Grade 4 Research Articles

Grade 4 Lymphopenia Might Associate with Pericardial Irradiation Dose and Worse Prognosis in Patients with Locally Advanced Esophageal Cancer Receiving Concurrent Chemo-Radiotherapy

The immune system may influence prognosis, and lymphopenia is a frequent side effect of concurrent chemo-radiotherapy (CCRT). Radical irradiation for locally advanced esophageal cancer (LA-EC) exposes significant vascular and heart volumes, and we hypothesized that lymphopenia is linked to cardiac and pericardial doses and affects patient prognosis. We identified 190 LA-EC patients who received radical CCRT between 2011 and 2019. Cardiac, pericardial, and lung dosimetric parameters were obtained and multivariate analysis (MVA) was performed to correlate clinical factors and dosimetric parameters with overall survival (OS). Absolute lymphocyte count (ALC), absolute platelet count (PLT), absolute white blood cell count (WBC), absolute neutrophil count (ANC), neutrophil-lymphocyte ratio (NLR = ANC/ALC), and platelet-lymphocyte ratio (PLR = PLT/ALC) were collected before and during CRT. Grade 4 (G4) lymphopenia was defined as Lymphocyte count nadir <0.2 103/mL during CRT and it was used to dichotomize the lymphocyte count nadir. MVA was performed to correlate hematologic toxicity with OS. Logistic stepwise regression was performed to determine the relationship between dosimetric parameters and G4 lymphopenia. Finally, a nomogram of G4 lymphopenia was developed and validated externally. Median follow-up time for all patients was 27.5 months (range 12-118 months). On MVA for OS (n = 190), higher pericardial V30 (PV30) was linked to worse survival (HR = 1.013, 95% CI 1.001-1.026, p = 0.039). The median OS stratified by PV30>55.3% and PV30≤55.3% was 24 months and 54 months, respectively (p = 0.004). G4 lymphopenia was shown to be linked with worse OS in the MVA of hematological toxicity (n = 161) with OS (HR = 2.042, 95% CI 1.335-3.126, p = 0.001). 24 (24%) of the 100 patients in the training set had G4 lymphopenia. Our final model comprised Stage-IVA (p = 0.017), PLR during CRT (p = 0.008), Heart V50 (p = 0.046), and PV30 (p = 0.048). External validation 26 of 90 patients (29%) had grade 4 lymphocytopenia. The ROC curve displays an AUC for internal validation of 0.775 and external validation of 0.843. Higher doses of pericardial radiation might affect LA-EC patients' prognosis by inducing G4 lymphopenia in CCRT process. Further prospective studies are warranted to confirm these findings, especially in the era of immune-checkpoint inhibitor treatment.

Factors Involved in Preoperative Edema in High-Grade Gliomas.

Background Expansion of preoperative edema (PE) is an independent poor prognostic factor in high-grade gliomas. Evaluation of PE provides important information that can be readily obtained from magnetic resonance imaging (MRI), but there are few reports on factors associated with PE. The goal of this study was to identify factors contributing to PE in Grade 3 (G3) and Grade 4 (G4) gliomas. Methodology PE was measured in 141 pathologically proven G3 and G4 gliomas, and factors with a potential relationship with PE were examined in univariate and multivariate analyses. The following eight explanatory variables were used: age, sex, Karnofsky performance status (KPS), location of the glioma, tumor diameter, pathological grade, isocitrate dehydrogenase (IDH)-1-R132H status, and Ki-67 index. Overall survival (OS) and progression-free survival (PFS) were calculated in groups divided by PE (<1 vs. ≥1 cm) and by factors with a significant correlation with PE in multivariate analysis. Results In univariate analysis, age (p = 0.013), KPS (p = 0.012), pathology grade (p = 0.004), and IDH1-R132H status (p = 0.0003) were significantly correlated with PE. In multivariate analysis, only IDH1-R132H status showed a significant correlation (p = 0.036), with a regression coefficient of -0.42. The median follow-up period in survivors was 38.9 months (range: 1.2-131.7 months). The one-, two-, and three-year OS rates for PE <1 vs. ≥1 cm were 77% vs. 68%, 67% vs. 44%, and 63% vs. 24% (p = 0.0001), respectively, and those for IDH1-R132H mutated vs. wild-type cases were 85% vs. 67%, 85% vs. 40%, and 81% vs. 21% (p < 0.0001), respectively.The one-, two-, and three-year PFS rates for PE <1 vs. ≥1 cm were 77% vs. 49%, 64% vs. 24%, and 50% vs. 18% (p = 0.0002), respectively, and those for IDH1-R132H mutated vs. wild-type cases were 85% vs. 48%, 77% vs. 23%, and 73% vs. 14% (p < 0.0001), respectively. Conclusions IDH1-R132H status was found to be a significant contributor to PE. Cases with PE <1 cm and those with the IDH1-R132H mutation clearly had a better prognosis.

A machine learning model for grade 4 lymphopenia prediction during pelvic radiotherapy in patients with cervical cancer.

