNNs) to consistently evaluate radiation dermatitis. MATERIALS AND METHODS: The radiation dermatitis segmentation system is designed to segment the radiation dermatitis occurrence area using skin photographs and skin-dose distribution. A CNN architecture with a dilated convolution layer and skip connection was designed to estimate the radiation dermatitis area. Seventy-three skin photographs obtained from patients undergoing radiotherapy were collected for training and testing. The ground truth of radiation dermatitis segmentation is manually delineated from the skin photograph by an experienced radiation oncologist and medical physicist. We converted the skin photographs to RGB (red-green-blue) and CIELAB (lightness (L∗), red-green (a∗) and blue-yellow (b∗)) colour information and trained the network to segment faint and severe radiation dermatitis using three different input combinations: RGB, RGB + CIELAB (RGBLAB) and RGB + CIELAB + skin-dose distribution (RGBLAB_D). The proposed system was evaluated using the Dice similarity coefficient (DSC), sensitivity, specificity and normalised Matthews correlation coefficient (nMCC). A paired t-test was used to compare the results of different segmentation performances. RESULTS: Optimal data composition was observed in the network trained for radiation dermatitis segmentation using skin photographs and skin-dose distribution. The average DSC, sensitivity, specificity and nMCC values of RGBLAB_D were 0.62, 0.61, 0.91 and 0.77, respectively, in faint radiation dermatitis, and 0.69, 0.78, 0.96 and 0.83, respectively, in severe radiation dermatitis. CONCLUSION: Our study showed that CNN-based radiation dermatitis segmentation in skin photographs of patients undergoing radiotherapy can describe radiation dermatitis severity and pattern. Our study could aid in objectifying the radiation dermatitis grading and analysing the reliable correlation between dosimetric factors and the morphology of radiation dermatitis.

A Comparison of Folinic Acid, Fluorouracil and Irinotecan (FOLFIRI) plus Bevacizumab and FOLFIRI plus Aflibercept as Second-line Treatment for Metastatic Colorectal Cancer.

AIM: To compare the efficacy and safety of folinic acid, fluorouracil and irinotecan (FOLFIRI) plus bevacizumab or aflibercept in metastatic colorectal cancer (mCRC) patients pretreated with oxaliplatin-based chemotherapy. MATERIALS AND METHODS: We analysed the treatment outcomes of patients receiving FOLFIRI in combination with bevacizumab or aflibercept as second-line treatment for mCRC between October 2017 and March 2020. This analysis included 67 patients receiving FOLFIRI plus aflibercept and 83 receiving FOLFIRI plus bevacizumab. RESULTS: The overall response rate (ORR) was 13.6% (95% confidence interval 4.85-22.34) in the FOLFIRI-aflibercept group and 14.7% (95% confidence interval 6.68-22.71) in the FOLFIRI-bevacizumab group. This difference in ORR was not statistically significant. The median progression-free survival was 8.6 months in the FOLFIRI-bevacizumab group and 8.5 months in the FOLFIRI-aflibercept group (P = 0.752). Patients in the FOLFIRI-bevacizumab group showed a median overall survival of 12.4 months, whereas patients in the FOLFIRI-aflibercept group had a median overall survival of 13.7 months (P = 0.276). There were no significant differences in survival between the two treatment groups. The adverse events were also largely similar between the two groups. However, hypertension of grade 3 or more was more frequent in the FOLFIRI-aflibercept group. CONCLUSION: FOLFIRI plus bevacizumab and FOLFIRI plus aflibercept had similar anti-tumour activities and toxicity profiles when used as second-line therapy in mCRC patients. Based on these data, both aflibercept and bevacizumab are suitable anti-angiogenic agents when used in combination with FOLFIRI for mCRC.

Learning curve of single-incision laparoscopic totally extraperitoneal repair (SILTEP) for inguinal hernia.

