Optimizing the combination of chemotherapeutic drugs along with radiotherapy for extranodal NK/T-cell lymphoma.

Background: Extranodal natural killer/T-cell lymphoma (ENKTCL) has a unique treatment principle. However, the optimal combination of drugs along with radiotherapy (RT) is unknown. Design: Retrospective cohort study. Objectives: We screened multiple drug combinations to identify the most efficacious therapeutic combinations. Methods: We reviewed 3105 patients who received 40 chemotherapy regimens with different combinations of 9 drug classes and/or RT. Least absolute shrinkage and selection operator and multivariable Cox regression analyses were used to screen efficacious single drugs and identify optimal combinations for overall survival (OS). Inverse probability of treatment weighting (IPTW) and multivariable analyses were used to compare survival between treatment regimens. Results: Screening and validation revealed RT, asparaginase (ASP), and gemcitabine (GEM) to be the most efficacious single modality/drug. RT remained an important component of first-line treatment, whereas ASP was a fundamental drug of non-anthracycline (ANT)-based regimens. Addition of RT to non-ANT-based or ASP/GEM-based regimens, or addition of an ASP-drug into ANT-based or GEM/platinum-based regimens, improved 5-year OS significantly. Use of ASP/GEM-based regimens was associated with significantly higher 5-year OS (79.9%) compared with ASP/ANT-based (69.2%, p = 0.001), ASP/methotrexate-based (63.5%, p = 0.011), or ASP/not otherwise specified-based (63.2%, p < 0.001) regimens. The survival benefit of ASP/GEM-based regimens over other ASP-based regimens was substantial across risk-stratified and advanced-stage subgroups. The survival benefits of a combination of RT, ASP, and GEM were consistent after adjustment for confounding factors by IPTW. Conclusion: These results suggest that combining ASP/GEM with RT for ENKTCL is an efficacious and feasible therapeutic option and provides a rationale and strategy for developing combination therapies.

Dosimetric benefit and clinical feasibility of deep inspiration breath-hold and volumetric modulated arc therapy-based postmastectomy radiotherapy for left-sided breast cancer.

To evaluate the dosimetric benefits and clinical feasibility of deep inspiratory breath-hold (DIBH) combined with volumetric modulated arc therapy (VMAT) in left-sided postmastectomy radiotherapy (PMRT). Eligible patients with left-sided breast cancer undergoing DIBH-based PMRT were prospectively included. Chest wall, supra/infraclavicular fossa, and/or internal mammary node irradiation (IMNI) were planned with a prescription dose of 43.5 Gy in 15 fractions. VMAT plans were designed on free breathing (FB)-and DIBH-CT to compare dosimetric parameters in heart, left anterior descending artery (LAD) and lung. Cone-beam computed tomography (CBCT) was performed before and after treatment to evaluate inter- and intra-fractional setup errors. Heart position and dose variations during treatment were estimated by fusing CBCT with DIBH-CT scans.Twenty patients were included with 10 receiving IMNI. In total, 193 pre-treatment and 39 pairs pre- and post-treatment CBCT scans were analyzed. The Dmean, Dmax, and V5-40 of the heart, LAD, and left lung were significantly lower in DIBH than FB (p < 0.05 for all), except for V5 of LAD (p = 0.167). The cardiopulmonary dosimetric benefits were maintained regardless of IMNI. The inter- and intra-fractional setup errors were < 0.3 cm; and the overall estimated PTV margins were < 1.0 cm. During treatment, the mean dice similarity coefficient of heart position and the mean ratio of heart Dmean between CBCT and DIBH-CT plans was 0.95 (0.88-1.00) and 100% (70.6-119.5%), respectively. DIBH-VMAT could effectively reduce the cardiopulmonary doses with acceptable reproducibility and stability in left-sided PMRT regardless of IMNI.

Implementing the optimized hippo-avoidance prophylactic cranial irradiation for limited-stage small cell lung cancer by tomotherapy and volumetric modulated arc therapy.

