Association of the advanced lung cancer inflammation index (ALI) with immune checkpoint inhibitor efficacy in patients with advanced non-small-cell lung cancer.

BACKGROUND: The advanced lung cancer inflammation index [ALI: body mass index × serum albumin/neutrophil-to-lymphocyte ratio (NLR)] reflects systemic host inflammation, and is easily reproducible. We hypothesized that ALI could assist guidance of non-small-cell lung cancer (NSCLC) treatment with immune checkpoint inhibitors (ICIs). PATIENTS AND METHODS: This retrospective study included 672 stage IV NSCLC patients treated with programmed death-ligand 1 (PD-L1) inhibitors alone or in combination with chemotherapy in 25 centers in Greece and Germany, and a control cohort of 444 stage IV NSCLC patients treated with platinum-based chemotherapy without subsequent targeted or immunotherapy drugs. The association of clinical outcomes with biomarkers was analyzed with Cox regression models, including cross-validation by calculation of the Harrell's C-index. RESULTS: High ALI values (>18) were significantly associated with longer overall survival (OS) for patients receiving ICI monotherapy [hazard ratio (HR) = 0.402, P < 0.0001, n = 460], but not chemo-immunotherapy (HR = 0.624, P = 0.111, n = 212). Similar positive correlations for ALI were observed for objective response rate (36% versus 24%, P = 0.008) and time-on-treatment (HR = 0.52, P < 0.001), in case of ICI monotherapy only. In the control cohort of chemotherapy, the association between ALI and OS was weaker (HR = 0.694, P = 0.0002), and showed a significant interaction with the type of treatment (ICI monotherapy versus chemotherapy, P < 0.0001) upon combined analysis of the two cohorts. In multivariate analysis, ALI had a stronger predictive effect than NLR, PD-L1 tumor proportion score, lung immune prognostic index, and EPSILoN scores. Among patients with PD-L1 tumor proportion score ≥50% receiving first-line ICI monotherapy, a high ALI score >18 identified a subset with longer OS and time-on-treatment (median 35 and 16 months, respectively), similar to these under chemo-immunotherapy. CONCLUSIONS: The ALI score is a powerful prognostic and predictive biomarker for patients with advanced NSCLC treated with PD-L1 inhibitors alone, but not in combination with chemotherapy. Its association with outcomes appears to be stronger than that of other widely used parameters. For PD-L1-high patients, an ALI score >18 could assist the selection of cases that do not need addition of chemotherapy.

Identification of non-Hodgkin lymphoma patients at risk for treatment-related vertebral density loss and fractures.

Information on bone loss in treated non-Hodgkin's lymphoma patients is limited. In this study, we used CT to analyze bone loss as well as prevalent and incident fractures. We found severe bone loss, a high rate of fractures, and a novel association between bone loss and the international prognostic index. INTRODUCTION: To investigate bone loss and fracture risk in non-Hodgkin-lymphoma (NHL) patients by (i) comparing treatment-related vertebral density (VD) loss in NHL patients with control subjects and (ii) investigating associations of VD loss versus fracture risk. Further, associations of VD loss and clinical parameters were investigated. METHODS: VD of 123 NHL patients was measured pre- and post-treatment in the L1, L2, and L3 vertebrae in routine computed tomography (CT) scans, performed between Jan 2016 and Mar 2017. Control measurements (n = 52) were obtained from CT colonographies between Sept 2003 and Sept 2017 and their subsequent follow-up-exams (10-137 months). Prevalent and incident (between baseline and follow-up) fractures were assessed in all subjects, and VD loss per year was calculated. Linear regression models were used to (i) compare VD loss between patients and controls and (ii) identify associations between VD loss and clinical parameters. Using logistic regression models, ORs for fractures per SD change in VD were assessed in patients. Analyses were adjusted for age, sex, and contrast application. RESULTS: NHL patients experienced significantly greater VDL1-3 loss than controls (P = 0.003), and greater VDL1-3 loss was associated with a greater likelihood of incident fractures (OR, [95%-CI], P 1.90, [1.03, 3.51], 0.04). Patients with an initial international prognostic index (IPI) of 5 suffered significantly greater VD loss compared with an IPI of 0 (P = 0.01). CONCLUSION: Using VD measurements in routine CT scans, substantial vertebral bone loss in NHL patients could be documented with a high incidence of fractures.

ABREAST: a prospective, real-world study on the effect of nab-paclitaxel treatment on clinical outcomes and quality of life of patients with metastatic breast cancer.

