27-gene Immuno-Oncology (IO) Score is Associated With Efficacy of Checkpoint Immunotherapy in Advanced NSCLC: A Retrospective BC Cancer Study

BackgroundImmune checkpoint inhibitors (ICI) are standard of care in advanced non-small cell lung cancer (NSCLC). However, not all patients benefit, even among PD-L1 tumor proportional score (TPS) ≥50%, indicating an unmet need for additional biomarkers such as those assessing the tumor immune microenvironment (TIME). DetermaIO is a 27-gene assay that classifies TIME and has previously demonstrated association with ICI response.MethodsFFPE samples were selected from BC Cancer and West Clinic Cancer Center patients with performance status (PS) ≤2 who received at least 2 cycles of ICI monotherapy in the first (1L) or second line (2L). IO scores were generated and analyzed for association with PFS and OS.ResultsIn the entire cohort (N=147), IO score was significantly associated with OS (HR=0.68, 95%CI 0.47-0.99, P = .042) and PFS (HR=0.62, 95%CI 0.43-0.88, P = .0069). In 1L treated patients (PD-L1≥50%, N=78), IO score was significantly associated with PFS (HR=0.55, 95%CI 0.32-0.94, P = .028). In exploratory analyses, IO score was associated with benefit in 1L PS2 patients for OS (HR = 0.26, 95%CI 0.091-0.74, P = .012) and PFS (HR = 0.27, 95%CI 0.098-0.72, P = .0095) which was confirmed in PFS subgroup analysis in the independent West Cancer Center study (N=13 HR=0.14, 95%CI 0.027-0.76, P = .023).ConclusionThese data confirm the association of DetermaIO with ICI clinical benefit in NSCLC, and expand on previous studies by demonstrating that first line treated PD-L1≥50% patients can further be stratified by IO score to identify efficacy. Exploratory analysis suggested that the IO score identifies benefit in patients with poor PS.     

Comparison of Immediate Breast Reconstruction Outcomes in Patients With and Without Prior Cosmetic Breast Surgery

BackgroundSkin-sparing (SSM) and nipple-sparing mastectomy (NSM) with immediate breast reconstruction (IBR) have significantly increased. There is limited information on complications of IBR in patients with prior cosmetic breast surgery (CBS). We compare IBR outcomes in patients undergoing SSM and/or NSM with and without prior CBS.Materials and MethodsPatients undergoing mastectomy from January 1, 2017 to December 31, 2019 were selected. Patient characteristics, surgical approach, and complications were compared between mastectomy and IBR cases for breasts with and without prior CBS. Binary logistic regression analysis was performed to identify predictors of complications and reconstruction loss.Results956 mastectomies were performed in 697 patients, with IBR performed for 545 mastectomies in 356 patients. Median age was 51 (range 19-83), 45.8% of patients were age < 50, 62.6% of mastectomies were performed for breast cancer. 95 mastectomies (17.4%) were performed in breasts with prior CBS and 450 (82.6%) without. NSM was more frequently utilized for breasts with prior CBS (P < .001). Complications occurred in 80 mastectomies (14.7%); reconstruction loss in 30 (5.5%). On multivariable analysis, age ≥ 50 (OR 1.76, 95%CI 1.01-3.09, P = .047) and NSM (OR 2.11, 95%CI 1.17-3.79, P = .013) were associated with an increased risk of any complication. Prior CBS was not associated with an increased risk of complications (OR 1.11, 95%CI 0.58-2.14, P = .743) or reconstruction loss (OR 1.32, 95%CI 0.51-3.38, P = .567).ConclusionIn this analysis of mastectomy and IBR, prior CBS was not associated with an increased risk of complications or reconstruction loss. In patients with prior CBS undergoing mastectomy, IBR may be safely performed.     

The Treatment Landscape of Myelofibrosis Before and After Ruxolitinib Approval

Introduction/BackgroundMyelofibrosis (MF) is a chronic myeloproliferative neoplasm that presents with a heterogeneous clinical phenotype and prognosis. Before the US Food and Drug Administration approval of ruxolitinib, treatment options were varied and had limited effect. The increased use of ruxolitinib has drastically altered the MF treatment landscape. In this study, we aimed to clarify the clinical situations in which ruxolitinib is being used and analyze its effect on this landscape.Patients and MethodsWe retrospectively assessed treatment choices for MF patients treated at our institution (n = 309). This population was divided into 2 cohorts on the basis of a diagnosis before (cohort BR: n = 174) or after (cohort AR: n = 135) ruxolitinib approval. Cohorts were further stratified for comparison according to presenting clinical factors.ResultsExpectedly, the first-line use of ruxolitinib markedly increased after its approval. AR patients were less likely to receive erythropoiesis-stimulating agents (ESAs; P = .0003) and thalidomide (P = .003) than BR patients. In patients with MF-related symptoms and/or splenomegaly, increased use of ruxolitinib was associated with decreased use of first-line ESA (P = .03) or thalidomide (P = .03). In anemic patients, increased use of first-line ruxolitinib was associated with a decreased use of thalidomide (P = .007). In patients with severe leukocytosis, ruxolitinib use did not significantly increase and hydroxyurea was the preferred first-line agent.ConclusionOverall, the increased use of ruxolitinib appears to have come predominantly at the expense of thalidomide and ESAs, while not having a large effect on the first-line use of hydroxyurea.     