Background/purposeSevere lymphopenia during pelvic radiotherapy (RT) predicts poor survival in patients with cervical cancer. However, the risk of severe lymphopenia has not been well predicted. We developed a machine learning model using clinical and dosimetric information to predict grade 4 (G4) lymphopenia during pelvic RT in patients with cervical cancer.MethodsThis retrospective study included cervical cancer patients treated with definitive pelvic RT ± induction/concurrent chemotherapy. Clinical information and a set of dosimetric parameters of external beam radiotherapy plan were collected. G4 lymphopenia during RT, which was also referred to as G4 absolute lymphocyte count (ALC) nadir, was defined as ALC nadir <0.2 × 109 cells/L during RT according to Common Terminology Criteria for Adverse Events (CTCAE) v4.03. Elastic-net logistic regression models were constructed for the prediction of G4 lymphopenia during pelvic RT using a repeated cross-validation methodology.ResultsA total of 130 patients were eligible, and 43 (33.1%) patients had G4 lymphopenia during RT. On multivariable analysis, G4 ALC nadir was associated with poor overall survival (OS) [hazard ratio (HR), 3.91; 95% confidence interval (CI), 1.34–11.38, p = 0.01]. Seven significant factors [Eastern Cooperative Oncology Group (ECOG) performance score, pre-RT hemoglobin, pre-RT lymphocytes, concurrent chemotherapy, gross tumor volume of regional lymphadenopathy (GTV_N volume), body volume, and maximum dose of planning target volume receiving at least 55 Gy (PTV_5500 Dmax)] were obtained by elastic-net logistic regression models and were included in the final prediction model for G4 ALC nadir. The model’s predicting ability in test set was area under the curve (AUC) = 0.77 and accuracy = 0.76. A nomogram of the final predicting model was constructed.ConclusionsThis study developed and validated a comprehensive model integrating clinical and dosimetric parameters by machine learning method, which performed well in predicting G4 lymphopenia during pelvic RT for cervical cancer and will facilitate physicians to identify patients at high risk of G4 lymphopenia who might benefit from modified treatment approaches.

Severe radiation-induced lymphopenia during postoperative radiotherapy or chemoradiotherapy has poor prognosis in patients with stage IIB-III after radical esophagectomy: A post hoc analysis of a randomized controlled trial.

ObjectiveTo investigate whether radiation-induced lymphopenia (RIL) affects survival and identify the predictors of RIL in postoperative esophageal cancer.Materials and methods Post hoc analysis was conducted on data from 116 patients with esophageal cancer from a randomized controlled trial comparing adjuvant therapy with surgery alone. Doses of 54 Gy in 27 fractions was delivered in the postoperative radiotherapy (PORT) group and 50.4 Gy in 28 fractions combined with chemotherapy was delivered in postoperative concurrent chemoradiotherapy (POCRT) group. Blood counts were obtained before, during, and at first follow-up after treatment. Lymphopenia was graded per version 4.03 of the Common Terminology Criteria for Adverse Events. Disease-free survival (DFS) and overall survival (OS) were analyzed using the Kaplan-Meier method, and compared between groups using the log-rank test. Receiver operating characteristic curves identified thresholds for preventing grade 4 (G4) lymphopenia.ResultsMedian follow-up duration was 56.0 months. During treatment, 16 patients (13.8%) had G4 lymphopenia. All cases of G4 lymphopenia occurred in group PORT (30.2% vs 0.0%, p<0.001). Baseline absolute lymphocyte count was comparable between G1-3 and G4 patients (2.0 ± 0.8 *109/L vs 1.7 ± 0.5 *109/L; p=0.101). The 3-year DFS was significantly lower in group G4 lymphopenia than that in group G1-3 (31.3% vs 57.6%, p=0.036). The 3-year OS was comparable between both groups (50.0% vs 66.5%, p=0.095). Logistic regression analysis revealed that exposed more thoracic marrow (TM V20 ≥75%; TVB V20 ≥71%), heart (V15 ≥40%) and PTV (volume ≥507 ml) were associated with G4 lymphopenia (p<0.05).ConclusionsG4 RIL had poor disease-free survival, which may be related to more dose exposure of thoracic marrow and heart due to larger PTV. Reasonably reducing the radiation field combined with concurrent chemotherapy, or radiation dose constraints for these normal tissues may be sufficient to decrease the incidence of G4 lymphopenia, but further prospective trials are needed to verify the results.Clinical Trial Registration clinicaltrials.gov, identifier NCT02279134

Prognostic value of absolute lymphocyte count in patients with advanced esophageal cancer treated with immunotherapy: a retrospective analysis.

