Preoperative chemoradiotherapy in older patients with rectal cancer guided by comprehensive geriatric assessment within a multidisciplinary team-a multicenter phase II trial.

BACKGROUND: The purpose of this study was to evaluate the safety and efficacy of preoperative concurrent chemoradiotherapy (preCRT) for locally advanced rectal cancer in older people who were classified as "fit" by comprehensive geriatric assessment (CGA). METHODS: A single-arm, multicenter, phase II trial was designed. Patients were eligible for this study if they were aged 70 years or above and met the standards of "fit" (SIOG1) as evaluated by CGA and of the locally advanced risk category. The primary endpoint was 2-year disease-free survival (DFS). Patients were scheduled to receive preCRT (50 Gy) with raltitrexed (3 mg/m2 on days 1 and 22). RESULTS: One hundred and nine patients were evaluated by CGA, of whom eighty-six, eleven and twelve were classified into the fit, intermediate and frail category. Sixty-eight fit patients with a median age of 74 years were enrolled. Sixty-four patients (94.1%) finished radiotherapy without dose reduction. Fifty-four (79.3%) patients finished the prescribed raltitrexed therapy as planned. Serious toxicity (grade 3 or above) was observed in twenty-four patients (35.3%), and fourteen patients (20.6%) experienced non-hematological side effects. Within a median follow-up time of 36.0 months (range: 5.9-63.1 months), the 2-year overall survival (OS), cancer-specific survival (CSS) and disease-free survival (DFS) rates were 89.6% (95% CI: 82.3-96.9), 92.4% (95% CI: 85.9-98.9) and 75.6% (95% CI: 65.2-86.0), respectively. Forty-eight patients (70.6%) underwent surgery (R0 resection 95.8%, R1 resection 4.2%), the corresponding R0 resection rate among the patients with positive mesorectal fascia status was 76.6% (36/47). CONCLUSION: This phase II trial suggests that preCRT is efficient with tolerable toxicities in older rectal cancer patients who were evaluated as fit based on CGA. TRIAL REGISTRATION: The registration number on ClinicalTrials.gov was NCT02992886 (14/12/2016).

The prognostic value of tumour-infiltrating lymphocytes, programmed cell death protein-1 and programmed cell death ligand-1 in Stage I-III triple-negative breast cancer.

BACKGROUND: Tumour-infiltrating lymphocytes (TILs) represent a robust biological prognostic biomarker in triple-negative breast cancer (TNBC); however, the contribution of different subsets of immune cells is unclear. We investigated the prognostic value of immune markers, including stromal TILs (sTILs), CD8+T and FOPX3+T cells, PD-1 and PD-L1 in non-metastatic TNBC. METHODS: In total, 259 patients with Stage I-III TNBC were reviewed. The density of sTILs along with the presence of total (t), stromal (s), and intratumoral (i) CD8+T cells and FOPX3+T cells were evaluated by haematoxylin and eosin and immunohistochemical staining. Immunohistochemical staining of PD-1, PD-L1 was also conducted. RESULTS: All immune markers were positively correlated with each other (P < 0.05). In the multivariate analysis, sTILs (P = 0.046), tCD8+T cells (P = 0.024), iCD8+T cells (P = 0.050) and PD-1 (P = 0.039) were identified as independent prognostic factors for disease-free survival (DFS). Further analysis showed that tCD8+T cells (P = 0.026), iCD8+T cells (P = 0.017) and PD-1 (P = 0.037) increased the prognostic value for DFS beyond that of the classic clinicopathological factors and sTILs. CONCLUSIONS: In addition to sTILs, inclusion of tCD8+T, iCD8+T cells, or PD-1 may further refine the prognostic model for non-metastatic TNBC beyond that including classical factors alone.

Risk stratification and prognostic value of multi-modal MRI-based radiomics for extranodal nasal-type NK/T-cell lymphoma.