BACKGROUND: Hippo-avoidance prophylactic cranial irradiation (HA-PCI) requires a hippocampal avoidance zone expanded from hippocampus to ensure dose fall-off and compensate for setup errors. Most studies recommend a 5-mm margin, while it could be optimized to a 2-mm expansion. Here, we showed the details of optimized HA-PCI for limited-stage small cell lung cancer (LS-SCLC). METHODS: This cohort study reviewed patients with LS-SCLC receiving optimized HA-PCI from August 2014 to June 2020 in the National Cancer Center of China. The hippo-related dose parameters were summarized. The comparison of the Hopkins Verbal Learning Test-Revised (HVLT-R) scores in different time points was conducted. The Kaplan-Meier method was used to calculate the survival rates. RESULTS: A total of 112 patients were included. The average doses of hippocampus and hippocampal avoidance zone were 6.80 Gy (IQR: 6.40-7.44) and 7.63 Gy (IQR: 7.14-8.39). No differences were observed in the two radiation techniques (tomotherapy [TOMO] vs. volumetric-modulated arc therapy [VMAT]). The decline of HVLT-R score remained in a low level and not significant in assessable patients (p = 0.095). With a median follow-up of 52 months (95% CI: 47.2-56.7), the 2-year overall survival and progression-free survival were 74.1% and 50.0%, respectively. Two intracranial recurrence lesions (2.3%) located <2 mm from the hippocampus. CONCLUSIONS: Optimized HA-PCI could achieve similar dose limitation by TOMO and VMAT techniques with favorable efficacy and minor toxicity.

[Prognostic and Predictive Value of a Modified Diagnostic Biopsy-Adapted Immunoscore in Patients with Rectal Cancer After Neoadjuvant Treatment- a translational study from the STELLAR trial].

BACKGROUND: The purpose of this study was to assess the prognostic significance of the modified diagnostic biopsy-adapted immunoscore (mISb) in determining the outcomes for patients with locally advanced rectal cancer (LARC) in a neoadjuvant setting. METHODS: We included 181 LARC patients from a single subcenter of a prospective study comparing total neoadjuvant therapy (TNT) based on short-course radiotherapy with long-term chemoradiotherapy (CRT). Tumor biopsies at baseline were stained for CD8+ and CD3+ T-cell densities. The mISb was developed using mean percentile of CD8+ T-cell density and CD8/CD3 ratios. Patients were classified into low (0%-25%), intermediate (>25%-70%), and high (>70%-100%) in both groups. The relativity among different lymphocytes and their correlation with survival were illustrated. Survival analyses and Cox regression models were used to compare the prognostic value of mISb and ISb for survival outcomes, and to assess the role of mISb in TNT and CRT subgroups respectively. RESULTS: In this study, 151 (83.4%) patients received surgery and 30 (16.6%) followed a watch and wait strategy. A strong correlation was found between CD8+ and CD3+ T-cell densities (R=0.86, P<0.001), while a weak correlation witnessed between CD8+ and CD8/CD3 ratio (R=0.45). The 3-year disease-free survival (DFS) for the entire cohort was 69.9%, with 57.2%, 68.6%, and 85.5% for the low, intermediate, and high mISb groups respectively (P=0.01), while ISb failed to distinguish survival outcomes. Multivariate analysis revealed mISb to be an independent prognostic factor for DFS in surgically treated patients (P=0.01). Specifically, patients with high mISb score showed longer PFS than other subgroups in the TNT cohort (P=0.049), but no significant difference was found in the CRT population. CONCLUSIONS: In this study, mISb demonstrates significant prognostic value in LARC patients receiving preoperative therapies, especially in the TNT subgroup. These findings may help tailor the intensity of neoadjuvant therapy for patients.

Significance of longitudinal Epstein-Barr virus DNA combined with multipoint tumor response for dynamic risk stratification and treatment adaptation in nasopharyngeal carcinoma.