BackgroundImmunotherapy has become the standard of treatment for recurrent metastatic esophageal cancer (EC), and the value of efficacy predictive markers represented by programmed death-ligand 1 (PD-L1) is limited. The purpose of this study is to analyze the prognostic value of peripheral blood absolute lymphocyte count (ALC) at baseline in patients with recurrent metastatic EC treated with immunotherapy, and to further investigate the relationship between the minimal ALC value (Min ALC) and radiotherapy (RT) parameters.MethodsThe main inclusion criteria were: histologically or imaging confirmed recurrent or metastatic EC; complete routine blood test data. A total of 105 patients were included in a single-center institution, 65 of whom had previously received RT. The optimal cut-off value for baseline lymphopenia was determined by the receiver operating characteristic (ROC) curve. The prognostic value of baseline phase lymphopenia for immunotherapy were determined by cox regression analysis and the associated factors affecting lymphopenia were explored by logistic regression analysis.ResultsThe cut-off value for baseline ALC predicting 1-year overall survival (OS) was 625 cells/µL. The OS was significantly lower in the lymphopenia group (ALC ≤625 cells/µL) than in the non-lymphopenia group (ALC >625 cells/µL) (median OS: 6 vs. 12 months, P=0.002). Multivariate analysis showed that pre-immunotherapy lymphopenia was an important factor influencing patient prognosis [hazard ratio (HR): 1.771, 95% confidence interval (CI): 1.051–2.985; P=0.032)] (adjusted for clinical factors including sex, age, tumor location, histology, degree of differentiation, distant metastasis, use of RT). Patients with a previous grade 4 (G4) Min ALC during RT were more likely to develop pre-immunotherapy lymphopenia following diagnosis of recurrent metastasis [odds ratio (OR): 10.809, 95% CI: 2.185–53.471; P=0.004]. Planning target volume (PTV) volume greater than 521.2 cm3 (OR: 19.981, 95% CI: 1.372–290.985; P=0.028) was an independent risk factor affecting the G4 Min ALC during RT.ConclusionsLymphopenia is associated with a poorer immunotherapy prognosis in patients with recurrent metastatic EC and those with previous G4 Min ALC after RT. RT-related parameters, especially irradiation volume, can significantly affect lymphocyte counts.

Phase 1b Study of Carfilzomib in Combination with Induction Chemotherapy in Children with Relapsed or Refractory Acute Lymphoblastic Leukemia (ALL)

Phase 1b Study of Carfilzomib in Combination with Induction Chemotherapy in Children with Relapsed or Refractory Acute Lymphoblastic Leukemia (ALL)

Integrated exposure\u2013response analysis of efficacy and safety of lurbinectedin to support the dose regimen in small-cell lung cancer

PurposeThese exposure–response (E–R) analyses integrated lurbinectedin effects on key efficacy and safety variables in relapsed SCLC to determine the adequacy of the dose regimen of 3.2 mg/m2 1-h intravenous infusion every 3 weeks (q3wk).MethodsLogistic models and Cox regression analyses were applied to correlate lurbinectedin exposure metrics (AUCtot and AUCu) with efficacy and safety endpoints: objective response rate (ORR) and overall survival (OS) in SCLC patients (n = 99) treated in study B-005 with 3.2 mg/m2 q3wk, and incidence of grade 4 (G4) neutropenia and grade 3–4 (G ≥ 3) thrombocytopenia in a pool of cancer patients from single-agent phase I to III studies (n = 692) treated at a wide range of doses. A clinical utility index was used to assess the appropriateness of the selected dose.ResultsEffect of lurbinectedin AUCu on ORR best fitted to a sigmoid-maximal response (Emax) logistic model, where Emax was dependent on chemotherapy-free interval (CTFI). Cox regression analysis with OS found relationships with both CTFI and AUCu. An Emax logistic model for G4 neutropenia and a linear logistic model for G ≥ 3 thrombocytopenia, which retained platelets and albumin at baseline and body surface area, best fitted to AUCtot and AUCu. AUCu between approximately 1000 and 1700 ng·h/L provided the best benefit/risk ratio, and the dose of 3.2 mg/m2 provided median AUCu of 1400 ng·h/L, thus maximizing the proportion of patients within that lurbinectedin target exposure range.ConclusionsThe relationships evidenced in this integrated E–R analysis support a favorable benefit-risk profile for lurbinectedin 3.2 mg/m2 q3wk.Trial registrationClinicaltrials.gov: NCT02454972; registered May 27, 2015.

Real-world safety and medication use of second-line (2L) 5-fluorouracil (5-FU)–based regimens among patients (pts) with metastatic pancreatic ductal adenocarcinoma (mPDAC).

