Association of the Time to Immune Checkpoint Inhibitor (ICI) Initiation and Outcomes With Second Line ICI in Patients With Advanced Urothelial Carcinoma

BackgroundEarly progression on first-line (1L) platinum-based therapy or between therapy lines may be a surrogate of more aggressive disease and poor outcomes in advanced urothelial carcinoma (aUC), but its prognostic role regarding immune checkpoint inhibitor (ICI) response and survival is unclear. We hypothesized that shorter time until start of second-line (2L) ICI would be associated with worse outcomes in aUC.Patients and MethodsWe performed a retrospective multi-institution cohort study in patients with aUC treated with 1L platinum-based chemotherapy, who received 2L ICI. Patients receiving switch maintenance ICI were excluded. We defined time to 2L ICI therapy as the time between the start of 1L platinum-based chemotherapy to the start of 2L ICI and categorized patients a priori into 1 of 3 groups: less than 3 months versus 3-6 months versus more than 6 months. We calculated overall response rate (ORR) with 2L ICI, progression-free survival (PFS) and overall survival (OS) from the start of 2L ICI. ORR was compared among the 3 groups using multivariable logistic regression, and PFS, OS using cox regression. Multivariable models were adjusted for known prognostic factors.ResultsWe included 215, 215, and 219 patients in the ORR, PFS, and OS analyses, respectively, after exclusions. ORR difference did not reach statistical significance between patients with less than 3 months versus 3-6 months versus more than 6 months to 2L ICI. However, PFS (HR 1.64; 95% CI 1.02-2.63) and OS (HR 1.77; 95% CI 1.10-2.84) was shorter among those with time to 2L ICI less than 3 months compared to those who initiated 2L ICI more than 6 months.ConclusionAmong patients with aUC treated with 2L ICI, time to 2L ICI less than 3 months was associated with lower, but not significantly different ORR, but shorter PFS and OS compared to 2L ICI more than 6 months. This highlights potential cross resistance mechanisms between ICI and platinum-based chemotherapy.     

An Exploration of Trifluridine/Tipiracil Monotherapy and in Combination With Bevacizumab or Immune Checkpoint Inhibitors for Patients With Metastatic Colorectal Cancer: A Real-World Study

BackgroundTrifluridine/tipiracil (TAS-102) has achieved modest efficacy in the late-line treatment of metastatic colorectal cancer. The present study aimed to explore the clinical efficacy and drug toxicities of TAS-102 for patients with metastatic colorectal cancer in real-world clinical setting.MethodsFrom October 2020 to February 2022, patients with metastatic colorectal cancer who failed from 2 or more lines of prior therapy and treated with TAS-102 monotherapy, in combination with bevacizumab or immune checkpoint inhibitors (ICIs) were analyzed. The evaluation indicators were progression free survival (PFS), objective response rate , disease control rate (DCR), overall survival (OS) and drug toxicities.ResultsA total of 70 patients were enrolled. The objective response rate and DCR were 1.4% and 68.6%. The median PFS and OS were 6.0 (95% CI: 4.1-7.9) and 10.0 (95% CI: 8.3-11.7) months. Compared with TAS-102 monotherapy and TAS-102 plus ICIs, TAS-102 plus bevacizumab obtained superior DCR (75.9% vs. 50% vs. 40%, P = .047), PFS (6.3m vs. 3.0 m vs. 3.0 m, P = .041) and OS (12.0 m vs. 6.5 m vs. 6.0m, P = .013). Patients without prior regorafenib or fruquintinib therapy obtained better median PFS (6.3 vs. 4.3 m, P = .031) and OS (NR vs. 9.0 m, P = .036). Other indicators, including age, tumor site, KRAS status and use of fluoropyrimidine as last regimen before TAS-102, did not affect the clinical efficacy of TAS-102. The most frequent adverse events were leukopenia, neutropenia, anemia, fatigue, nausea, and vomiting.ConclusionIn real-world clinical setting, TAS-102 showed consistent clinical efficacy and manageable safety with previous prospective clinical studies. Compared with monotherapy and TAS-102 plus ICIs, TAS-102 plus bevacizumab demonstrated better clinical efficacy for metastatic colorectal cancer.     