Dynamic therapy response is strongly associated with cancer outcomes. This study aimed to evaluate the significance of longitudinal Epstein-Barr virus (EBV) DNA and radiological tumor regression in risk stratification and response-adaptive treatment in locally-advanced nasopharyngeal carcinoma (LA-NPC). In total, 1312 patients from two centers were assigned to the training and validation cohorts. Based on the multipoint examination of EBV-DNA and tumor response, four post-induction chemotherapy, four mid-radiotherapy, and four post-radiotherapy subgroups were established. Then seven phenotypes were further generated according to different permutations and combinations. These phenotypes were subsequently congregated into four response clusters, which reflect distinct biological treatment responses. The four response clusters correlated with an evident 5-year progression-free survival in both the training and external validation cohorts (5-year: training cohort 91.1 %, 82.8 %, 30.6 %, and 10.0 %; external validation 94.4 %, 55.6 %, 40.0 %, and 12.7 %) had superior prognostic performance compared to TNM staging and nomogram model (concordance index: training cohort-0.825 vs. 0.603 vs. 0.756 and external validation-0.834 vs. 0.606 vs. 0.789). Importantly, the response clusters exhibited an excellent capability in selecting candidates who can benefit from adjuvant chemotherapy. In conclusion, risk stratification based on the dynamic assessment of both radiological and biological responses can significantly enhance prognostic insights and shed light on individualized treatment modifications in LA-NPCs.

Post-hoc analysis of clinicopathological factors affecting lateral lymph node metastasis based on STELLAR study for rectal cancer.

PURPOSE: In post-hoc analyses of phaseIII randomized controlled study(STELLAR), to analyzethe prognostic impact oflateral pelvic lymph node (LPLN)metastasis in locally advanced rectal cancer (LARC). METHODS: LPLN metastasis was defined as a short diameter > 7 mm on magnetic resonance imaging (MRI).The studyincluded 591 patients with LARC.All patients received neoadjuvant (chemo)radiotherapy combined withradical resection. RESULTS: Among 591 patients, 99 (16.8 %) were diagnosed with LPLN metastasis, mostly with unilateral metastasis (79.8 %), with internal iliac lymph node metastasis being more common (81.8 %).Significant differences were found among with and without LPLN metastasis in rectal segmentation (P=0.001),N disease (P<0.001), mesenteric LN metastasis or not (P=0.030). The median follow-up timewas 34.0 months, three-year disease-free survival (DFS),overall survival (OS), andmetastasis-free survival (MFS)were significantly lower in LPLN metastaticgroup than those in LPLN non-metastaticgroup (51.4 % vs. 68.2 %, P<0.001; 71.8 % vs. 84.2 %, P=0.006; 60.8 % vs. 80.1 %,P<0.001), respectively; while there were no significant differences in locoregional recurrence(11.4 % vs. 8.5 %, P=0.564). Multivariate analysis found that LPLN metastasis was an independent prognostic factor affecting DFS (P=0.005), OS (P=0.036),MFS (P=0.001).No significantly survival benefit was observed for the short-term radiotherapy based total neoadjuvant therapy compared to long-term concurrent chemoradiotherapy. CONCLUSIONS: LPLN metastasis observed byMRI should be considered in LARC patients, especially in populations with lowrectal cancer, N2 disease, and mesenteric LN metastasis. LPLN metastasis diagnosed by MRI is a significant and independent risk factor and is associated with worse DFS, OS, MFS.

Radiotherapy with Targeted Therapy or Immune Checkpoint Inhibitors for Hepatocellular Carcinoma with Hepatic Vein and/or Inferior Vena Cava Tumor Thrombi.