e16248 Background: Chemotherapy-related adverse events (AEs) can negatively impact the treatment of pts. Managing and preventing these toxicities often require additional medications. This study examined the proportion of pts with mPDAC treated with 5-FU–based regimens in 2L who experienced AEs during treatment, and the proportion who received medication to manage those AEs. Methods: Data were extracted for pts diagnosed with mPDAC who initiated 2L treatment Jan 2016 to Aug 2020 from the Flatiron Health database. Pts included were treated with FOLFIRINOX (FFX), FOLFOX, FOLFIRI, or liposomal irinotecan (nal-IRI). The occurrence of grade 3 (G3) and grade 4 (G4) neutropenia and G3/G4 thrombocytopenia were determined using lab results and the grading criteria from the CTCAE v4.03. The occurrence of diarrhea and nausea/vomiting (N/V) were identified via ICD-10-CM codes. The use of atropine and granulocyte colony stimulating factor (G-CSF) during treatment was assessed. Duration of therapy (DOT) was assessed for each regimen. Descriptive statistics for AEs, medication use, and DOT were reported. Results: Of the 825 eligible pts, 29.0% (n=239) received FFX, 40.2% (n=332) received regimens containing nal-IRI, 24.0% (n=198) received FOLFOX, and 6.8% (n=56) received FOLFIRI. The median DOT (IQR) was 15.1 weeks (wks) (7.1 – 30.1), 12.9 wks (6.0 – 24.8), 11 wks (6.4 – 24.0), and 12.7 wks (8.3 – 24.6) for pts who received FFX, nal-IRI, FOLFOX, and FOLFIRI, respectively. G3/G4 thrombocytopenia (&lt;50,000/mm3) presented in 9.6%, 2.4%, 8.1%, and 14.3% of pts treated with FFX, nal-IRI, FOLFOX, and FOLFIRI, respectively. G3/G4 neutropenia (&lt;1000/mm3) presented in 22.6%, 12.3%, 14.6%, and 19.6% of pts treated with FFX, nal-IRI, FOLFOX, and FOLFIRI, respectively. The median (Q1-Q3) cumulative dose of the G-CSF pegfilgrastim was 18mg (12 – 45), 18mg (12 – 48), 24mg (12 – 36), and 30mg (13 – 48) for pts treated with FFX, nal-IRI, FOLFOX, and FOLFIRI, respectively. Atropine use was higher in pts treated with FFX and FOLFIRI (90.8% and 94.6%, respectively) than for pts treated with nal-IRI (75.6%). The full study results are reported in the table. Conclusions: In this study of AEs among pts with mPDAC treated in 2L, pts who received liposomal irinotecan had the lowest proportion of thrombocytopenia and neutropenia. Diarrhea was similar across the cohorts despite the high proportion of use in atropine for pts treated with FFX and FOLFIRI.[Table: see text]

Real-world safety data and differentiation of second-line (2L) 5-fluorouracil (5-FU) based regimens among patients with metastatic pancreatic ductal adenocarcinoma (mPDAC).

390 Background: Chemotherapy related adverse events (AEs) can impact the treatment of patients, reducing quality of life and leading to dose delays and treatment discontinuation. This study examined the proportion of patients (pts) with mPDAC treated with 5-FU-based regimens in the 2L setting who experienced AEs during treatment. Methods: Data were extracted for pts diagnosed with mPDAC who initiated 2L treatment between January 2016 and July 2020 from the Flatiron Health electronic health database. Pts included in the study were treated with FOLFIRINOX (FFX), FOLFOX, FOLFIRI, or a regimen containing liposomal irinotecan. The occurrence of grade 3 (G3) and grade 4 (G4) neutropenia, G3/G4 elevated alanine transaminase (ALT) and anemia where transfusion was indicated were determined using lab results and the grading criteria from the Common Terminology Criteria for Adverse Events v4.03. The occurrence of diarrhea, fatigue, nausea and vomiting (N/V), and neuropathy were identified from structured diagnosis records through ICD-10-CM codes. Duration of therapy (DOT) was assessed for each regimen. Descriptive statistics for AEs and DOT were reported. Results: Of the 804 pts included in the study, 28.4% (n=228) received FFX, 39.8% (n=320) received regimens containing liposomal irinotecan, 24.8% (n=199) received FOLFOX, and 7.1% (n=57) received FOLFIRI. The median DOT (IQR) was 86 days (d) (43 – 206), 79d (41 – 169), 72d (43 – 166), and 84d (46 – 148) for pts who received FFX, liposomal irinotecan, FOLFOX, and FOLFIRI, respectively. G3/G4 neutropenia (&lt;1000/mm3) presented in 28.1% (n=64) of pts treated with FFX, 11.9% (n=38) of pts treated with liposomal irinotecan, 17.1% (n=34) of pts treated with FOLFOX, and 36.8% (n=21) of pts treated with FOLFIRI. NV occurred in 14.9% (n=34), 13.1% (n=42), 12.6% (n=25), and 10.5% (n=6), respectively. The full AE results are summarized in the table. Conclusions: In this assessment of often dose-limiting AEs among pts with mPDAC treated in 2L, pts who received liposomal irinotecan had the lowest proportion of neutropenia. No clear pattern was noted for N/V, neuropathy, fatigue, anemia, and elevated ALT. Further research is necessary to determine the real-world cost implications of AEs in this patient population. [Table: see text]

Feature fusion of Raman chemical imaging and digital histopathology using machine learning for prostate cancer detection.

The diagnosis of prostate cancer is challenging due to the heterogeneity of its presentations, leading to the over diagnosis and treatment of non-clinically important disease. Accurate diagnosis can directly benefit a patient's quality of life and prognosis. Towards addressing this issue, we present a learning model for the automatic identification of prostate cancer. While many prostate cancer studies have adopted Raman spectroscopy approaches, none have utilised the combination of Raman Chemical Imaging (RCI) and other imaging modalities. This study uses multimodal images formed from stained Digital Histopathology (DP) and unstained RCI. The approach was developed and tested on a set of 178 clinical samples from 32 patients, containing a range of non-cancerous, Gleason grade 3 (G3) and grade 4 (G4) tissue microarray samples. For each histological sample, there is a pathologist labelled DP-RCI image pair. The hypothesis tested was whether multimodal image models can outperform single modality baseline models in terms of diagnostic accuracy. Binary non-cancer/cancer models and the more challenging G3/G4 differentiation were investigated. Regarding G3/G4 classification, the multimodal approach achieved a sensitivity of 73.8% and specificity of 88.1% while the baseline DP model showed a sensitivity and specificity of 54.1% and 84.7% respectively. The multimodal approach demonstrated a statistically significant 12.7% AUC advantage over the baseline with a value of 85.8% compared to 73.1%, also outperforming models based solely on RCI and mean and median Raman spectra. Feature fusion of DP and RCI does not improve the more trivial task of tumour identification but does deliver an observed advantage in G3/G4 discrimination. Building on these promising findings, future work could include the acquisition of larger datasets for enhanced model generalization.