BACKGROUND: Magnetic resonance imaging (MRI) performs well in the locoregional assessment of extranodal nasal-type NK/T-cell lymphoma (ENKTCL). It's important to assess the value of multi-modal MRI-based radiomics for estimating overall survival (OS) in patients with ENKTCL. METHODS: Patients with ENKTCL in a prospectively cohort were systemically reviewed and all the pretreatment MRI were acquisitioned. An unsupervised spectral clustering method was used to identify risk groups of patients and radiomic features. A nomogram-revised risk index (NRI) plus MRI radiomics signature (NRI-M) was developed, and compared with the NRI. RESULTS: The 2 distinct type I and II groups of the MRI radiomics signatures were identified. The 5-year OS rates between the type I and type II groups were 87.2% versus 67.3% (P = 0.002) in all patients, and 88.8% versus 69.2% (P = 0.003) in early-stage patients. The discrimination and calibration of the NRI-M for OS prediction demonstrated a better performance than that of either MRI radiomics or NRI, with a mean area under curve (AUC) of 0.748 and 0.717 for predicting the 5-year OS in all-stages and early-stage patients. CONCLUSIONS: The NRI-M model has good performance for predicting the prognosis of ENKTCL and may help design clinical trials and improve clinical decision making.

Outcome and risk prediction of early progression in patients with extranodal natural killer/T cell lymphoma from the CLCG study.

Recently, progression-free survival at 24 months (PFS24) was defined as clinically relevant for patients with extranodal NK/T cell lymphoma. Herein, the clinical data from two independent random cohorts (696 patients each in the primary and validation datasets) were used to develop and validate a risk index for PFS24 (PFS24-RI), and evaluate its ability to predict early progression. Patients achieving PFS24 had a 5-year overall survival (OS) of 95.8%, whereas OS was only 21.2% in those failing PFS24 (P<0.001). PFS24 was an important predictor of subsequent OS, independent of risk stratification. The proportion of patients achieving PFS24 and 5-year OS rates correlated linearly among risk-stratified groups. Based on multivariate analysis of the primary dataset, the PFS24-RI included five risk factors: stage II or III/IV, elevated lactate dehydrogenase, Eastern Cooperative Oncology Group score ≥2, primary tumor invasion, and extra-upper aerodigestive tract. PFS24-RI stratified the patients into low-risk (0), intermediate-risk (1-2), high-risk (≥3) groups with different prognoses. Harrell's C-index of PFS24-RI for PFS24 prediction was 0.667 in the validation dataset, indicating a good discriminative ability. PFS24-RI calibration indicated that the actual observed and predicted probability of failing PFS24 agreed well. PFS24-RI provided the probability of achieving PFS24 at an individual patient level.

Phase 2 Study of Adjuvant Radiotherapy Following Narrow-Margin Hepatectomy in Patients With HCC.

BACKGROUND AND AIMS: Surgical resection is the primary treatment for HCC; however, it is associated with a high rate of recurrence and death. We conducted this phase 2 study to investigate the efficacy and safety of postoperative intensity-modulated radiotherapy (IMRT) for HCC after narrow-margin hepatectomy. APPROACH AND RESULTS: We designed a single-arm, prospective phase 2 trial to evaluate overall survival (OS), disease-free survival (DFS), recurrence patterns, and toxicity in patients receiving adjuvant radiotherapy. The eligibility criteria included the following: pathological diagnosis of HCC after hepatectomy, with narrow pathological margins (< 1 cm); age > 18 years; and Eastern Cooperative Oncology Group performance status score of 0 or 1. Patients received IMRT within 4-6 weeks after surgical resection. This trial was registered at ClinicalTrials.gov (NCT01456156). Between 2008 and 2016, a total of 76 eligible patients who underwent narrow-margin resection were enrolled. The median follow-up duration was 70 months; the 3-year OS and DFS rates were 88.2% and 68.1%, respectively; and the 5-year OS and DFS rates were 72.2% and 51.6%, respectively. Intrahepatic recurrence was the primary recurrence pattern. No marginal recurrence was found. Intrahepatic, extrahepatic, and combined recurrences at the first relapse were found in 33, 5, and 1 patient, respectively. The most common radiation-related grade-3 toxicities were leukopenia (7.9%), elevated alanine aminotransferase (3.9%) and aspartate aminotransferase (2.6%) levels, and thrombocytopenia (1.3%). Classical or nonclassical radiation-induced liver disease was not noted. CONCLUSIONS: Adjuvant radiotherapy is an effective, well-tolerated, and promising adjuvant regimen in patients with HCC who have undergone narrow-margin hepatectomy. Our trial provides evidence and a rationale for planning a future phase 3 trial.