Purpose: This study evaluated the clinical outcomes of patients with hepatocellular carcinoma (HCC) with hepatic vein tumor thrombus (HVTT) and/or inferior vena cava tumor thrombus (IVCTT) receiving radiotherapy (RT) combined with systemic therapies. Patients and Methods: Patients with HCC with HVTT and/or IVCTT who received RT were identified at our institution. The prescription doses were 30-65 Gy for planning target volume and 40-65 Gy for the gross tumor volume. Targeted therapy and immune checkpoint inhibitors were used concurrently if patients were at a high risk of or already had distant metastasis. After RT completion, follow-up was performed at 1, 3, 6, and 12 months, and 3 to 6 months thereafter. The objective response rate (ORR), overall survival (OS), progression-free survival (PFS) and toxicity were recorded. Results: Thirty-four patients were retrospectively enrolled between January 2016 and September 2021. Most patients received concurrent targeted therapy (70.6%) and/or post-RT (79.4%). The in-field ORR and disease control rates were 79.4% and 97.1%, respectively. The OS rates were 77.6% at 1 year and 36.3% at 2 years (median OS, 15.8 months). The median PFS and median in-field PFS were 4.2 months and not reached, respectively. The PFS and in-field PFS rates were 24.6% and 79.2% at 1 year, 19.7% and 72.0% at 2 years, respectively. An alpha-fetoprotein level >1000 ng/mL was a significant prognostic factor for worse OS (HR, 5.674; 95% CI, 1.588-20.276; p=0.008); in-field complete/partial response was a significant prognostic factor for better OS (HR, 0.116; 95% CI, 0.027-0.499; p=0.004). The most common site of first failure was the lungs (13/34 patients, 38.2%), followed by the liver (7/34 patients, 20.6%). No patients developed radiation-induced liver disease or pulmonary embolism during follow-up. Conclusion: Combining RT and systemic therapy was safe and effective in treating patients with HCC with HVTT and IVCTT.

Prognostic value of lymphocytes in patients with breast cancer receiving radiotherapy after breast-conserving surgery: A post hoc analysis of a phase III randomized trial.

PURPOSE: To evaluate the prognostic value of peripheral lymphocyte count (PLC) in the breast cancer patients after breast-conserving surgery (BCS) with radiotherapy (RT). METHODS AND MATERIALS: This post hoc analysis was performed using data of 628 patients from a phase III, randomized controlled trial comparing hypofractionated RT (HFRT) with conventional fractionated RT (CFRT) after BCS. PLCs were obtained before, during, and after RT until the 1-year follow-up. The optimal cut-off PLCs were determined using the maxstat package in R. Survival rates were estimated using the Kaplan-Meier method and compared with the log-rank test. RESULTS: A total of 275 (46.1 %) patients developed lymphopenia during RT, among them, 17 (2.8 %) had grade 3 lymphopenia and no one developed grade 4 lymphopenia. With a median follow-up of 110.8 months, patients with pre-RT PLCs of < 1.77 × 109/L had a significantly lower 10-year breast cancer-specific survival (BCSS) rate (P = 0.013) and overall survival (OS) rate (P = 0.026). Patients with a nadir PLC of < 1.35 × 109/L had a significantly poorer 10-year OS rate (P = 0.048). Multivariate analysis showed that a pre-RT PLC of < 1.77 × 109/L was an independent factor influencing BCSS and OS, while the effect of the nadir PLC did not remain significant. Neither PLC nor lymphopenia recovery at post-RT 1, 3, and 6 months and 1 year was associated with survival. CONCLUSIONS: Radiation-induced lymphopenia in patients with breast cancer after BCS tends to be mild. The lower pre-RT PLC predicted poorer survival.

Estimating the long-term survival of unresectable stage III non-small cell lung cancer based on cure model analysis.

BACKGROUND: The predictors of long-term survival and appropriate surrogate endpoints in unresectable stage III non-small cell lung cancer (NSCLC) treated with radiotherapy remain unclear, especially in the immune therapy era. METHODS: This study retrospectively analyzed a prospective cohort of 822 patients treated at the Chinese National Cancer Center from 2013 to 2022. Cure fractions, surrogates for long-term survival, and associated factors were assessed using a mixture cure model, with validation against a matched Surveillance, Epidemiology, and End Results (SEER) dataset. RESULTS: 27.3% of patients with unresectable stage III NSCLC can achieve long-term survival after treated by radiotherapy. 4-year PFS and 5-year OS, when 80% of patients were considered cured, showed significant correlations with cure rates based on background mortality-adjusted PFS and relative survival, with R-squared values exceeding 0.85. Independent predictors of long-term survival included non-squamous cell carcinoma (non-SCC) pathological type, N category, gross tumor volume, and treatment combination with immune checkpoint inhibitors (ICIs). CONCLUSIONS: Radiotherapy, especially when combined with ICIs, offers a potential cure for a proportion of patients with unresectable stage III NSCLC. Tumor burden and ICIs are key predictors of long-term survival. The study suggested 4-year PFS and 5-year OS as surrogate endpoints for cure and long-term survival assessment.