Neoadjuvant Chemotherapy in Locally Advanced Cervical Carcinoma – a Role in Patients with Para-aortic Lymph Node Involvement? A 10-year Institutional Experience

AimsOverall survival and progression-free survival with concomitant chemoradiotherapy for locally advanced cervical carcinoma have been described as 66% and 58%, respectively, at 5 years. Para-aortic lymph node involvement significantly increases the risk of relapse and death. The role of additional chemotherapy in these patients is as yet undefined. This aim of the present study was to determine the outcome of a cohort of para-aortic lymph node-positive patients treated with neoadjuvant chemotherapy followed by extended-field chemoradiation compared with patients treated with extended-field chemoradiation without neoadjuvant chemotherapy.Materials and methodsWe reviewed patients with International Federation of Gynaecology and Obstetrics (FIGO) 2014 stage IB1–IVA cervical carcinoma who received extended-field radiotherapy in addition to standard pelvic chemoradiotherapy with or without neoadjuvant chemotherapy, at University College London Hospital (January 2007 to January 2018). Patients in open clinical trials were excluded.ResultsOverall, 47 patients (15.8% of 298 eligible patients) with pelvic and/or para-aortic lymph node-positive cervical carcinoma received extended-field radiotherapy. Nineteen patients (40.4%) had both neoadjuvant chemotherapy (all received six cycles) and extended-field radiotherapy (median 44 days); 28 (59.6%) patients received extended-field radiotherapy alone (median 43 days). All patients completed radical radiotherapy within 49 days. We observed evidence that patients receiving neoadjuvant chemotherapy and extended-field radiotherapy had a lower risk of death (median follow-up 4.8 years, three deaths) compared with extended-field radiotherapy alone (median follow-up 3.0 years, 11 deaths; hazard ratio = 0.27, 95% confidence interval 0.08–1.00; P = 0.05). Three-year overall survival rates were 83.3% (95% confidence interval 66.1–100) and 64.6% (95% confidence interval 44.6–84.6), respectively. A PFS benefit was seen (hazard ratio 0.25, 95% confidence interval 0.08–0.77; P = 0.02), with 3-year PFS rates of 77.8% (95% confidence interval 58.6–97.0) and 35.0% (95% confidence interval 14.0–56.0), respectively.ConclusionsOur institutional experience suggests that the use of additional systemic therapy before chemoradiotherapy benefits patients with locoregionally advanced (FIGO 2018 IIIC2) cervical cancer. Neoadjuvant chemotherapy was associated with longer overall survival and PFS, without compromising definitive extended-field chemoradiation.     

Tumor-Infiltrating Lymphocytes (TIL), Tertiary Lymphoid Structures (TLS), and Expression of PD-1, TIM-3, LAG-3 on TIL in Invasive and In Situ Ductal Breast Carcinomas and Their Relationship with Prognostic Factors

IntroductionImmunotherapy has been determined as an important choice in breast carcinomas, especially in tumors with markedly inflammatory response. About this promising subject, tumor-infiltrating lymphocytes (TIL) and the expression of immune control point receptors on TIL have gained importance.Materials and MethodsIn this study, stromal TIL and tertiary lymphoid structures (TLS) were determined in tumor tissues of 312 invasive and 68 in situ breast cancer patients. Expression rates of PD-1, LAG-3, and TIM-3 on intratumoral and stromal TIL were immunohistochemically evaluated.ResultsIn invasive breast carcinomas, stromal TIL was found to be significantly associated with lymph node metastasis, HR and HER2 expression, and basal-like phenotype, as the presence of TLS with neoadjuvant therapy, recurrence, death, and expression of HR and HER2. PD-1, LAG-3, and TIM-3 expressions were found to be associated with HR and HER2 status, stromal TIL rates, and TLS. In multivariate analysis, high stromal TIL and PD-1 expression in intratumoral TIL were found to be independent prognostic factors in terms of overall survival and disease-free survival.ConclusionEvaluation of TIL and immune control point receptor expressions in breast cancer is particularly important in terms of planning the therapeutic approaches based on immunotherapy protocols.     

Margetuximab Versus Trastuzumab in Patients With Advanced Breast Cancer: A Cost-effectiveness Analysis

BackgroundIn the international, randomized, open-label, phase III study SOPHIA trial, margetuximab plus chemotherapy showed improved progression-free survival (PFS), and overall survival (OS) compared with trastuzumab plus chemotherapy. This study aimed to investigate whether margetuximab plus chemotherapy is cost-effective compared with trastuzumab plus chemotherapy in pretreated patients with ERBB2-positive advanced breast cancer.Materials and MethodsThe clinical data for this model was derived from the SOPHIA trial. Costs and utility were either derived from the standard fee database or extracted from previously published literature. A three-state Markov model was developed to simulate the disease process of patients with advanced breast cancer. One-way sensitivity analyses were conducted to investigate the impact of variables in the analysis model. Probabilistic sensitivity analysis was performed based on 10,000 Monte-Carlo simulations. A subgroup analysis was performed to test whether margetuximab is cost-effective in CD16A-158F allele carriers.ResultsMargetuximab plus chemotherapy provided an incremental 0.04 QALYs with an incremental cost of $66,109.78, compared with the trastuzumab plus chemotherapy, resulting in the incremental cost-effectiveness ratio (ICER) of $1,486,442.35/QALY, which exceeded the willingness to pay (WTP) threshold. While in the CD16A-158F allele carriers subgroup, the ICER decreased to $592,669.73/QALY. The variance of the utility of PFS state, costs of margetuximab, and utility of progressive disease state were the most influential factors in the sensitivity analysis.ConclusionUnder current WTP threshold, margetuximab plus chemotherapy is not cost-effective compared with trastuzumab plus chemotherapy in pretreated patients with ERBB2-positive advanced breast cancer. Selecting CD16A-158F allele carriers might be a considerable option to optimize the cost-effectiveness of margetuximab.     