Age-related differences in symptom distress among patients with cancer

IntroductionDifferences in symptom distress among older (age 65–74) and very old (age 75+) patients with cancer, compared to younger patients, remain to be well explored. These differences are important to understand given the heterogeneity of older populations and may have implications for age-appropriate symptom detection and management.Materials and MethodsWe examined routinely collected Edmonton Symptom Assessment System Revised (ESAS-r) scores from 9,143 patients age 40+ initiating chemotherapy for solid malignancies at a single academic cancer centre, between September 2011 and May 2019. We used multivariable logistic regression models to determine associations between the most common symptoms and age group (ages 40–64, 65–74, 75–84, and 85+), cancer site, clinical stage, sex, and income levels. We focused our findings on patients with the five most common cancers, breast (n = 1,532), prostate (n = 923), lung (n = 889), pancreatic (n = 429), and colorectal (n = 368), prior to receiving treatment.ResultsWithin our sample, 58.0% were age 40–64, 27.3% age 65–74, 11.8% age 75–84, and 2.9% age 85+. Among the nine symptoms in the ESAS-r (anxiety, depression, tiredness, wellbeing, nausea, pain, drowsiness, appetite, and shortness of breath), the most common symptoms overall were anxiety (moderate-severe scores [ESAS-r 4 or higher] were reported by 33.8% of patients), lack of well-being (38.3%), and tiredness (38.3%). Older age was associated with lower odds of moderate/severe anxiety (odds ratio [OR] 0.81, 95% confidence interval [CI] 0.73–0.90 for age 65–74; OR 0.81, 95%CI 0.70–0.93 for age 75–84; OR 0.62, 95%CI 0.47–0.82 for age 85+; referent is 40–64-year-olds for all analyses), and increased odds of tiredness (OR 1.00, 95%CI 0.90–1.11 for age 65–74; OR 1.19, 95%CI 1.04–1.37 for age 75–84; and OR 1.34, 95%CI 1.04–1.72 for age 85+). Advanced stage, female sex, and lower income levels were associated with higher odds of moderate/severe tiredness, anxiety, and lack of well-being in adjusted models. Patients with pancreatic and lung cancers reported worse scores for these three symptoms than patients with other cancers.DiscussionOlder age was associated with differences in symptom experiences such as increased tiredness and reduced anxiety. Supportive care interventions and future research should focus on addressing these symptoms to improve patient quality of life.     

Frailty assessment can predict textbook outcomes in senior adults after minimally invasive colorectal cancer surgery

AimColorectal cancer (CRC) surgery can be associated with suboptimal outcomes in older patients. The aim was to identify the correlation between frailty and surgical variables with the achievement of Textbook Outcome (TO), a composite measure of the ideal postoperative course, by older patients with CRC.MethodAll consecutive patients ≥70years who underwent elective CRC-surgery between January 2017 and November 2021 were analyzed from a prospective database. To obtain a TO, all the following must be achieved: 90-day survival, Clavien-Dindo (CD) < 3, no reintervention, no readmission, no discharge to rehabilitation facility, no changes in the living situation and length of stay (LOS) ≤5days/≤14days for colon and rectal surgery respectively. Frailty and surgical variables were related to the achievement of TO.ResultsFour-hundred-twenty-one consecutive patients had surgery (97.7% minimally invasive), 24.9% for rectal cancer, median age 80 years (range 70–92), median LOS of 4 days (range 1–96). Overall, 288/421 patients (68.4%) achieved a TO. CD 3–4 complications rate was 6.4%, 90-day mortality rate was 2.9%.At univariate analysis, frailty and surgical variables (ileostomy creation, p = 0.045) were related to. However, multivariate analysis showed that only frailty measures such as flemish Triage Risk Screening Tool≥2 (OR 1.97, 95%CI: 1.23–3.16; p = 0.005); Charlson Index>6 (OR 1.61, 95%CI: 1.03–2.51; p = 0.036) or Timed-Up-and-Go>20 s (OR 2.06, 95%CI: 1.01–4.19; p = 0.048) independently predicted an increased risk of not achieving a TO.ConclusionThe association between frailty and comprehensive surgical outcomes offers objective data for guiding family counseling, managing expectations and discussing the possible loss of independence with patients and caregivers.     