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).

Treatment outcome, toxicity, and quality of life of patients with bronchus-associated lymphoid tissue lymphoma.

The disease failure patterns and optimal treatment of bronchus-associated lymphoid tissue (BALT) lymphoma are unknown. This retrospective study involved 71 patients with primary BALT lymphoma who had received radiotherapy (RT), surgery, immunochemotherapy (IC), or observation. The median follow-up time was 66 months. The 5-year overall survival and lymphoma-specific survival were 91.2% and 96.1%, respectively, and were not significantly different among treatments. The 5-year cumulative incidence of overall failure for RT, surgery, IC, and observation was 0%, 9.7% (p = .160), 30.8% (p = .017), and 31.3% (p = .039). There was no grade ≥3 toxicity in RT group according to the CTCAE 5.0 reporting system. Quality of life (QoL) was at similarly good levels among the treatment groups. BALT lymphoma had a favorable prognosis but persistent risk of relapse after IC or observation. Given the very low disease failure risk and good QoL, RT remains an effective initial treatment for BALT lymphoma.

BALT lymphoma has a favorable prognosis but a persistent progression and relapse risk.Radiotherapy is associated with lower failure of disease progression and relapse, low toxicity and good quality of life.

A prospective phase II clinical trial of total neoadjuvant therapy for locally advanced gastric cancer and gastroesophageal junction adenocarcinoma.

To investigate the safety and efficacy of the neoadjuvant chemoradiotherapy (NCRT) followed by neoadjuvant consolidation chemotherapy (NCCT) and surgery for locally advanced gastric cancer (GC) or gastroesophageal junction (GEJ) adenocarcinoma. Patients diagnosed as locally advanced GC or Siewert II/III GEJ adenocarcinoma with clinical stage T3-4 and/or N positive were prospectively enrolled. Patients underwent NCRT (45 Gy/25 fractions) with concurrent S-1, followed by NCCT (4 to 6 cycles of the SOX regimen) 2 to 4 weeks after NCRT. Gastric cancer radical resection with D2 lymph node dissection was performed 4 to 6 weeks after the total neoadjuvant therapy. The study was conducted from November 2019 to January 2023, enrolling a total of 46 patients. During the NCRT, all patients completed the treatment without dose reduction or delay. During the NCCT, 32 patients (69.6%) completed at least 4 cycles of chemotherapy. Grade 3 or higher adverse events in NCRT (5 cases) were non-hematological. During the course of NCCT, a notable occurrence of hematological toxicities was observed, with grade 3 or higher leukopenia (9.7%) and thrombocytopenia (12.2%) being experienced. A total of 28 patients (60.9%) underwent surgery, achieving R0 resection in all cases. A significant proportion of cases (71.4%) exhibited pathological downstaging to ypT0-2, while 10 patients (35.7%) demonstrated a pathologic complete response (pCR). The total neoadjuvant therapy comprising NCRT followed by NCCT and surgery demonstrates a low severe adverse reactions and promising efficacy, which could be considered as a viable treatment for locally advanced GC or GEJ adenocarcinoma.Trial registration: Clinicaltrials.gov (registration number: NCT04062058); the full date of first trial registration was 20/08/2019.

Disparities in mortality risk after diagnosis of hematological malignancies in 185 countries: A global data analysis.

This study was to report proxy measures for mortality risk in patients with hematological malignancies across 185 countries globally and explore its association with their socioeconomic status and treatment. The incidence, mortality, and 5-year prevalence data were extracted from the GLOBOCAN database. The data regarding the human development index (HDI), gross national income (GNI), vulnerability index, and concordance with cancer Essential Medicines List (EML) were obtained from open-source reports. The ratio of mortality to 5-year-prevalence (MPR) and that of mortality to incidence (MIR) were calculated and age-standardized using Segi's world standard population. Finally, the possible associations were assessed using Pearson correlation analyses. In 2020, the global incidence, mortality, and 5-year prevalence of HMs were 1,278,362, 711,840, and 3,616,685, respectively. Global age-standardized MPR and MIR were 0.15 and 0.44, respectively; they varied significantly among 6 regions, 185 countries, 4 HM types, and 4 HDI groups worldwide. Older populations always had higher ratios. The correlation of MPRs and MIRs with HDI, GNI, and concordance with cancer EML was negative, whereas it was positive with the vulnerability index (lower was better). Increasing access to cancer drugs in resource-limited regions with a focus on vulnerable children may aid in reducing HM-related mortality risk.