The clinical outcomes of undifferentiated pleomorphic sarcoma (UPS): A single-centre experience of two decades with the assessment of PD-L1 expressions

IntroductionLittle is known about undifferentiated pleomorphic sarcoma (UPS) because of the low incidence and heterogeneous diagnosis of sarcoma. We investigated the oncologic outcomes of patients with UPS in a real-practice setting in association with adjuvant treatments and assessment of PD-L1 expression.Materials and methodsWe retrospectively reviewed consecutive patients who were diagnosed with UPS in Asan Medical Center between January 1995 and December 2016. PD-L1 staining was performed using formalin-fixed paraffin-embedded tumour tissue by immunohistochemistry, and positive PD-L1 expression was defined as staining in ≥1% of tumour cells. The PD-L1 H-score, which was calculated for statistical analysis as intensity (0–3) multiplied by proportion (0–100), ranged from 0 to 300.ResultsOf 205 patients included in our analysis, 176 underwent a curative-intent operation for localised disease. The five-year disease-free survival (DFS) rate of resected UPS patients was 54.3%. Administration of adjuvant therapy did not overcome the poor prognostic factors such as primary tumour size (>5 cm) and locations, especially the abdomen and pelvis. The PD-L1 analysis was available for 114 patients, and 83 (72.8%) showed immunoreactivity for PD-L1 with weak (44/83), intermediate (29/83), and strong (10/83) staining intensities. The positive PD-L1 expression seemed to be associated with prolonged DFS, though no statistical significance was observed.ConclusionComplete surgical resection was the most important UPS treatment strategy, and adjuvant radio- or chemotherapy was insufficient to improve survival. Our results raise the possibility that immunotherapy could be a breakthrough in the treatment of UPS patients.     

Adequate Number of Lymph Nodes Sampled May Determine Appropriate Surgical Modality for Early-Stage NSCLC: A Population-Based Real-World Study

BackgroundThe standard surgical procedure for ≤ 2 cm non-small cell lung cancer (NSCLC), including the number of lymph nodes sampled (nLN) and surgical modality, remains controversial. This study was designed to determine the optimal cohort in which sublobectomy could be an alternative to lobectomy.Materials (or Patients) and MethodsPatients from 1998 to 2017 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. The optimal cutoff value of nLN was identified using a restrictive cubic spline graph (RCS). Kaplan–Meier analysis was used to determine cancer-specific survival (CSS). The COX proportional hazard regression model was used to identify the influence of clinical and demographic variables on survival, and propensity score matching (PSM) was used to balance differences in baseline characteristics. Finally, we used an external cohort from a single-center medical institution to verify the conclusions drawn from the SEER database.ResultsA total of 6150 patients were included. The sublobectomy subgroup included segmentectomy (308, 5.0%) and wedge resection (1611, 26.2%). The cutoff value for nLN was 7. In the nLN ≥7 subgroup of the PSM cohort, the CSS of segmentectomy and wedge resection was close to that of the lobectomy subgroup (P = .12), whereas in the nLN <7 subgroup, the CSS of the lobectomy subgroup was significantly higher than that of the sublobectomy with P < .001). Surgical methods, nLN, age, sex, and differentiated grade were independent predictors of CSS. External cohort validation: A total of 1106 patients from the Affiliated Jinhua Hospital of Zhejiang University School of Medicine between 2013 and 2020 were included. The grouping criteria were consistent with the SEER database. In the nLN≥7 subgroup, sublobectomy had a survival outcome similar to that of lobectomy (P = .81).ConclusionSublobectomy and nLN < 7 were strongly associated with poorer CSS for early-stage NSCLC. On the premise of nLN ≥ 7, sublobectomy could provide similar survival outcomes to lobectomy for these patients.     