POstmastectomy radioThErapy in Node-posiTive breast cancer with or without Internal mAmmary nodaL irradiation (POTENTIAL): a study protocol for a multicenter prospective phase III randomized controlled trial.

BACKGROUND: Various randomized trials have demonstrated that postmastectomy radiotherapy (RT) to the chest wall and comprehensive regional nodal areas improves survival in patients with axillary node-positive breast cancer. Controversy exists as to whether the internal mammary node (IMN) region is an essential component of regional nodal irradiation. Available data on the survival benefit of IMN irradiation (IMNI) are conflicting. The patient populations enrolled in previous studies were heterogeneous and most studies were conducted before modern systemic treatment and three-dimensional (3D) radiotherapy (RT) techniques were introduced. This study aims to assess the efficacy and safety of IMNI in the context of modern systemic treatment and computed tomography (CT)-based RT planning techniques. METHODS: POTENTIAL is a prospective, multicenter, open-label, parallel, phase III, randomized controlled trial investigating whether IMNI improves disease-free survival (DFS) in high-risk breast cancer with positive axillary nodes (pN+) after mastectomy. A total of 1800 patients will be randomly assigned in a 1:1 ratio to receive IMNI or not. All patients are required to receive ≥ six cycles of anthracycline and/or taxane-based chemotherapy. Randomization will be stratified by institution, tumor location (medial/central vs. other quadrants), the number of positive axillary nodes (1-3 vs. 4-9 vs. ≥10), and neoadjuvant chemotherapy (yes vs. no). Treatment will be delivered with CT-based 3D RT techniques, including 3D conformal RT, intensity-modulated RT, or volumetric modulated arc therapy. The prescribed dose is 50 Gy in 25 fractions or 43.5 Gy in 15 fractions. Tiered RT quality assurance is required. After RT, patients will be followed up at regular intervals. Oncological and toxilogical outcomes, especially cardiac toxicities, will be assessed. DISCUSSION: This trial design is intended to overcome the limitations of previous prospective studies by recruiting patients with pN+ breast cancer, using DFS as the primary endpoint, and prospectively assessing cardiac toxicities and requiring RT quality assurance. The results of this study will provide high-level evidence for elective IMNI in patients with breast cancer after mastectomy. TRIAL REGISTRATION: ClinicalTrails.gov , NCT04320979 . Registered 25 Match 2020, https://clinicaltrials.gov/ct2/show/NCT04320979.

Nomogram predicting survival as a selection criterion for postmastectomy radiotherapy in patients with T1 to T2 breast cancer with 1 to 3 positive lymph nodes.