Safety and Efficacy of Ruxolitinib in Patients with Myelofibrosis and Low Platelet Counts (50 – 100 × 109/L): Final Analysis of an Open-Label Phase 2 Study

IntroductionTreatment options in patients with myelofibrosis (MF) presenting with thrombocytopenia are limited. Final results of the phase 2 study (NCT01348490) of ruxolitinib in patients with MF and low baseline platelet counts (50 – 100 × 10⁹/L) are reported.Patients and MethodsPatients received ruxolitinib 5 mg twice daily (BID), with optional up-titration to a maximum of 15 mg BID, provided platelet count remained ≥40 × 10⁹/L. Assessments included spleen volume and length, Total Symptom Score (TSS), quality of life, and safety.ResultsOf 66 patients, 52 (78.8%) completed the first 24 weeks of treatment. Median (range) percentage change from baseline in spleen volume and TSS (coprimary endpoints) were −20.5% (−55.8% to 38.5%, n=51) and −39.8% (−98.6% to 226.4%, n=53), respectively; greatest median reductions were in the 10 mg BID final titrated dose group. Of patients achieving ≥35% or ≥10% reduction in spleen volume, 8/11 (72.7%) and 21/34 (61.8%), respectively, were in the 10 mg BID final titrated dose group. Thirty-seven of 65 patients (56.9%) had ≥20% improvement in TSS, and 35/66 patients (53.0%) were Patient Global Impression of Change responders. Treatment-emergent adverse events led to dose interruption in 17/66 patients (25.8%), most commonly thrombocytopenia (n=3).ConclusionA starting dose of ruxolitinib 5 mg BID with gradual up-titration and dose optimization based on hematologic parameters and response was efficacious and generally well-tolerated in patients with MF and low platelet counts. Median improvement in spleen volume and symptoms was greatest for patients receiving ruxolitinib 10 mg BID.     

Tumor-Infiltrating PD-1+ Immune Cell Density is Associated with Response to Neoadjuvant Chemoradiotherapy in Rectal Cancer

BackgroundElevated tumor-infiltrating T-cell density is associated with favorable outcomes in patients with rectal cancer treated with neoadjuvant chemoradiotherapy (CRT). Here, we evaluated the significance of programmed cell death 1 (PD-1)-positive cells, regulatory T cells, and macrophages in response to CRT and prognosis.Patients and MethodsWe assessed CD8+, PD-1+, FOXP3+, CD68+, and CD163+ intratumoral and stromal cell densities by immunohistochemistry using pre-treatment biopsies from 275 patients with rectal cancer treated with neoadjuvant CRT. We determined the impact of these measurements on response to CRT and survival. Response to CRT was determined by tumor regression grade (TRG) of surgical specimens, with good responders defined as TRG3-4.ResultsIntratumoral CD8+ and PD-1+ cell densities were significantly higher in good responders than in poor responders, whereas stromal CD68+ cell density was significantly lower in good responders as compared with poor responders. The multivariable analysis revealed high intratumoral CD8+ and PD-1+ cell densities to be independently associated with good responders (CD8: odds ratio [OR], 2.27; 95% confidence interval [CI], 1.21 – 4.34, P = .010; PD-1: OR, 1.97; 95%CI, 1.03 – 3.84, P = .039), and improved recurrence-free survival (CD8: hazard ratio [HR], 0.56; 95%CI, 0.32 – 0.98, P = .044; PD-1: HR, 0.37; 95%CI, 0.19 – 0.71, P = .002). Only high intratumoral CD8+ cell density was associated with improved overall survival (P = .022).ConclusionPre-treatment high intratumoral PD-1+ and CD8+ cell densities were independently associated with good response to CRT and improved recurrence-free survival, with high intratumoral CD8+ cell density additionally associated with improved overall survival. These values may serve as predictive and prognostic biomarkers in rectal cancer.     