Pre-treatment 18F-RGD Uptake may Predict Adverse Events during Apatinib Antiangiogenic Therapy

AimsThe adverse events during antiangiogenic therapy inevitably influence a patient's quality of life. Therefore, biomarkers to identify patients who will experience adverse events would be very valuable in treatment planning.Materials and methodsBetween September 2016 and December 2019, patients scheduled for single-agent apatinib were prospectively enrolled and underwent ¹⁸F-RGD positron emission tomography/computed tomography (PET/CT) pre-treatment. Maximum and mean standard uptake values (SUV_max and SUV_mean) were obtained from thyroid, liver, gastric cardia, gastric body, gastric pylorus and spleen. Statistical methods included the independent sample t-test, Mann-Whitney U-test, receiver operating characteristic curve analysis and chi-squared test.ResultsIn total, 60 patients were initially screened and consented for ¹⁸F-RGD PET/CT scans. The three most frequent adverse events were fatigue (50%), hypertension (36%) and nausea (36%), accounting for 72% in the 50 patients included in the analysis. SUV_max and SUV_mean of thyroid and liver were significantly associated with fatigue, whereas SUV_max and SUV_mean of thyroid and spleen were significantly associated with hypertension and SUV_max and SUV_mean of thyroid and gastric cardia were significantly associated with nausea (all P < 0.05). The most significant predictors of adverse events were ¹⁸F-RGD SUV_max-liver for fatigue (area under the curve [AUC] = 0.682), SUV_max-spleen for hypertension (AUC = 0.688) and SUV_{max-gastric cardia} for nausea (AUC = 0.698). Classified by the cut-off values for SUV_max-liver (4.57), SUV_max-spleen (6.77) and SUV_{max-gastric cardia} (2.10), patients with low RGD SUV_max in liver, spleen and gastric cardia had statistically higher incidence of fatigue (67.9% versus 27.3%, P = 0.002), hypertension (55.6% versus 13.0%, P = 0.004) and nausea (61.1% versus 21.9%, P = 0.006).ConclusionsLow pre-treatment ¹⁸F-RGD uptake in the liver, spleen and gastric cardia were predictive of the adverse events fatigue, hypertension and nausea during apatinib treatment, respectively.     

Vinorelbine After Prior Treatment With Eribulin for Advanced Breast Cancer: A Single-Centre Experience Suggesting Cross-Resistance

IntroductionThe tubulin inhibitor, eribulin, improves survival for previously treated advanced breast cancer (ABC) compared to chemotherapy of physician's choice, including vinorelbine, an older anti-tubulin. Vinorelbine is commonly still used after eribulin, but potentially risks cross-resistance and its efficacy in this setting is unproven.Materials and MethodsA retrospective analysis of all patients who received vinorelbine after prior eribulin (VAE) 2011-2015 and a parallel cohort of consecutive patients who received vinorelbine without prior eribulin (VWE) for previously treated ABC between 2005 and 2011. Patient demographics, histopathological features, treatment duration and responses were recorded. The primary endpoint was progression-free survival from date of first vinorelbine for each cohort. Secondary endpoints included radiological response rate, and overall survival (OS).ResultsThirty-five VAE and 103 VWE patients were identified, all female, 71.4% and 78.6% were ER positive/HER2 negative, 8.6% and 6.8% HER2 positive, and 20.0% and 14.6% triple negative for VAE and VWE cohorts, respectively. The median number of lines of chemotherapy lines prior to vinorelbine was 4 (range 2-6) and 2 (range 0-4), respectively. Fifteen VAE patients (42.9%) received ≥1 line of chemotherapy between eribulin and vinorelbine. VAE and WWE Patients received a median of 3 cycles of vinorelbine (range 1-9 and 1-12, respectively). The median progression-free survival for VAE patients was 2.1 months and 2.0 months for VWE patients. No VAE patients were progression-free at 24 weeks, compared to 15.5% of VWE patients. Median OS from commencing vinorelbine was 4.3 months for VAE and 6.4 months for VWE patients.ConclusionVinorelbine was of limited benefit after prior eribulin in our study, suggesting cross-resistance. Even without prior eribulin, only 15% of patients experienced clinical benefit from vinorelbine monotherapy.     