PURPOSE: Laparoscopic totally extraperitoneal hernia repair (TEP) is a widely used treatment for inguinal hernia. Single-incision laparoscopic TEP (SILTEP) has attracted the attention of several surgeons, given its superior cosmetic results and patient satisfaction, as well as comparable outcomes to multiport surgery. Nonetheless, no relevant studies have evaluated the learning curve (LC) of SILTEP in terms of both operation time (OT) and surgical failure. Therefore, we aimed to investigate the LC of SILTEP for inguinal hernia. METHODS: Medical records of 180 patients who underwent SILTEP performed by a single surgeon from a single institution between October 2012 and November 2017 were retrospectively reviewed. The LC was analyzed using the moving average method and cumulative sum control chart (CUSUM) for OT and surgical failure. Surgical failure was defined as the need for additional ports, open conversion, severe postoperative complications (Clavien-Dindo ≥ IIIa), and recurrence. Eight patients who underwent combined surgery or bilateral hernia repair were excluded from the OT analysis. RESULTS: From CUSUM graphs, the study period was divided into three phases: OT-phases 1 (1st-32nd), 2 (33rd-83rd), and 3 (84th-172nd) for OT and failure-phases 1 (1st-29th), 2 (30th-58th), and 3 (59th-180th) for surgical failure. Mean OTs were statistically different in the three OT phases (64.6 vs. 50.8 vs. 35.2 min; p < 0.001). Open conversion (31.0% vs. 0% vs. 2.5%) and additional port insertion (6.9% vs. 24.1% vs. 2.5%) stabilized consecutively at failure-phases 2 and 3 (p < 0.001). Surgical failure rates decreased to 5.7% by failure-phase 3 (37.9% vs. 24.1% vs. 5.7%; p < 0.001). CONCLUSION: For an experienced laparoscopic surgeon, we estimated that approximately 60 cases are needed to overcome the LC for SILTEP in terms of both reducing OT and achieving a surgical failure rate < 10%. Further proficiency could be achieved after approximately 85 SILTEP procedures with a stable OT of approximately 35 min.

Patterns of Regional Failure after Pancreaticoduodenectomy in Patients with Distal Extrahepatic Cholangiocarcinoma: Suggestion of the Clinical Target Volume for Elective Nodal Irradiation.

AIMS: To evaluate the pattern of locoregional recurrence (LRR) after pancreaticoduodenectomy in patients with distal extrahepatic cholangiocarcinoma (DEHC) and to identify an optimal target volume for elective nodal irradiation. MATERIALS AND METHODS: We analysed the medical records of DEHC patients who underwent pancreaticoduodenectomy and had LRR between 1991 and 2015. Among these patients, 30 received adjuvant chemotherapy alone, 14 underwent radiotherapy with or without chemotherapy and 28 received no treatment. After reviewing computed tomography or magnetic resonance imaging scans, the sites of LRR were identified and mapped to the corresponding locations on the representative computed tomography images. RESULTS: In total, 136 LRRs were identified in 72 patients from four institutions. Local recurrences were observed at 44 sites (32.4%): tumour bed in 15, choledochojejunostomy in 25 and pancreaticojejunostomy in four. Regional recurrences were observed at 92 sites (67.6%); the most common site was the portal vein area (n = 18), followed by the para-aortic area (n = 17). Based on the mapped plots of regional recurrence, a clinical target volume covering 90% of regional recurrences was generated using the appropriate margin for the vascular structures of the portal vein, celiac axis, superior mesenteric artery, left gastric artery and aorta. CONCLUSIONS: Given the pattern of LRR, we showed that the nodal clinical target volume based on vascular structures could appropriately cover high-risk regions of nodal involvement. These findings may help physicians construct a target volume in postoperative radiotherapy for DEHC patients undergoing pancreaticoduodenectomy.

Short-term outcomes of a multicentre randomized clinical trial comparing laparoscopic pylorus-preserving gastrectomy with laparoscopic distal gastrectomy for gastric cancer (the KLASS-04 trial).