Integrative analysis of mRNA and miRNA sequencing data for gliomas of various grades

BackgroundThe purpose of this study was to characterize subtype-specific patterns of mRNA and miRNA expression of gliomas using The Cancer Genome Atlas (TCGA) data to search for genetic determinants that predict prognosis in terms of overall survival and to create interaction networks for grade 2 and 3 (G2 and G3) astrocytomas, oligodendrogliomas and grade 4 (G4) glioblastoma multiforme. Based on open-access TCGA data, 5 groups were formed: astrocytoma G2 (n = 58), astrocytoma G3 (n = 128), oligodendroglioma G2 (n = 102), oligodendroglioma G3 (n = 72) and glioblastoma G4 (n = 564); normal samples of brain tissue were also analysed (n = 15). Data of patient age, sex, survival and expression patterns of mRNA and miRNA were extracted for each sample. After stratification of the data into groups, a differential analysis of expression was carried out, genes and miRNAs that affect overall survival were identified and gene set enrichment analysis (GSEA) and interaction analysis were performed.ResultsA total of 939 samples of glial tumours were analysed, for which subtype-specific expression profiles of genes and miRNAs were identified and networks of mRNA-miRNA interactions were constructed. Genes whose aberrant expression level was associated with survival were determined, and pairwise correlations between differential gene expression (DEG) and differential miRNA expression (DE miRNA) were calculated.ConclusionsThe developed panel of genes and miRNAs allowed us to differentiate glioma subtypes and evaluate prognosis in terms of the overall survival of patients. The regulatory miRNA-mRNA pairs unique to the five glioma subtypes identified in this study can stimulate the development of new therapeutic approaches based on subtype-specific mechanisms of oncogenesis.

Grade 4 Lymphopenia Induced by High Cardiac Radiation Exposure Predicted the Poor Prognosis in Left Non-Small Cell Lung Cancer Receiving Postoperative Radiotherapy

Aimed to investigate the correlation between grade 4 (G4) lymphopenia and cardiac dosimetric and the role of G4 lymphopenia in predicting prognosis in left non-small cell lung cancer (NSCLC) receiving postoperative radiotherapy (PORT). Between 2009 and 2018, the clinical characteristics and radiation parameters of patients with PORT for left NSCLC were reviewed retrospectively. Lymphopenia was graded according to the CTCAE 4.0. Absolute lymphocyte count (ALC) nadir < 0.2 × 103/ul was defined as grade 4 (G4) lymphopenia. Logistic regressions were performed to analyzed potential related factors of lymphopenia. The overall survival (OS) was measured from the date of RT started to the date of death from any cause or the follow-up date. Kaplan-Meier was performed to calculate survival, and log-rank test was used to compare survival between the G4 and non-G4 group. Two-sided p values < 0.05 were considered statistically significant. A total of 151 patients were reviewed in this study. The major patients were female (52.3%), age ≥ 60 (60.3%), former/current smoker (74.8%), lobectomy (79.5%), stage III (84.1%), postoperative chemotherapy (75.5%) and intensity-modulated radiotherapy (IMRT, 64.2%). The clinical characteristics (e.g. Cardiac disease, body mass index, baseline ALC) and radiation dosimetric (PTV dose, and Heart/Lung RT dosimetric) of G4 (18 pts., 11.9%) and non-G4 (133 pts., 88.1%) were well balanced. The median PTV dose was 60 Gy in G4, whereas it was 54 Gy in non-G4. However, the PTV of G4 was significantly larger than that of non-G4 (563.51 ± 276.07 vs. 395.86 ± 254.58, p = 0.005). Multivariate logistic regression indicated PTV volume (HR 1.00, p = 0.01), PTV dose (HR 1.08, p = 0.04), RT fraction size (HR 0.23, p = 0.02), and Heart V5 (HR 1.09, p = 0.03) were associated with G4 lymphopenia. The median survival time of the whole cohorts was 36.8 months, while it was 23.2 months in the G4 group and 37.5 months in the non-G4 group (p = 0.01). The 1- and 3-year survival in G4 were 77.8% and 33.3%, respectively, compared to 85.2% and 53.1%, respectively, in non-G4. Multivariate analysis revealed former/current smoker (HR 1.57, p = 0.04), postoperative chemotherapy (HR 0.58, p = 0.02) and G4 lymphopenia (HR 1.78, p = 0.04) were significant prognostic factors for OS. Grade 4 lymphopenia was common in left NSCLC patients with PORT and correlated with heart V5. Grade 4 lymphopenia could predict poor survival in this population.