BACKGROUND: The role of postmastectomy radiotherapy (PMRT) in women with pT1-T2N1 breast cancer is controversial. The authors developed a nomogram that was predictive for overall survival (OS) and identified patients who derived no benefit from PMRT. METHODS: The authors retrospectively evaluated 4869 patients with pT1-T2N1 breast cancer who were treated with mastectomy between 2000 and 2014 in 11 Chinese hospitals. Rates of locoregional recurrence and distant metastasis were calculated using competing risk analysis, and disease-free survival and OS rates were calculated using the Kaplan-Meier method. Based on the risk factors identified from Cox regression analysis in 3298 unirradiated patients, a nomogram predicting OS was developed. The benefit of PMRT was evaluated in different risk groups stratified by the nomogram model. RESULTS: After a median follow-up of 65.9 months, the 5-year OS, disease-free survival, locoregional recurrence, and distant metastasis rates were 93.3%, 84.3%, 5.2%, and 8.3%, respectively. A total of 1571 patients (32.3%) underwent PMRT. On multivariable analyses, PMRT was found to increase OS significantly (hazard ratio, 0.61; P = .002). An OS prediction nomogram evaluated the effect of age; tumor location; tumor size; positive lymph node ratio; estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 status; and treatment with trastuzumab. Based on nomogram scores, the entire patient cohort was classified into 3 risk groups. PMRT significantly improved the OS of patients in the intermediate-risk (P < .001) and high-risk groups (P = .004), but not in the low-risk group (P = .728). CONCLUSIONS: The authors developed a nomogram that is predictive of OS among women with pT1-T2N1 breast cancer after mastectomy. This nomogram may help to select a subgroup of patients with a good prognosis who will not benefit from PMRT.

Radiotherapy plays an important role in improving the survival outcome in patients with T1-2N1M0 breast cancer - a joint analysis of 4262 real world cases from two institutions.

BACKGROUND: To compare the survival outcomes between breast-conserving surgery (BCS) and modified radical mastectomy (MRM), and to investigate the role of radiotherapy (RT) in patients with pT1-2N1M0 breast cancer. METHODS: A total of 4262 women with T1-2N1M0 breast cancer treated at two institutions were retrospectively reviewed. A total of 3858 patients underwent MRM, and 832 (21.6%) of them received postoperative RT (MRM + RT). A total of 404 patients received BCS plus postoperative RT (BCS + RT). All patients received axillary lymph node dissection, while 3.8% of them had upfront sentinel node biopsy. The association of survival outcomes with different surgical modalities (BCS vs. MRM) and the role of RT were evaluated using multivariable proportional hazards regression and confirmed by the propensity score-matching (PSM) method. RESULTS: At a median follow-up of 71 months (range of 6-230 months), the 5-year overall survival (OS) rates of the BCS and MRM groups were 96.5 and 92.7%, respectively (P = .001), and the corresponding 5-year disease-free-survival (DFS) and locoregional recurrence (LRR) rates were 92.9 and 84.0%, and 2.0 and 7.0% (P = .001), respectively (P < .001). Multivariate analysis revealed that RT was an independent prognostic factor for improved OS (P = .001) and DFS (P = .009), and decreased LRR (P < .001). However, surgery procedure was not independently associated with either OS (P = .495), DFS (P = .204), or LRR (P = .996), which was confirmed by PSM analysis. CONCLUSION: Postoperative radiotherapy rather than the surgery procedures was associated with superior survival outcomes in patients with T1-2N1M0 breast cancer.

[A multicenter survey of antibiotic use in very and extremely low birth weight infants in Hunan Province].

OBJECTIVE: To investigate the current status of antibiotic use for very and extremely low birth weight (VLBW/ELBW) infants in neonatal intensive care units (NICUs) of Hunan Province. METHODS: The use of antibiotics was investigated in multiple level 3 NICUs of Hunan Province for VLBW and ELBW infants born between January, 2017 and December, 2017. RESULTS: The clinical data of 1 442 VLBW/ELBW infants were collected from 24 NICUs in 2017. The median antibiotic use duration was 17 days (range: 0-86 days), accounting for 53.0% of the total length of hospital stay. The highest duration of antibiotic use was up to 91.4% of the total length of hospital stay, with the lowest at 14.6%. In 16 out of 24 NICUs, the antibiotic use duration was accounted for more than 50.0% of the hospitalization days. There were 113 cases with positive bacterial culture grown in blood or cerebrospinal fluid, making the positive rate of overall bacterial culture as 7.84%. The positive rate of bacterial culture in different NICUs was significantly different from 0% to 14.9%. The common isolated bacterial pathogens Klebsiella pneumoniae was 29 cases (25.7%); Escherichia coli 12 cases (10.6%); Staphylococcus aureus 3 cases (2.7%). The most commonly used antibiotics were third-generation of cephalosporins, accounting for 41.00% of the total antibiotics, followed by penicillins, accounting for 32.10%, and followed by carbapenems, accounting for 13.15%. The proportion of antibiotic use time was negatively correlated with birth weight Z-score and the change in weight Z-score between birth and hospital discharge (rs=-0.095, -0.151 respectively, P<0.01), positively correlated with death/withdrawal of care (rs=0.196, P<0.01). CONCLUSIONS: Antibiotics used for VLBW/ELBW infants in NICUs of Hunan Province are obviously prolonged in many NICUs. The proportion of routine use of third-generation of cephalosporins and carbapenems antibiotics is high among the NICUs.