Retrospective Study to Examine Prognostic Value of C-Reactive Protein in Patients With Surgically Resectable Non-Small-Cell Lung Cancer

BackgroundThis study evaluated the association between elevated C-reactive protein (CRP) and clinical outcomes among adults treated with surgery for non-small cell lung cancer (NSCLC) in the US.Materials and MethodsAdults with NSCLC who underwent lung cancer surgery and had ≥1 CRP measurement prior to, or >1 month following, index surgery were identified in the Optum Clinformatics claims database. The association between elevated CRP (>10 mg/L) and risk of NSCLC recurrence/death was assessed separately during the 6 months before surgery (pre surgery cohort) and 2 years following surgery (post-surgery cohort) using multivariate regressions and Kaplan-Meier analysis.ResultsAfter adjusting for baseline demographic and clinical characteristics among patients in the pre surgery cohort with index surgery between 2016 to 2020 (n = 104), the incidence rate ratio (IRR) for NSCLC recurrence between elevated vs. non-elevated CRP was 2.17 (95% confidence interval [CI]=1.03-4.60; P = .04). In the post surgery cohort (n = 264), the adjusted IRR for disease recurrence (elevated vs. non-elevated CRP) was 2.22 (95% CI=1.05-4.70; P = .04). In the pre surgery cohort, the odds of death were nearly two-fold (odds ratio [OR]=1.91; 95% CI=1.06-3.42; P = .03) among patients with elevated CRP. In the post surgery cohort, the OR was 1.62 (95% CI=0.88-2.97; P = .12). Among those with persistently elevated CRP prior to surgery, there was a significant overall trend of increased CRP over the 5-year period.ConclusionThese results support the association between elevated CRP and a higher risk of NSCLC recurrence/death in pre- and postsurgery cohorts. This study may shed lights on inflammation-suppressing treatments in patients with NSCLC.     

Phase 1/2 Study of the Pan-PIM Kinase Inhibitor INCB053914 Alone or in Combination With Standard-of-Care Agents in Patients With Advanced Hematologic Malignancies

BackgroundThe Proviral Integration site of Moloney murine leukemia virus (PIM) kinases are implicated in tumorigenesis; the pan-PIM kinase inhibitor, INCB053914, demonstrated antitumor activity in hematologic malignancy preclinical models.Patients and MethodsThis phase 1/2 study evaluated oral INCB053914 alone or combined with standard-of-care agents for advanced hematologic malignancies (NCT02587598). In Parts 1/2 (monotherapy), patients (≥18 years) had acute leukemia, high-risk myelodysplastic syndrome (MDS), MDS/myeloproliferative neoplasm, myelofibrosis (MF), multiple myeloma, or lymphoproliferative neoplasms. In Parts 3/4 (combination therapy), patients had relapsed/refractory or newly diagnosed (≥65 years, unfit for intensive chemotherapy) acute myeloid leukemia (AML) or MF with suboptimal ruxolitinib response.ResultsParts 1/2 (n = 58): 6 patients experienced dose-limiting toxicities (DLTs), most commonly aspartate aminotransferase/alanine aminotransferase-elevated (AST/ALT; each n = 4). Fifty-seven patients (98.3%) had treatment-emergent adverse events (TEAEs), most commonly ALT-elevated and fatigue (36.2% each); 48 (82.8%) had grade ≥3 TEAEs, most commonly anemia (31.0%); 8 (13.8%) had grade ≥3 ALT/AST-elevated TEAEs. Parts 3/4 (n = 39): for INCB053914 + cytarabine (AML; n = 6), 2 patients experienced DLTs (grade 3 maculopapular rash, n = 1; grade 3 ALT-elevated and grade 4 hypophosphatemia, n = 1); for INCB053914 + azacitidine (AML; n = 16), 1 patient experienced a DLT (grade 3 maculopapular rash). Two complete responses were observed (1 with incomplete count recovery). For INCB053914 + ruxolitinib (MF; n = 17), no DLTs occurred; 3 patients achieved best reduction of >25% spleen volume at week 12 or 24.ConclusionINCB053914 was generally well tolerated as monotherapy and in combinations; TEAEs were most commonly ALT/AST-elevated. Limited responses were observed with combinations. Future studies are needed to identify rational, effective combination strategies.     

Tumour grade and stage are associated with specific body composition phenotypes with visceral obesity predisposing the host to a less aggressive tumour in colorectal cancer