Lymphopenia During Definitive Chemoradiotherapy in Esophageal Squamous Cell Carcinoma: Association with Dosimetric Parameters and Patient Outcomes

The objective of this study was to investigate the relationship between clinical characteristics, as well as dosimetric parameters, and the risk of treatment-related lymphopenia in esophageal squamous cell carcinoma (ESCC) treated with definitive chemoradiotherapy (CRT). Clinical characteristics and dosimetric parameters were collected from 436 patients with ESCC who received definitive CRT from 2010 through 2017. Absolute lymphocyte counts (ALCs) were obtained before, during, and 1 month after CRT. Grade 4 (G4) lymphopenia was defined as ALC <0.2 × 109 /L during CRT. Logistic regression analysis was used to evaluate the effect of each factor on predicting G4 lymphopenia. The relationship between lymphopenia and overall survival (OS) was examined, and a nomogram was developed to predict OS. G4 lymphopenia was observed in 103 patients (23.6%) during CRT. Multivariate analysis indicated that planning target volume (PTV), lung V10 , heart V10 , performance status, and pretreatment lymphopenia were significant risk factors for G4 lymphopenia. Patients with G4 lymphopenia had significantly worse survival than those without. Based on multivariate analysis, clinical TNM stage, radiotherapy modality, pretreatment ALC, and G4 lymphopenia were predictive of OS and were incorporated into the nomogram, yielding a concordance index of 0.71. G4 lymphopenia during definitive CRT was associated with larger PTVs, higher lung V10 and heart V10 , and worse survival. The purpose of this study was to investigate the relationship between clinical characteristics, as well as dosimetric parameters, and the risk of treatment-related lymphopenia in 436 patients with esophageal squamous cell carcinoma who received definitive chemoradiotherapy. Grade 4 (G4) lymphopenia was observed in 23.6% of patients during radiotherapy. G4 lymphopenia was associated with larger planning target volumes, higher lung V10 and heart V10 , and worse survival. Then, a nomogram was built based on multivariate analysis, yielding excellent performance to predict overall survival. Prospective studies are needed to investigate potential approaches for mitigating severe lymphopenia, which may ultimately convert into survival benefits.

Lymphopenia during radiotherapy in patients with oropharyngeal cancer

Purpose/ObjectiveRadiation-induced lymphopenia has been associated with poor survival outcomes in certain solid tumors such as esophageal, lung, cervical and pancreatic cancers. We aim to determine the effect of treatment-related lymphopenia during radiotherapy on outcomes of patients with oropharyngeal cancer. Materials/MethodsA retrospective analysis of all patients who completed definitive radiotherapy for oropharyngeal cancer at The University of Texas MD Anderson Cancer Center and had blood counts taken during radiotherapy from 2002 to 2013 were included. Patient, tumor and treatment characteristics, clinical outcomes and lymphocyte counts during radiotherapy were recorded. Lymphopenia was graded according to the CTCAE v4.0. Survival rates were estimated using the Kaplan-Meier method and compared with log-rank tests. Results850 patients were evaluated. The median age was 57 years. The majority of the cohort had p16/HPV-positive disease (71%), 8% had HPV-negative disease and 21% were unknown. The median radiation total dose was 70 Gy. 45% of patients had induction chemotherapy, and 87% had concurrent chemotherapy. 703 (83%) patients developed ≥grade 3 (G3) lymphopenia and 209 (25%) had grade 4 (G4) lymphopenia during radiotherapy. The median follow-up was 59 months; the 5-year overall survival rate was 81%. There were no significant differences in overall survival rates nor in disease control rates, in those who developed G3/G4 lymphopenia compared with those who did not. No significant effect of lymphopenia on survival was observed when analyzed according to p16/HPV status. ConclusionIn this large cohort of patients with oropharyngeal cancer, the development of lymphopenia during radiotherapy did not impact outcomes.

A phase II trial cohort of nivolumab plus ipilimumab in patients (Pts) with recurrent/metastatic adenoid cystic carcinoma (R/M ACC).

6084 Background: R/M ACC is a malignant neoplasm most commonly of salivary gland origin with no standard treatment. The impact of combined PD-1/CTLA-4 checkpoint blockade in R/M ACC is unknown. Methods: In a two-stage minimax phase II trial, pts with progressive R/M ACC (non-salivary primaries allowed) were enrolled and treated with nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks (1 cycle = 6 weeks). Imaging, using RECIST v1.1 response assessment, was scheduled to be performed approximately every 12 weeks. The primary endpoint was overall response rate (ORR = complete response [CR]+partial response [PR]) per RECIST v1.1. To detect a difference between an unacceptable ORR of 5% and a desirable ORR of 20% (one-sided type I error of 10%, power of 90%), at least 1 in the first 18 pts required an observed response. At least 4 responses of 32 total pts were needed to meet the primary endpoint. Treatment beyond progression of disease (PD) was allowed at the discretion of the investigator. A second cohort of pts with non-ACC salivary cancer is still accruing for separate analysis. Results: From 6/12/2017-6/20/2018, 32 pts were enrolled and evaluable for the primary endpoint. There was 1 confirmed PR in the first 18 pts, therefore enrollment of the second stage continued. ORR was 6% (2/32). One additional pt had an unconfirmed PR (-31% regression before CNS PD). For best overall response, there were 2 PRs, 15 SD, and 11 PD. Four pts never reached a first disease assessment: 3 due to death from clinical PD and 1 was removed for toxicity. Six pts discontinued the trial for toxicities (Grade 4 (G4) neutropenia/sepsis and G3 adrenal insufficiency (1), G2 hypophysitis (2), G3 arthritis &gt; 7 days (1), G3 colitis (1), and G3 hepatitis/G4 creatinine kinase (CK) elevation (1)). The 2 confirmed PRs consisted of -73.1% and -58.4% regressions, with a duration of therapy of 18.4 and 7.8 months, respectively (treatment ongoing for both). Conclusions: The study did not meet its primary endpoint, though the responses observed were dramatic. Paired biopsy and peripheral blood samples will be analyzed to elucidate insights into mechanisms of response and resistance to dual checkpoint blockade. Clinical trial information: NCT03172624.