Hypofractionated versus conventional fractionated postmastectomy radiotherapy for patients with high-risk breast cancer: a randomised, non-inferiority, open-label, phase 3 trial.

BACKGROUND: To our knowledge, no randomised study has compared postmastectomy hypofractionated radiotherapy with conventional fractionated radiotherapy in patients with breast cancer. This study aimed to determine whether a 3-week schedule of postmastectomy hypofractionated radiotherapy is as efficacious and safe as a 5-week schedule of conventional fractionated radiotherapy. METHODS: This randomised, non-inferiority, open-label, phase 3 study was done in a single academic hospital in China. Patients aged 18-75 years who had undergone mastectomy and had at least four positive axillary lymph nodes or primary tumour stage T3-4 disease were eligible to participate. Patients were randomly assigned (1:1) according to a computer-generated central randomisation schedule, without stratification, to receive chest wall and nodal irradiation at a dose of 50 Gy in 25 fractions over 5 weeks (conventional fractionated radiotherapy) or 43·5 Gy in 15 fractions over 3 weeks (hypofractionated radiotherapy). The modified intention-to-treat population (including all eligible patients who underwent randomisation but excluding those who were considered ineligible or withdrew consent after randomisation) was used in primary and safety analyses. The primary endpoint was 5-year locoregional recurrence, and a 5% margin was used to establish non-inferiority (equivalent to a hazard ratio <1·883). This trial is registered at ClinicalTrials.gov, number NCT00793962. FINDINGS: Between June 12, 2008, and June 16, 2016, 820 patients were enrolled and randomly assigned to the conventional fractionated radiotherapy group (n=414) or hypofractionated radiotherapy group (n=406). 409 participants in the conventional fractionated radiotherapy group and 401 participants in the hypofractionated radiotherapy group were included in the modified intention-to-treat analyses. At a median follow-up of 58·5 months (IQR 39·2-81·8), 60 (7%) patients had developed locoregional recurrence (31 patients in the hypofractionated radiotherapy group and 29 in the conventional fractionated radiotherapy group); the 5-year cumulative incidence of locoregional recurrence was 8·3% (90% CI 5·8-10·7) in the hypofractionated radiotherapy group and 8·1% (90% CI 5·4-10·6) in the conventional fractionated radiotherapy group (absolute difference 0·2%, 90% CI -3·0 to 2·6; hazard ratio 1·10, 90% CI 0·72 to 1·69; p<0·0001 for non-inferiority). There were no significant differences between the groups in acute and late toxicities, except that fewer patients in the hypofractionated radiotherapy group had grade 3 acute skin toxicity than in the conventional fractionated radiotherapy group (14 [3%] of 401 patients vs 32 [8%] of 409 patients; p<0·0001). INTERPRETATION: Postmastectomy hypofractionated radiotherapy was non-inferior to and had similar toxicities to conventional fractionated radiotherapy in patients with high-risk breast cancer. Hypofractionated radiotherapy could provide more convenient treatment and allow providers to treat more patients. FUNDING: National Key Projects of Research and Development of China; the Chinese Academy of Medical Science Innovation Fund for Medical Sciences; and Beijing Marathon of Hope, Cancer Foundation of China.