BackgroundSarcopenia, myosteatosis and visceral obesity (VO) are known to negatively impact on outcomes from colorectal cancer (CRC). Little is known about tumour factors associated with these body composition (BC) phenotypes. We aimed to identify whether histopathological tumour characteristics were associated with various BC phenotypes.MethodsA prospectively collected database of patients undergoing surgery for primary CRC at a tertiary referral unit in the United Kingdom was analysed. Sarcopenia, myosteatosis and VO were identified on preoperative CT. Binary logistic regression modelling was performed to determine significant associations between tumour stage, grade and BC phenotype.ResultsFinal analysis included 795 patients; median age 69, 56% male, 65% were sarcopenic, 72% myosteatotic, 52% VO and 20% had sarcopenic obesity (SO). VO patients were significantly less likely to have advanced T Stage (T3-4) OR0.62(95%CI 0.44–0.86, p = 0.005); nodal metastases OR0.60(95%CI 0.44–0.82, p = 0.001); vascular invasion OR0.63(95%CI 0.46–0.88, p = 0.006) and poor tumour differentiation OR0.49(95%CI 0.28–0.86, p = 0.012). Myosteatotic patients were more likely to have metastatic disease OR2.31(95%CI 1.15–4.63, p = 0.018) but less likely to have poorly differentiated tumours OR0.48(95%CI 0.27–0.86, p = 0.013). SO patients were significantly more likely to have poorly differentiated tumours OR2.01(95%CI 1.04–3.87, p = 0.037).ConclusionVO predisposes to earlier stage tumours with a less aggressive tumour phenotype. The SO group have adverse tumour characteristics which may be explained by differences in fat distribution. Myosteatosis relates to increased likelihood of distant metastasis that may be related to a systemic inflammatory response, despite the association with better differentiated tumours.     

Practical Measures of Clinical Benefit With Ruxolitinib Therapy: An Exploratory Analysis of COMFORT-I

BackgroundThe phase III COMFORT (Controlled Myelofibrosis Study With Oral JAK inhibitor Treatment)-I and COMFORT-II trials in patients with intermediate-2 or high-risk myelofibrosis (MF) showed that ruxolitinib was superior to placebo and best available therapy, respectively, for improvements in spleen volume, MF-related symptoms, and overall survival (OS). However, patients managed in community settings might not have access to the methods used in the COMFORT trials. In this exploratory analysis we summarize efficacy findings of COMFORT-I using practical, community-oriented measures of patient outcomes.Patients and MethodsIn this post hoc analysis of data from COMFORT-I we evaluated changes from baseline to week 12 in spleen size (palpable length and volume), patient-reported outcomes (Patient Global Impression of Change; Myelofibrosis Symptom Assessment Form; Patient-Reported Outcomes Measurement System Fatigue Scale), body weight, and serum albumin levels in 5 subgroups of ruxolitinib-treated patients on the basis of week 12 spleen length changes from baseline: (1-4) ≥ 50%, 25% to < 50%, 10% to < 25%, or < 10% reduction; and (5) worsening. OS was evaluated in ruxolitinib-treated patients with week 12 spleen length reductions from baseline ≥ 50%, 25% to < 50%, or < 25% (including worsening).ResultsIn all spleen length subgroups, including patients with worsening spleen length at week 12, ruxolitinib (n = 150) was associated with improvements in spleen volume, patient-reported symptom burden, body weight, and serum albumin levels. Greater reductions in spleen length were associated with prolonged OS.ConclusionA variety of assessment methods beyond palpable spleen length that are easily accessible in the community setting might be useful in evaluating the clinical benefit of ruxolitinib over time in patients with MF.     

Comparing the performance of the CARG and the CRASH score for predicting toxicity in older patients with cancer

ObjectivesTo compare the CARG (Cancer and Aging Research Group) and CRASH (Chemotherapy Risk Assessment Scale for High-Age Patients) score regarding the predictive performance for severe toxicity in older patients with cancer.MethodsWe recruited patients ≥70 years and applied the CARG and CRASH score before the start of systemic cancer treatment. The CARG predicts severe overall toxicity; the CRASH additionally predicts hematologic and nonhematologic toxicity. We captured ≥ grade 3 toxicity according to Common Terminology Criteria for Adverse Events (CTCAE) from medical records. Predictive performance was assessed using logistic regression and the area under the receiver operating characteristic curve (ROC-AUC).ResultsThe study cohort comprised 120 patients (50% female, mean age 77.2 years, 57% solid tumors). The median of the CARG (range 0–23) and the combined CRASH (range 0–12) were 9 and 8, respectively. 81% of patients experienced toxicity; 67% showed hematologic toxicity. The predictive performance of the CARG and the combined CRASH was similar for overall toxicity (CARG: Odds ratio per unit increase (OR) 1.266, P = .015; ROC-AUC 0.681, P = .010; combined CRASH: OR 1.337, P = .029; ROC-AUC 0.650, P = .032). For hematologic toxicity, the hematologic CRASH was a significant predictor and showed numerically a higher ROC-AUC than the CARG which was not statistically different (CARG: OR 1.048, P = .462; ROC-AUC 0.564, P = .271; hematologic CRASH: OR 1.602, P = .007; ROC-AUC 0.665, P = .005).ConclusionBoth scores exhibited similar predictive performance for toxicity in older patients with cancer.     