BACKGROUND: There remain concerns about the safety and functional benefit of laparoscopic pylorus-preserving gastrectomy (LPPG) compared with laparoscopic distal gastrectomy (LDG). This study evaluated short-term outcomes of a randomized clinical trial (RCT) comparing LPPG with LDG for gastric cancer. METHODS: The Korean Laparoendoscopic Gastrointestinal Surgery Study (KLASS)-04 trial was an investigator-initiated, open-label, parallel-assigned, superiority, multicentre RCT in Korea. Patients with cT1N0M0 cancer located in the middle third of the stomach at least 5 cm from the pylorus were randomized to undergo LPPG or LDG. Participants, care givers and those assessing the outcomes were not blinded to group assignment. Outcomes were 30-day postoperative morbidity rate and death at 90 days. RESULTS: Some 256 patients from nine institutions were randomized (LPPG 129 patients, LDG 127 patients) between July 2015 and July 2017 and outcomes for 253 patients were analysed. Postoperative complications within 30 days were seen in 19.3 and 15.5 per cent in the LPPG and LDG groups respectively (P = 0·419). Postoperative pyloric stenosis was observed in nine (7.2 per cent) and two (1·5 per cent) patients in the LPPG and LDG groups (P = 0·026) respectively. In multivariable analysis higher BMI was a risk factor for postoperative complications (odds ratio 1·17, 95 per cent c.i. 1·04 to 1·32; P = 0·011). Death at 90 days was zero in both groups. CONCLUSION: Postoperative complications and mortality was comparable in patients undergoing LPPG and LDG. Registration number: NCT02595086 (http://www.clinicaltrials.gov).

Potential role of CMPK1, SLC29A1, and TLE4 polymorphisms in gemcitabine-based chemotherapy in HER2-negative metastatic breast cancer patients: pharmacogenetic study results from the prospective randomized phase II study of eribulin plus gemcitabine versus paclitaxel plus gemcitabine (KCSG-BR-13-11).

BACKGROUND: In this study, we evaluated the association between genetic polymorphisms of 23 genes associated with gemcitabine metabolism and the clinical efficacy of gemcitabine in breast cancer patients. PATIENTS AND METHODS: This prospective, pharmacogenetic study was conducted in cooperation with a phase II clinical trial. A total of 103 genetic polymorphisms of the 23 genes involved in gemcitabine transport and metabolism were selected for genotyping. The associations of genetic polymorphisms with overall survival, progression-free survival (PFS), and 6-month PFS were analyzed. RESULTS: A total of 91 breast cancer patients were enrolled in this study. In terms of 6-month PFS, rs1044457 in CMPK1 was the most significant genetic polymorphism [55.9% for CT and TT and 78.9% for CC, P < 0.001, hazard ratio (HR): 4.444, 95% confidence interval (CI): 1.905-10.363]. For the rs693955 in SLC29A1, the median duration of PFS was 5.4 months for AA and 10.5 months for CA and CC (P = 0.002, HR: 3.704, 95% CI: 1.615-8.497). For the rs2807312 in TLE4, the median duration of PFS was 5.7 months for TT and 10.4 months for CT and CC (P = 0.005, HR: 4.948, 95% CI: 1.612-15.190). In survival analysis with a multi-gene model, the TT genotype of rs2807312 had the worst PFS regardless of other genetic polymorphisms, whereas the CA genotype of rs693955 or the CT genotype of rs2807312 without the AA genotype of rs693955 had the best PFS compared with those of other genetic groups (P < 0.001). CONCLUSIONS: Genetic polymorphisms of rs1044457 in CMPK1, rs693955 in SLC29A1, and rs2807312 in TLE4 were significantly associated with the 6-month PFS rate and/or the duration of PFS. Further studies with a larger sample size and expression study would be helpful to validate the association of genetic polymorphisms and clinical efficacy of gemcitabine.