Lymphopenia During Radiation Therapy In Patients with Oropharyngeal Cancer: Does It Affect Survival Outcomes?

Radiation-induced lymphopenia have been associated with poor survival outcomes in certain solid tumors such as breast, colorectal, lung, cervical and pancreatic cancers. We aim to determine the effect of treatment-related lymphopenia during radiotherapy on outcomes of patients with oropharyngeal cancer. A retrospective analysis of patients who completed definitive radiotherapy for oropharyngeal cancer and had blood counts taken during radiotherapy from 2002 to 2013 were included. Patient, tumor and treatment characteristics, clinical outcomes and lymphocyte counts during radiotherapy were recorded. Lymphopenia was graded according to the CTCAE v4.0. Survival rates were estimated using the Kaplan-Meier method and compared with log-rank tests. A total of 850 patients were evaluated. The median age was 57 years. The most common primary sites were base of tongue (55%) and tonsil (43%). The majority of the cohort had p16/HPV-positive disease (71%), 8% had HPV-negative disease and 21% were unknown. The median radiation total dose was 70 Gy. A total of 45% of patients had induction chemotherapy, and 87% had concurrent chemotherapy. A total of 703 (83%) patients developed ≥grade 3 (G3) lymphopenia and 209 (25%) had grade 4 (G4) lymphopenia during radiotherapy. The median follow-up was 59 months; the 5-year overall survival rate was 81%. There were no significant differences in overall survival rates nor in disease control rates, in those who developed G3/G4 lymphopenia compared with those who did not. No significant effect of lymphopenia on survival was observed when analyzed according to p16/HPV status. In this large cohort of patients with oropharyngeal cancer, the development of lymphopenia during radiotherapy did not impact outcomes.

Chemotherapy-Induced Neutropenia and Outcome in Patients With Metastatic Castration-Resistant Prostate Cancer Treated With First-Line Docetaxel.

Neutropenia is a common side effect associated with docetaxel use. We retrospectively investigated the association between chemotherapy-induced neutropenia and survival in metastatic castration-resistant prostate cancer (mCRPC) patients receiving first-line docetaxel. Metastatic castration-resistant prostate cancer patients treated with first-line docetaxel, with known neutrophils value 10 days after first administration, were included in this retrospective analysis. Neutropenia was categorized in Grade 0 to 1 (G0-1), Grade 2 to 3 (G2-3), and Grade 4 (G4). Outcome measures were progression-free survival (PFS) and overall survival (OS). Eighty patients were analyzed. Median PFS was 5.4 months in patients with G0-1 neutropenia, 6.9 months with G2-3 neutropenia (hazard ratio [HR] vs. G0-1, 0.69; 95% confidence interval [CI], 0.35-1.35; P= .27) and 9.5 months with G4 neutropenia (HR vs. G0-1, 0.30; 95% CI, 0.16-0.57; P< .0001). Median OS was 11.6 months in patients with G0-1 neutropenia, 25.5 months in patients with G2-3 neutropenia (HR vs. G0-1, 0.36; 95% CI, 0.16-0.80; P= .012) and 39.3 months in patients with G4 neutropenia (HR vs. G0-1, 0.19; 95% CI, 0.09-0.41; P<.0001). In multivariate analysis, the occurrence of severe neutropenia showed a statistically significant association with OS (HR G4 vs. G0-1, 0.14; 95% CI, 0.03-0.67; P= .013; HR G2-3 vs. G0-1, 0.42; 95% CI, 0.11-1.57; P=.20) and PFS (HR G4 vs. G0-1, 0.28; 95% CI, 0.09-0.86; P= .03; HR G2-3 vs. G0-1, 1.07; 95% CI, 0.38-2.96; P= .90). Docetaxel-induced neutropenia is associated with better survival of mCRPC.

Phase I study of intraperitoneal paclitaxel combined with S-1 plus cisplatin for gastric cancer with peritoneal metastasis.