Development of a predictive score of axillary lymph node dissection based on targeted axillary dissection in patients with breast cancer diagnosis,affected lymph nodes,and neoadjuvant treatment

AimTo determine predictive factors of axillary lymph node dissection (ALND) results in breast cancer (BC) patients undergoing neoadjuvant chemotherapy (NACT), and subsequent staging using Targeted Axillary Dissection (TAD).Material and methodCase-control study between January 2016 and August 2019. Patients with BC, cN1 staging, marked with a metallic clip prior to NACT, and subsequently staged with TAD and ALND were included. They were divided into 2 groups: ALND patients with or without metastatic involvement (group 1 and group 2, respectively). We carried out a univariate analysis comparing clinical, radiological, surgical and pathological variables, and a logistic regression, (dependent variable: positive result of ALND; independent variables: number of suspicious lymph nodes in diagnostic ultrasound, positive hormone receptors, HER2 positive, complete clinical-radiological response to NACT, positive TAD, and biopsy of ≤2 nodes in TAD). A score for prediction of a metastatic ALND was proposed, with an internal validation study.Results60 patients were included: Group 1: 33 (55.0%); Group 2: 27 (45.0%). Tumor size (Odds Ratio (OR) = 1.67; 95%CI 1.02–2.74), number of suspected nodes in ultrasound (OR = 2.20; 95%CI 1.01–4, 77), HER2 positive (OR 0.04; 95%CI 0.003–0.54), clinical-radiological response to NACT (OR = 0.07; 95%CI 0.01–0.75), and positive TAD (OR 15.48; 95%CI 1.68–142.78) were independent predictors of a positive result in ALND. We developed a “positive ALND predictive score”, with good calibration (Hosmer-Lemeshow test: p = 0.65), and discrimination (AUC = 0.93; 95% CI 0, 87–0.99), with highest Youden index (0.7) at cut-off point of 17% risk of positive ALND (sensitivity = 100%; specificity = 70%).ConclusionTumor size, number of suspected nodes, positive HER2, response to NACT, and metastatic TAD are independent predictors of ALND. The predictive score for positive ALND would be a good indicator to safely omit ALND.     

Neoadjuvant Androgen Deprivation Therapy for Prostate Volume Reduction,Lower Urinary Tract Symptom Relief and Quality of Life Improvement in Men with Intermediate- to High-risk Prostate Cancer: A Randomised Non-inferiority Trial of Degarelix versus Goserelin plus Bicalutamide

AimsThe treatment of intermediate- to high-risk prostate cancer with radical radiotherapy is usually in combination with neoadjuvant androgen deprivation therapy. The aim of the present trial was to investigate whether degarelix achieves comparable efficacy with that of goserelin plus bicalutamide as neoadjuvant therapy before radiotherapy.Materials and methodsThe study was a randomised, parallel-arm, active-controlled, open-label trial in 244 men with a UICC prostate cancer TNM category T2b–T4, N0, M0, Gleason score ≥7, or prostate-specific antigen ≥10 ng/ml and a total prostate volume >30 ml, who were scheduled to undergo radical radiotherapy and in whom neoadjuvant androgen deprivation therapy was indicated. Eligible patients received treatment with either monthly degarelix (240/80 mg) or goserelin (3.6 mg) for 12 weeks, the latter patients also receiving bicalutamide (50 mg) for 17 days initially. The primary efficacy measure was the mean percentage reduction in total prostate volume from baseline at week 12 measured by transrectal ultrasound. The severity and relief of lower urinary tract symptoms were assessed by the International Prostate Symptom Score questionnaire. Quality of life was assessed by the eighth question of the International Prostate Symptom Score. About 50% of the patients had moderate to severe lower urinary tract symptoms at baseline.ResultsThe total prostate volume decreased significantly from baseline to week 12 in both treatment groups, reaching ?36.0 ± 14.5% in degarelix-treated patients and ?35.3 ± 16.7% in goserelin-treated patients (adjusted difference: ?0.3%; 95% confidence interval: ?4.74; 4.14%). At the end of the therapy, more degarelix- than goserelin-treated patients reported International Prostate Symptom Score decreases of ≥3 points (37% versus 27%, P = 0.21). In addition, in patients with a baseline International Prostate Symptom Score of ≥13, the magnitude of the decrease was larger in degarelix- (n = 53) versus goserelin-treated patients (n = 17) (6.04 versus 3.41, P = 0.06).ConclusionsThe efficacy of degarelix in terms of prostate shrinkage is non-inferior to that of goserelin plus bicalutamide. The added benefits of degarelix in terms of more pronounced lower urinary tract symptom relief in symptomatic patients could be the reflection of differences in the direct effects on extra-pituitary receptors in the lower urinary tract [Clinicaltrials.gov ID: NCT00833248].     