Management of Patients With Advanced Urothelial Carcinoma in an Evolving Treatment Landscape: A Qualitative Study of Provider Perspectives of First-Line Therapies

IntroductionThe treatment landscape in locally advanced/unresectable or metastatic urothelial carcinoma (aUC) has evolved with the use of immune checkpoint inhibitors (ICIs) in the first line (1L) and platinum-refractory settings and with the recent approval of avelumab as 1L maintenance therapy for patients achieving disease control with platinum-containing regimens. Oncology provider perspectives and decision-making processes regarding aUC management, especially with the integration of recently approved strategies, such as maintenance therapy, have not been well-described.Patients and MethodsQualitative interview study with US oncologists and oncology nurses in academic and community settings in August 2020. Interviews explored decision-making around aUC 1L treatment eligibility determinants and selection, programmed cell death 1 ligand 1 (PD-L1) testing practices, and use of maintenance therapy. Thematic analysis was used to identify drivers of 1L treatment decisions.ResultsEighteen oncologists (women, 11%; >15 years in practice, 55%; academic, 39%) and 18 oncology nurses (women, 94%; >15 years in practice, 34%; academic, 50%) participated. Providers preferred platinum-based regimens in 1L setting and reserved 1L ICI monotherapy for frail patients. Providers preferred chemotherapy followed by switch maintenance ICI, as opposed to concurrent combination chemotherapy and ICI, followed by ICI as continuation maintenance. Decision-making was driven by need to adhere to treatment decision-making guidelines, characteristics of the patient, treatment efficacy and patient preference.ConclusionProviders adhered to guidelines and level I evidence in decision-making in the aUC 1L setting. Future studies should further evaluate barriers to the adoption of standard-of-care strategies and factors impacting decision-making in the real-world setting.     

Immunotherapy in NSCLC patients with brain metastases. Understanding brain tumor microenvironment and dissecting outcomes from immune checkpoint blockade in the clinic

BackgroundBrain metastases are frequent complications in patients with non-small-cell lung cancer (NSCLC) associated with significant morbidity and poor prognosis. Our goal is to give a global overlook on clinical efficacy from immune checkpoint inhibitors in this setting and to review the role of biomarkers and molecular interactions in brain metastases from patients with NSCLC.MethodsWe reviewed clinical trials reporting clinical outcomes of patients with NSCLC with brain metastases as well as publications assessing the tumor microenvironment and the complex molecular interactions of tumor cells with immune and resident cells in brain metastases from NSCLC biopsies or preclinical models.ResultsAlthough limited data are available on immunotherapy in patients with brain metastases, immune checkpoint inhibitors alone or in combination with chemotherapy have shown promising intracranial efficacy and safety results. The underlying mechanism of action of immune checkpoint inhibitors in the brain niche and their influence on tumor microenvironment are still not known. Lower PD-L1 expression and less T CD8⁺ infiltration were found in brain metastases compared with matched NSCLC primary tumors, suggesting an immunosuppressive microenvironment in the brain. Reactive astrocytes and tumor associated macrophages are paramount in NSCLC brain metastases and play a role in promoting tumor progression and immune evasion.ConclusionsDiscordances in the immune profile between primary tumours and brain metastases underscore differences in the tumour microenvironment and immune system interactions within the lung and brain niche. The characterization of immune phenotype of brain metastases and dissecting the interplay among immune cells and resident stromal cells along with cancer cells is crucial to unravel effective immunotherapeutic approaches in patients with NSCLC and brain metastases.     

Validation of the American Joint Committee on Cancer 8th edition staging system for the pancreatic ductal adenocarcinoma

Background & aimsThe American Joint Commission on Cancer (AJCC) 8th edition staging system for pancreatic ductal adenocarcinoma (PDA) contains several significant changes. This study aimed to validate the AJCC 8th edition staging system of PDA.MethodsWe analyzed patients with resected PDA between 2001 and 2017 using the Korean Pancreatic Cancer (K-PaC) registry. Overall survival (OS) was estimated using the Kaplan-Meier survival curves and compared via the log-rank test.ResultsIn total, 701 resected PDA patients were identified. During a median follow-up of 24.5 months, the median OS was 21.7 months. Meanwhile, the median OS of each stage according to the AJCC 8th edition was 73.5 months (stage IA), 41.9 months (stage IB), 24.2 months (stage IIA), 18.3 months (stage IIB), and 16.8 months (stage III). However, the new N-category (pN1 vs. pN2) did not subdivide prognosis, although the lymph node ratio (i.e., the ratio of the number of LN involved to the number of examined LN) did. Although pT3 and pN2 belong under stage III, pN2 has a significantly longer median OS than pT3 (16.9 months vs 11.2 months; p < 0.01).ConclusionThe AJCC 8th edition staging system appropriately stratifies the prognosis of PDA patients. However, the cutoff of the N-category is not statistically valid, and the new stage III includes a heterogeneous category (pN2 and pT4). Therefore, we propose that stage III be divided into stage IIIA (Tany N2 M0) and stage IIIB (T4 Nany M0).     