115 Background: Intraperitoneal (IP) chemotherapy is a promising treatment option for gastric cancer (GC) with peritoneal metastasis (PM). Efficacy of IP paclitaxel (PTX) combined with S-1 and intravenous PTX was reported in a phase II study. Attempts to combine IP PTX with other systemic therapies with higher efficacy are warranted. We designed a new regimen combining IP PTX with S-1/cisplatin (SP) which is regarded as the standard first-line treatment of metastatic GC in Japan. We subsequently carried out a dose-escalation study to determine the maximum-tolerated dose (MTD) and recommended dose (RD). Methods: The combination was a five-week regimen. IP PTX was to be administered on days 1, 8 and 22 with an initial dose of 15 mg/m2 at level 1 and 20 mg/m2 at level 2. S-1 was to be administered orally at a fixed dose of 80 mg/m2 bid for 21 days followed by a 14-day rest. Cisplatin was to be administered intravenously at a dose of 60 mg/m2 on day 8, and was to be decreased to 50 mg/m2 (level 0) if necessary. Since the dosage of S-1 at the fixed dose and cisplatin at level 1 were identical to SP regimen, no further dose-escalation was planned. Dose-limiting toxicities (DLTs) were defined as Grade 4 (G4) leukopenia, G3 febrile neutropenia, G3 thrombocytopenia, and G3 non-hematological toxicity. The MTD was defined as the dose level at which ≥2 of 3 or 6 patients developed DLTs during the first course of treatment. The RD was defined as one level below the MTD. Results: A total of 9 patients with macroscopic PM were enrolled. No DLTs were observed among the 3 patients at level 1 and 6 patients at level 2. Furthermore, no G3 toxicities were observed in any of the patients enrolled. Anemia in 1 patient at level 2 was the only G2 toxicity observed. No adverse events or technical problems associated with the IP administration were observed. Consequently, the MTD was not reached, and the RD of IP PTX was determined as 20 mg/m2 (level 2). As for the efficacy, peritoneal lavage cytology turned negative after the first course in 4 of 7 patients who had positive cytology before treatment. Conclusions: Addition of IP PTX at 20 mg/m2 to the SP regimen at an established dose/schedule was safe and promising, and further evaluation in a phase II trial is underway. Clinical trial information: UMIN000013528.

Porphyromonas gingivalis biofilm formation in different titanium surfaces, an invitro study.

The aim of this work was to evaluate the biofilm formation of Porphyromonas gingivalis on disks of titanium (Ti) grade 4 (G4) and Ti-6Al-4V alloy grade 5 (G5) with different surface topographies. Porphyromonas gingivalis ATCC 33277 was used to develop an invitro mature biofilm on a total of 96 disk-shaped specimens of laser-treated (L), sandblasted (S), and machined (M) surfaces of Ti G4 and Ti G5. Surface roughness (Ra) and the wettability contact angle (WCA) were measured to characterize the surface of the specimens. The bacterial biofilm was evaluated by biomass quantification, bacterial viability, visualization of the biofilm extracellular matrix, and bacterial cell count. Data were analyzed using one-way ANOVA and Holm-Sidak tests and expressed as mean±standard deviation. The Ra for the L group was 0.10 (±0.07) μm inside the craters and 0.40 (±0.08) μm in the area surrounding the craters resulting the smoothest (P<0.05) in respect to the S group (1.30±0.61μm) and the M group (0.75±0.23μm). The L group showed a higher WCA than S and M groups for both G4 (109.9°±6.6) and G5 (104.2°±5.9) materials (P<0.05). The L group displayed both the less P.gingivalis bacterial biomass (0.38±0.01 for G4; 0.62±0.02 for G5) that was significant in respect to G4-S (P<0.001), G4-M (P<0.001), and G5-M (P=0.001) and the less total cell number (215±18 for G4 and 244±9 for G5) than S and M groups for both G4 and G5 materials (P<0.01). Within the limits of the present study, the results showed that G4-L appears to be significantly efficient in the reduction of the P.gingivalis biofilm formation.

Not all gleason pattern 4 prostate cancers are created equal: A study of latent prostatic carcinomas in a cystoprostatectomy and autopsy series.

The Gleason grading system represents the cornerstone of the management of prostate cancer. Gleason grade 4 (G4) is a heterogeneous set of architectural patterns, each of which may reflect a distinct prognostic value. We determined the prevalence of the various G4 architectural patterns and intraductal carcinoma (IDC) in latent prostate cancer in contemporary Russian (n = 220) and Japanese (n = 100) autopsy prostates and in cystoprostatectomy (CP) specimens (n = 248) collected in Italy. We studied the association of each G4 pattern with extraprostatic extension (EPE) and tumor volume to gain insight into their natural history. Presence of IDC and nine architectural features of Gleason grade 4 and 5 cancer were recorded. The prevalence of Gleason score ≥ 7 PC was higher in the autopsy series (11%) compared to the CP series (6.5%, P = 0.04). The prevalence of IDC and carcinoma with a cribriform architecture was 2.2% and 3.4% in the autopsy series and 0.8% and 3.6% in the cystoprostatectomy series, respectively. In multivariable analysis, cribriform architecture was significantly associated with increased tumor volume (P < 0.001) and EPE (OR:11.48, 95%CI:2.30-57.16, P = 0.003). IDC was also significantly associated with EPE (OR:10.08, 95%CI:1.58-64.28, P = 0.014). Small fused glands had a strong negative association with EPE in the autopsy series (OR:0.06, 95%CI:0.01-0.58, P = 0.015). Our study revealed that in latent prostate cancer both cribriform architecture and IDC are uniquely associated with poor pathological outcome features. In contrast, Gleason score 7 (3 + 4) cancers with small-fused gland pattern might possibly include some prostate cancers with a more indolent biology.