Nodal recurrence mapping and clinical target volumes after resection of intrahepatic cholangiocarcinoma or combined hepatocellular-cholangiocarcinoma.

Background: Scarce evidence exists for clinical target volume (CTV) definitions of regional lymph nodes (LNs) in intrahepatic cholangiocarcinoma (iCCA) or combined hepatocellular-cholangiocarcinoma (cHCC-CCA). We investigated the mapping pattern of nodal recurrence after surgery for iCCA and cHCC-CCA and provided evidence for the nodal CTV definition. Methods: We retrospectively reviewed the medical records of patients with iCCA or cHCC-CCA who underwent surgery between 2010 and 2020. Eligibility criteria included patients pathologically diagnosed with iCCA or cHCC-CCA after surgery and a first recurrent event in regional LNs during follow-up. All recurrent LNs were registered onto reference computed tomography images based on the vascular structures to reconstruct the node mapping. Fifty-three patients were eligible. LN regions were classified into four risk groups. Results: Hepatic hilar and portal vein-vena cava were the most common recurrent regions, with recurrence rates of 62.3 % and 39.6 % (high-risk regions), respectively. Recurrence rates in the left gastric, diaphragmatic, common hepatic, superior mesenteric vessels, celiac trunk, and paracardial regions ranged from 15.1 % to 30.2 % (intermediate-risk regions). There were fewer recurrences in the para-aortic (16a1, a2, b1) and splenic artery and hilum regions, with rates <10 % (low-risk regions). No LN recurrence was observed in the para-oesophageal or para-aortic region (16b2) (very low-risk regions). Based on node mapping, the CTV should include high- and intermediate-risk regions for pathologically negative LN patients during postoperative radiotherapy. Low-risk regions should be included for pathologically positive LN patients. Conclusion: We provide evidence for CTV delineation in patients with iCCA and cHCC-CCA based on recurrent LN mapping.

Optimizing the prognostic capacity of baseline 18F-FDG PET/CT metabolic parameters in extranodal natural killer/T-cell lymphoma by using relative and absolute thresholds.

Objectives: To investigate the prognostic capacity of baseline 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) metabolic parameters in extranodal natural killer/T-cell lymphoma (ENKTCL), and the influence of relative thresholds (RT) and absolute thresholds (AT) selection on prognostic capacity. Materials and methods: Metabolic tumor volume (MTV)-based parameters were defined using RTs (41 % or 25 % of maximum standardized uptake value [SUVmax]), ATs (SUV 2.5, 3.0, 4.0, or mean liver uptake) in 133 patients. Metabolic parameters were classified into avidity-related parameters (SUVmax, mean SUV [SUVmean], standard deviation of SUV [SUVsd]), volume-related parameters (RT-MTV), and avidity- and volume-related parameters (total lesion glycolysis [TLG] and AT-MTV). The prognostic capacity of the metabolic parameters and the effects of different threshold types (RT vs. AT) were evaluated. Results: All metabolic parameters were moderately associated with prognosis. However, the area under the receiver operating characteristic curve of MTV and TLG was slightly higher than that of avidity-related parameters for predicting 5-year progression-free survival (PFS) (0.614-0.705 vs. 0.563-0.609) and overall survival (OS) (0.670-0.748 vs. 0.562-0.593). Correlations of MTV and avidity-related parameters differed between RTs (r < 0.06, P = 0.324-0.985) and ATs (r 0.56-0.84, P ≤ 0.001). AT-MTV was the optimal predictor for PFS and OS, while RT-TLG was the optimal predictor for PFS, and the combination of RT-MTV with SUVmax was the optimal predictor for OS. Conclusion: The incorporation of volume and avidity significantly improved the prognostic capacity of PET in ENKTCL. Composite parameters that encompassed both avidity and volume were recommended.