Disease and Clinical Characteristics of Patients With a Clinical Diagnosis of Myelofibrosis Enrolled in the MOST Study

BackgroundClinical characteristics and treatment patterns of patients with lower-risk myelofibrosis (MF) are not well described. This analysis from the MOST (NCT02953704) assessed the demographic and clinical characteristics and treatment patterns of patients with the clinical diagnosis of lower-risk MF at enrollment.Patients and MethodsMOST is an ongoing, prospective, observational study in patients with clinical diagnoses of MF or essential thrombocythemia enrolled at clinical practices throughout the United States. Patients included in the MF cohort (≥18 years of age) had low-risk MF by the Dynamic International Prognostic Scoring System or intermediate-1 (INT-1) risk MF (by age >65 years only) at enrollment. Patient data were entered into an electronic case report form during usual-care visits over a planned 36 month observation period.ResultsTwo hundred five patients were eligible for this analysis (low risk, n = 85; INT-1 risk, n = 120; median age, 68 years [range, 35–88]); 166 patients (81.0%) had mutation testing results available. The median time from MF diagnosis to enrollment was 1.8 years. Hemoglobin and hematocrit levels were below the normal range in 50.5% and 48.7% of patients, respectively. Nearly all (98.0%) patients had comorbid conditions, most commonly hypertension (49.8%). Fatigue was the most common physician-reported MF symptom (30.7%). At enrollment, 55.6% of patients were receiving MF-directed monotherapy, most frequently hydroxyurea (46.5%) or ruxolitinib (40.4%).ConclusionFuture longitudinal analyses of data from MOST will help identify unmet needs and characterize how patients with lower-risk MF are managed throughout the disease course.     

Comparison of long term survival outcomes between D1+ and D2 lymph node dissection for ≥ pT2 or pN+ gastric carcinoma: A large scale case-control study using propensity score matching

BackgroundD2 lymph node dissection (LND) is a widely performed as a standard procedure for advanced gastric cancer (AGC). However, there is little evidence supporting D2 over D1+ LND for gastric cancer treatment. This study compared the long-term outcomes of D2 and D1+ LND for AGC.MethodsWe retrospectively reviewed data on 1121 patients who underwent curative distal gastrectomy and had pathologic stage of ≥ pT2 or pN+. The patients were categorized into the D1+ and D2 LND groups, and long-term survival was compared in the original and propensity score matching (PSM) cohorts.ResultsOverall, 909 and 212 patients underwent D2 and D1+ LND, respectively. The D2 group showed more advanced stage and more frequently underwent open surgery. Postoperative morbidity was significantly higher in the D2 group (19.5% vs. 13.2%, p = 0.034); however, mortality or ≥ grade III complications did not significantly differ between the groups. The 5-year overall survival (OS) and disease-free survival (DFS) did not significantly differ between D2 and D1+ groups at the same stage. Multivariate analysis of prognostic factors revealed that the extent of LND did not significantly affect survival, after adjusting for tumor stage and other clinicopathological factors. In the PSM cohort, the D2 and D1 groups showed no significant difference in OS (p = 0.488) and DFS (p = 0.705).ConclusionsLong-term survival with D1+ LND was comparable to that with D2 LND for ≥ pT2 or pN + gastric carcinoma. A large randomized trial is warranted to validate the optimal extent of LND for gastric carcinoma.     

Olverembatinib Treatment in Pediatric Patients With Relapsed Philadelphia-Chromosome-Positive Acute Lymphoblastic Leukemia

Treatment outcomes for children with Philadelphia chromosome-positive (Ph⁺) acute lymphoblastic leukemia (ALL) remained poor despite the use of intensive chemotherapy, imatinib or dasatinib, and consolidative allogeneic hematopoietic cell transplantation. Oleverembatinib, a third-generation ABL inhibitor, was found to be highly effective and safe in adults with chronic myeloid leukemia and in some adults with relapsed or refractory Ph⁺ ALL. We reviewed the efficacy and safety profile of olverembatinib treatment in 6 children with relapsed Ph⁺ ALL and 1 with T-ALL and ABL class fusion, all of whom had previously received dasatinib or intolerance to dasatinib. The median duration of olverembatinib treatment was 70 days (range: 4-340) and the median cumulative dose was 600 mg (range: 80-3810). Complete remission with negative minimal residual level (<0.01%) was achieved in 4 of the 5 evaluable patients, 2 of whom were treated with olvermbatinib as a single agent. Safety profile in 6 evaluable patients was excellent with grade 2 extremity pain occurred in 2 patients and grade 2 myopathy of lower extremity and grade 3 fever in 1 patient each. Olverembatinib appeared to be safe and effective in children with relapsed Ph⁺ ALL.     