Predictive Impact of Early Changes in Serum C-Reactive Protein Levels in Nivolumab Plus Ipilimumab Therapy for Metastatic Renal Cell Carcinoma

BackgroundSerum C-reactive protein (CRP) is reportedly associated with metastatic renal cell carcinoma (mRCC) activity. However, in the era of immune checkpoint inhibitors, the predictive value of CRP is unclear. In this study, we investigated the predictive impact of pretreatment CRP levels and early changes in CRP levels for the treatment of mRCC with nivolumab plus ipilimumab (NIVO-IPI) therapy.MethodsForty-eight patients with mRCC treated with NIVO-IPI as a first-line therapy were retrospectively analyzed. First, patients were divided into 2 groups: initial CRP ≥ 1.0 mg/dL and < 1.0 mg/dL. Progression-free survival (PFS) was compared between the 2 groups. Second, based on the CRP change within the first 3 months of NIVO-IPI, patients were placed in the normal group (CRP remains < 1.0 mg/dL), normalized group (CRP decreased < 1.0 mg/dL), and non–normalized group (CRP remained or increased to ≥ 1.0 mg/dL). The predictive association between CRP change and PFS was evaluated.ResultsPFS was significantly lower in the high initial CRP group (n = 24, 50%) compared to the normal CRP group (n = 24, 50%) (median: 4.3 vs. 28.1 months, P = .03). As for the early CRP change, the normal (2.7 vs. 28.1, P = .0002) and normalized (2.7 vs. 11.0, P = .0094) groups showed significantly higher PFS, compared to the non–normalized group. Meanwhile, there was no significant difference between normal, and normalized groups (P = .51). The objective response rate was higher in the normal (57.1% vs. 18.7%, P = .015) and normalized (81.8 vs. 18.7%, P = .0008) groups, compared to the non–normalized group. Multivariate Cox regression analysis showed that normal [Hazard ratio (HR) = 0.15, 95% Confidence interval (CI) = 0.02-0.70, P = .026] and normalized (HR 0.21, 95% CI = 0.05-0.73, P = .015) CRP showed significant association with PFS.ConclusionIn the NIVO-IPI therapy for mRCC, early changes in CRP could predict PFS. This data may be useful for the early detection of ineffective NIVO-IPI therapy and conversion to subsequent therapies.     

Interferon Therapy in Myelofibrosis: Systematic Review and Meta-analysis

BackgroundMyelofibrosis (MF) is a Philadelphia chromosome–negative myeloproliferative neoplasm characterized by progressive bone marrow failure, increased risk of progression to acute myeloid leukemia, and constitutional symptoms. For over 3 decades, various formulations of interferon (IFN) have been used for the treatment of MF, with variable results, and the role of IFN in the treatment of MF is evolving.Patients and MethodsFor this systematic review and meta-analysis, Medline and Embase via Ovid, Scopus, Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science were searched from inception through March 2019 for studies of pegylated IFN (peg-IFN) and non–peg-IFN in MF patients. The primary outcome of overall response rate was defined as a composite of complete response, partial response, complete hematologic response, and partial hematologic response. Random-effects models were used to pool overall response rate, and metaregression analyses were performed to compare peg-IFN and non-–peg-IFN formulations.ResultsAmong the 10 studies with 141 MF patients included, the overall response rate was 49.9% (95% confidence interval [CI], 30.4-69.3), and there was no statistically significant difference (P = .99) between peg-IFN (50.0%; 95% CI, 26.2-73.9; I² = 76.9%) and non–peg-IFN (49.6%; 95% CI, 20.5-79.0; I² = 56.7%). Treatment discontinuation resulting from adverse events was common with non–peg-IFN at 35.8% (95% CI, 3.5-68.1) per year, and less in the one study on peg-IFN (0.5% per year).ConclusionIFN can lead to hematologic improvements in a subset of MF patients, but study quality is limited and heterogenous. Biomarkers predicting response to IFN and formulations with improved tolerability are needed.     