Regulation of AMPK activation by extracellular matrix stiffness in pancreatic cancer.

The adenosine monophosphate (AMP)-activated protein kinase (AMPK) sits at a central node in the regulation of energy metabolism and tumor progression. AMPK is best known to sense high cellular ADP or AMP levels, which indicate the depletion of energy stores. Previous studies have shown that the low expression of phosphorylated AMPK is associated with a poor prognosis of pancreatic cancer. In this study, we report that AMPK is also highly sensitive to extracellular matrix (ECM) stiffness. We found that AMPK is activated in cells when cultured under low ECM stiffness conditions and is functionally required for the metabolic switch induced by ECM stiffness. This regulation of AMPK requires the Hippo kinases but not LKB1/CaMKKß. Hippo kinases directly phosphorylate AMPKα at Thr172 to activate AMPK at low ECM stiffness. Furthermore, we found AMPK activity is inhibited in patients with pancreatic ductal adenocarcinoma (PDAC) with high ECM stiffness and is associated with a poor survival outcome. The activation of Hippo kinases by ROCK inhibitor Y-27632 in combination with the mitochondrial inhibitor metformin synergistically activates AMPK and dramatically inhibits PDAC growth. Together, these findings establish a novel model for AMPK regulation by the mechanical properties of ECMs and provide a rationale for simultaneously targeting the ECM stiffness-Hippo kinases-AMPK signaling and low glucose-LKB1-AMPK signaling pathways as an effective therapeutic strategy against PDAC.

Prediction of 5-year overall survival of diffuse large B-cell lymphoma on the pola-R-CHP regimen based on 2-year event-free survival and progression-free survival.

This study aimed to predict the 5-year overall survival (OS) benefit of pola-R-CHP versus R-CHOP in the POLARIX trial based on the 2-year event-free survival (EFS) and progression-free survival (PFS) rates in diffuse large B-cell lymphoma (DLBCL). We identified randomized controlled trials (RCT) published before 31 May 2023. The correlation between the logarithmic (log) hazard ratio (HR) for EFS (HREFS) or PFS (HRPFS) and the HR for OS (HROS) was estimated at the trial-level. Correlation analysis was performed between 2-year PFS or EFS and 5-year OS rates at the treatment arm-level. Linear regression models were used to calculate the 5-year OS of pola-R-CHP and R-CHOP. In the included 20 RCTs, a linear correlation between HREFS (r = 0.765) or HRPFS (r = 0.534) and HROS was observed at the trial- level. Two-year EFS (r = 0.918) or 2-year PFS (r = 0.865) correlated linearly with 5-year OS. Linear regression analysis between 2-year EFS/PFS and 5-year OS gave estimated 5-year OS rates between pola-R-CHP and R-CHOP of 6.4% and 6.3%, respectively. Two-year EFS and PFS are feasible early endpoints in patients with DLBCL treated primarily with immunochemotherapy. The pola-R-CHP regimen is expected to improve 5-year OS.

Multicenter phase II study of moderate low-dose radiotherapy in indolent non-Hodgkin lymphoma: CLCG-iNHL-01 protocol.

Background: Radiotherapy is an effective treatment for indolent non-Hodgkin lymphoma (iNHL); however, the optimal radiotherapy dose remains to be determined. We hypothesize that a suitable dose may exist between 4 and 24 Gy. Methods: This prospective multicenter phase II trial intends to recruit 73 sites of iNHL patients, who will receive involved-site radiotherapy of 12 Gy in four fractions. The primary objective is the 6-month clinical complete response rate. Tumor tissue, blood and conjunctival specimens will be collected to identify potential predictive biomarkers. Discussion: The CLCG-iNHL-01 trial will evaluate the efficacy and toxicity of 12 Gy in patients with iNHL and provide information on a novel hypofractionation regimen of low-dose radiotherapy. Clinical Trial Registration: NCT05543070 (ClinicalTrials.gov).