Treatment of Patients with Metastatic Hormone-Sensitive Prostate Cancer: A Systematic Review of Economic Evaluations

The management of patients with metastatic hormone-sensitive prostate cancer (mHSPC) has been significantly modified by the availability of innovative but expensive treatments, increasing the economic burden of prostate cancer. Here, we aimed to systematically identify and review published economic evaluations (EEs) related to the treatment of mHSPC and assess their quality. A systematic search was performed of the PubMed and Cochrane databases. Three reviewers independently selected EEs by defined inclusion and exclusion criteria. They extracted all data from each EE (general information, study population, data about the EE, interventions and comparators, and outcomes). They also assessed the quality of the selected EEs according to Drummond's checklist. Fourteen EEs published between 2016 and 2021 were eligible for the systematic review. The EEs found ADT + docetaxel to be the most cost-effective of all available treatments as a first-line strategy for mHSPC (abiraterone acetate plus prednisone, enzalutamide, and apalutamide). Five EEs showed that a simple price reduction of abiraterone acetate of 50% to 75% could change the results to render this treatment also cost-effective relative to that with docetaxel. Twelve EEs were of high quality, with a Drummond score ≥ 7. Analysis of the 14 EEs identified by our systematic review, amongst which 78.6% met high quality standards, showed that ADT + docetaxel tends to be the most cost-effective alternative for mHSPC. These results were assessed by sensitivity analysis. The data provided by this systematic review help to provide a better understanding of these treatments and the better use of healthcare resources.     

Impact of TP53 Mutations on EGFR-Tyrosine Kinase Inhibitor Efficacy and Potential Treatment Strategy

BackgroundWe investigated the impact of factors that influence TP53 mutations on the efficacy of EGFR-tyrosine kinase inhibitors and potential treatment strategies.Materials and MethodsTumor samples were collected to screen gene mutations by next-generation sequencing, as well as the patients’ baseline characteristics. The overall response to treatment with TKIs was evaluated based on interval computed tomography scans at each follow-up time point. A Fisher's exact test and log-rank test were used to determine the statistical differences in this study.ResultsA total of 1134 clinical samples were collected from NSCLC patients, and TP53^mut was identified in 644 cases and EGFR^mut in 622 cases. A low frequency of TP53^mut or more than 50% EGFR co-mutation rate were related to the prognosis of TKI-treated patients. In addition, TP53^mut in the region outside of the DB domain had the strongest correlation with TKI resistance, whereas various types of mutations in the DB domain only had an impact on PFS. A grouping study of EGFR-TKI-based treatment revealed that EGFR-TKIs with chemotherapy were associated with more significant survival benefits for patients with prognostic TP53^mut, whereas EGFR-TKI therapy was favorable for TP53^wt patients. Furthermore, TP53^mut could shorten the time to the relapse of postoperative patients, who will also likely respond well to EGFR-TKIs with chemotherapy.ConclusionVarious characteristics of TP53^mut affect the prognosis of TKI-treated patients to varying degrees. EGFR-TKIs with chemotherapy were benefit for patients’ survival with prognostic TP53^mut, which provides an important reference for treatment management of EGFR^mut patients.     

Trans-arterial chemoembolization + radiofrequency ablation versus surgical resection in hepatocellular carcinoma – A meta-analysis

BackgroundHepatocellular Carcinoma (HCC) remains the third most common cause of cancer death worldwide, with countries in Asia being affected the most. The mainstay of curative therapy for early HCC is radiofrequency ablation (RFA) or surgery; either surgical resection (SR) or liver transplantation. Latest evidence however suggests that combination of TACE+ RFA may provide outcomes comparable to SR.AimTo compare oncologic outcomes and safety profile of TACE + RFA to SR alone in HCC.Materials and methodsA systematic review was conducted through Pubmed, EMBASE and Cochrane Library for literature published before April 2019. Outcomes measured were disease-free survival(DFS), overall survival(OS) and major complications. DFS was further divided into local tumour progression(LTP), intrahepatic distant recurrence(IDR) and distant metastasis(DM).ResultsEight retrospective studies and one randomized controlled trial, involving 1892 patients met eligibility criteria and were included. Unadjusted pooled analysis demonstrated no significant difference in 1-year, 3-year and 5-year OS and 1-year DFS between TACE+RFA and SR. SR had superior 3-year DFS (OR 0.78, 95% CI 0.62–0.98, p = 0.03) and 5-year DFS (OR 0.74, 95% CI 0.58–0.95, p = 0.02) compared to TACE+RFA. When analysing only the propensity matched data, the difference in 3-year DFS and 5-year DFS was not significant. TACE+RFA had a higher LTP rate (OR 2.48, 95% CI 1.05–5.86, p = 0.04) compared to SR but IDR and DM rates were not significant.Discussion and conclusionTACE+RFA offer comparable oncologic outcomes in patients with HCC as compared with SR and with added benefit of lower morbidity.     