Oncologic Outcomes of Squamous Cell Carcinoma Versus Urothelial Carcinoma With Squamous Differentiation After Radical Cystectomy for Bladder Carcinoma

IntroductionIn this study we aim to compare clinicopathological characteristics and cancer specific survival between patients treated with radical cystectomy for pure squamous cell carcinoma (SCC) and urothelial carcinoma with squamous differentiation (SqD).Patients and MethodsWe reviewed data of 1737 consecutive patients treated with radical cystectomy and urinary diversion between January 2004 and February 2014. Only patients with pure SCC or SqD were included in the analysis. Squamous differentiation was defined as intercellular bridges or keratinization in the tumor. Clinicopathological data and recurrence free survival (RFS) were compared between patients diagnosed with SCC and SqD.ResultsSCC and SqD were found in 318 and 223 patients, respectively. Mean age was 57 ± 8.3 years in SCC and 58.8 ± 7.8 in SqD (P = .008). A higher proportion of female patients was observed in SCC group compared to SqD (31.8% vs. 22% P < .0001). Patients with SqD were more likely to have extravesical (58.3% vs. 46.2%: P = .006) and nodal positive disease (34.5% vs. 14.5%: P < .0001) than pure SCC patients. Bilharzial eggs were found in 61% of SCC vs. 46% of SqD (P = .001).; The median (IQR) follow up period for SCC and SqD was 63 (12-112) months and 23 months (9-74.7), respectively. The 5-year RFS for SCC and SqD were 77% and 59.8 %, respectively (P < .0001).; Multivariate cox regression analysis identified advanced pT stage (OR: 1.9, 95% CI: 1.3-2.86, P = .0001), nodal positive disease (OR: 1.6, 95% CI: 1.1-2.48, P = .01) and SqD histology (OR: 1.6, 95% CI: 1.14-2.31, P = .007 as independent predictors of 5-year RFS.ConclusionPatient with SCC had significantly higher 5-year RFS in comparison to SqD. The higher rate of extravesical disease and lymph node metastasis in SqD patients is indicative of aggressive behavior of this histologic type.     

Potentially inappropriate medication use in older people with cancer: Prevalence and correlates

ObjectivesPotentially inappropriate medication (PIM) use has been associated with an increase in adverse drug events, hospitalization and mortality. This study investigated the prevalence and factors associated with PIM use in patients presenting to a medical oncology outpatient clinic.Materials and MethodsConsecutive patients (n = 385) aged ≥ 70 years referred to a medical oncology outpatient clinic between January 2009 and July 2010 completed a structured data collection instrument. The instrument assessed medication use, diagnoses, self-reported falls in the previous six months, pain (10-point visual analog scale [VAS]) and distress (10-point VAS). Frailty was defined using exhaustion, weight loss, Karnofsky Performance Scale, instrumental activities of daily living and physical function. PIM use was defined by the Beers Criteria. Logistic regression was used to compute odds ratios (ORs) and 95% confidence intervals (CIs) for factors associated with PIM use.ResultsIn total, 26.5% (n = 102) of the sample used ≥ 1 PIM. The five most prevalent classes of PIMs were benzodiazepines (n = 34, 8.8%), tricyclic antidepressants (n = 16, 4.2%), alpha-adrenoreceptor antagonists (prazosin) (n = 15, 3.9%), propulsives (metoclopramide) (n = 15, 3.9%) and non-steroidal anti-inflammatory drugs (n = 14, 3.6%). In multivariate analyses, PIM use was associated with age 75–79 years (OR 1.83; 95%CI 1.02–3.26) compared to age 70–74 years, using ≥ 5 medications (OR 4.10; 95%CI 2.26–7.44) compared to < 5 medications and being frail (OR 3.05; 95%CI 1.18–7.87) compared to being robust.ConclusionMore than one quarter of older people with cancer used one or more PIMs, and this was associated with being frail compared to being robust.     

Clinical Significance of Bone Marrow Blast Percentage in Patients With Myelofibrosis and the Effect of Ruxolitinib Therapy

BackgroundThe effect of bone marrow (BM) blasts on the outcome of patients with myelofibrosis (MF) is poorly understood, unless they are ≥ 10% and represent a more aggressive accelerated phase. Similarly, the role of the JAK inhibitor, ruxolitinib (RUX), has not been assessed in correlation with BM blasts.Patients and MethodsHerein, we present clinical characteristics and outcomes of 1412 patients with MF stratified by BM blasts and therapy.ResultsSeven percent and 4% of patients had 5% to 9% and ≥ 10% BM blasts, respectively. Forty-four percent of patients were treated with RUX throughout their disease course. Overall survival (OS) differed among patients with 0% to 1%, 2% to 4%, and 5% to 9% BM blasts, with median OS of 64, 48, and 22 months, respectively (P < .001). Patients with 5% to 9% BM blasts had similar OS as patients with ≥ 10% BM blasts (22 vs. 14 months; P = .73). All patients with < 10% blasts who were treated with RUX showed superior OS to patients who did not receive RUX.ConclusionsOur results indicate that patients with MF with ≥ 5% BM blasts represent a high-risk group with adverse clinical characteristics and inferior outcome. However, they still appear to derive substantial survival benefit from therapy with RUX.