High-risk factors for lymph node metastasis in contralateral central compartment in unilateral papillary thyroid carcinoma（cT1N0）

ObjectiveThe incidence of papillary thyroid carcinoma (PTC) increases yearly. Central lymph node metastasis (CLNM) is common in PTC. Many studies have addressed ipsilateral CLNM; however, few studies have evaluated contralateral CLNM. The purpose of this study is to investigate the high-risk factors of lymph node metastasis in the contralateral central compartment of cT1 stage in PTC.MethodsIn total, 369 unilateral PTC (cT1N0) patients who underwent total-thyroidectomy with bilateral central lymph node dissection (CLND) between 2013 and 2016 in our hospital were retrospectively enrolled. Univariate and multivariate analyses identified the high-risk factors for contralateral CLNM of PTC.ResultsThe total metastasis rate of the ipsilateral central neck compartment was 31.71% (117/369). The total metastasis rate of the contralateral central neck compartment was 8.13% (30/369). The multivariate analysis showed that multifocality (p = 0.009), ipsilateral CLNM (p＜0.001), number of ipsilateral CLNM ＞2 (p = 0.006), tumor located at the inferior pole (p = 0.032) and tumor diameter ＞ 1 cm (p = 0.029) were independent risk factors for contralateral CLNM at cT1 stage in PTC, with odds ratios (ORs) of,4.132 (95% confidence intervals (CI): 1.430–11.936) ，8.591 (95% CI: 3.200–23.061) ，0.174 (95% CI: 0.050–0.601) ，0.353 (95% CI: 0.136–0.917)and 0.235 (95% CI: 0.064–0863), respectively.ConclusionThe combinational use of these risk factors will help surgeons devise an appropriate surgical plan preoperatively. This information could provide reference for the readers who are interested and help to determine the optimal extent of CLND in patients with PTC, especially for cT1b patients.     

Hemangiosis carcinomatosa as an independent risk factor for long-term survival in Non-Small Cell Lung Cancer patients

ObjectivesRecent studies have shown that blood vessel invasion (V1) influences the long-term survival of patients with Non-Small Cell Lung Cancer (NSCLC). The aim of the present study was to emphasize V1 as an independent risk factor. We evaluated the effects of V1 on the survival of NSCLC patients with UICC stages I, II, and III after surgery.MethodsThis retrospective study includes 747 consecutive patients with NSCLC who underwent anatomic resection and radical lymphadenectomy at our institution between January 2012 and December 2020. V1- were compared to V0-patients (no blood vessel invasion). All patients received adjuvant therapy according to European guidelines when indicated. After excluding patients with detection of lymphangiosis carcinomatosa, tumor-cells at the resection margin, distant metastases and those, that received neoadjuvant therapy, 1-, 3- and 5- year survival rates were assessed by Kaplan-Meier method. To proof V1 as an independent risk factor, a propensity score matched (PSM) analysis was performed regarding age, gender, UICC-stage, lymph-node involvement, and comorbidities.ResultsA total of 461 patients (V0: 440; V1: 21) were included in this analysis. Baseline characteristics did not show any significant difference. Mean age in V0-group was 65.7 ± 10.5 years and 64.1 ± 8.6 years in V1-group (p-value = 0.5). In the V0-group 54.8% were male, whereas in the V1-group this number was 66.7% (p-value = 0.37). Mean survival in V1-group was significantly shorter compared to V0-group (V1: 45.8 ± 9.3 months; V0: 81.1 ± 1.1 months; p-value<0.001). This was confirmed after applying a propensity score matched analysis (V0: 99.9 ± 4.9 months; V1: 45.8 ± 9.3 months; p-value<0.001) - V1 is a prognostic marker independent of UICC stage. The 1-, 3- and 5-year survival rates were significantly shorter for V1-patients (1-year: V0: 100%; V1: 70.6%; p-value = 0.012) (3-year: V0: 95.2%; V1: 46.2%; p-value = 0.002) (5-year: V0: 90.5%; V1: 36.4%; p-value = 0.003).ConclusionAs we have shown with our investigations, V1 has a major impact on long-term survival in NSCLC patients and furthermore, acts as an independent risk factor. Due to our small but specified sample size, our statement should be confirmed by a multicenter study. In the meantime, we suggest making the implementation of the V0/V1 specification mandatory in the tumor classification.