PURPOSE: The efficacy of nab-paclitaxel in patients with metastatic breast cancer (MBC) has been demonstrated in randomized clinical trials. However, real-world evidence on effectiveness remains limited. PATIENTS AND METHODS: The primary objective of this multicenter prospective study was to assess the overall response rate (ORR) of patients with MBC treated with nab-paclitaxel. Secondary objectives included progression-free survival (PFS), overall survival (OS) and quality of life, assessed with the Functional Assessment of Cancer Therapy-Breast (FACT-B) instrument. RESULTS: Eligible patients (N = 150; 36% with de novo MBC presentation) with a median age of 64.5 years were enrolled (86% were ER+, 33.3% (50/150) were ≥ 70 years of age and 53% were treated in the third or later line of treatment). A median of 6 cycles were administered but 26% of patients required dose reduction due to toxicity. The ORR was 26.7% [95% confidence interval (CI) 19.6-33.7], the median PFS was 6.2 months (95% CI 5.2-7.3), and the median OS 21.1 months (95% CI 17.2-not estimable). There was no statistical significant difference in the median PFS of patients < and ≥ 70 years of age. The patients' baseline FACT-B total score remained unchanged. The serious and non-serious adverse event incidence rates were 13% and 48%, respectively. CONCLUSIONS: This prospective study provides further evidence on quality of life, efficacy, and safety of nab-paclitaxel in patients with MBC and sheds more light in special subpopulations such as the elderly and those treated beyond the second line.

NCCN Guidelines Insights: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Version 1.2017.

Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are different manifestations of the same disease and managed in much the same way. The advent of novel CD20 monoclonal antibodies led to the development of effective chemoimmunotherapy regimens. More recently, small molecule inhibitors targeting kinases involved in a number of critical signaling pathways and a small molecule inhibitor of the BCL-2 family of proteins have demonstrated activity for the treatment of patients with CLL/SLL. These NCCN Guidelines Insights highlight important updates to the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for CLL/SLL for the treatment of patients with newly diagnosed or relapsed/refractory CLL/SLL.

Increased CD14+ and decreased CD14- populations of monocytes 48 h after zolendronic acid infusion in breast cancer patients.

It has been proposed that bisphosphonates cause osteonecrosis of the jaws through impairment of the monocyte population function and proliferation. Such changes have been confirmed in jaw tissues, ex vivo. In this clinical study, we report for the first time a similar pattern of changes in peripheral blood monocytes. INTRODUCTION: The aim of this study is to examine the effect of zolendronic acid administration in the peripheral blood white cell population, seeking a plausible pathophysiological link between bisphosphonates and osteonecrosis of the jaw. METHODS: Twenty-four breast cancer patients, under zolendronic acid treatment for bone metastasis, were included. Peripheral blood samples were obtained prior to and 48 h following zolendronic acid administration. Flow cytometry gated at leukocyte, monocyte, and the granulocyte populations for the CD4/CD8/CD3, CD3/CD16+56/CD45/CD19, CD14/CD123, and CD14/23 stainings were performed. RESULTS: We were able to record a number of changes in the white cell populations after 48 h of zolendronic acid administration. Most importantly, in the monocyte populations, we were able to detect statistically significant increased populations of CD14+/CD23+ (p = 0.038), CD14+/CD23- (p = 0.028), CD14+/CD123+ (p = 0.070, trend), and CD14+/CD123- (p = 0.043). In contrast, statistically significant decreased populations of CD14-/CD23+ (p = 0.037) and CD14-/CD123+ (p = 0.003) were detected. CONCLUSIONS: Our results provide evidence supporting the hypothesis that bisphosphonate administration modifies the monocyte-mediated immune response. An increase of CD14+ peripheral blood monocyte (PBMC) populations along with a decrease of CD14- PBMC populations has been recorded. The latter finding is in accordance with limited-currently existing-evidence and warrants further elucidation.

NCCN Guidelines Insights: Non-Hodgkin's Lymphomas, Version 3.2016.

Peripheral T-cell lymphomas (PTCLs) represent a relatively uncommon heterogeneous group of non-Hodgkin's lymphomas (NHLs) with an aggressive clinical course and poor prognosis. Anthracycline-based multiagent chemotherapy with or without radiation therapy followed by first-line consolidation with high-dose therapy followed by autologous stem cell rescue (HDT/ASCR) is the standard approach to most of the patients with newly diagnosed PTCL. Relapsed or refractory disease is managed with second-line systemic therapy followed by HDT/ASCR or allogeneic stem cell transplant, based on the patient's eligibility for transplant. In recent years, several newer agents have shown significant activity in patients with relapsed or refractory disease across all 4 subtypes of PTCL. These NCCN Guideline Insights highlight the important updates to the NCCN Guidelines for NHL, specific to the management of patients with relapsed or refractory PTCL.

Diffuse Large B-Cell Lymphoma Version 1.2016.

Diffuse large B-cell lymphomas (DLBCL) are now considered a heterogeneous group of distinct molecular subtypes (germinal center B-cell DLBCL, activated B-cell DLBCL, and primary mediastinal large B-cell lymphoma (PMBL) with varied natural history and response to therapy. In addition, a subset of patients with DLBCL have concurrent MYC and/or BCL2 gene rearrangements (double-hit lymphomas; DHL) and others have a dual expression of both MYC and BCL2 proteins (double-expressing DLBCL; DEL). The standard of care for the treatment of patients with PMBL, DHL, or DEL has not been established. Adequate immunophenotyping and molecular testing (in selected circumstances) are necessary for the accurate diagnosis of different subtypes of DLBCL. The NCCN Guidelines included in this issue, part of the NCCN Guidelines for non-Hodgkin's lymphomas, address the diagnosis and management of DLBCL and its subtypes.

Chronic lymphocytic leukemia/small lymphocytic lymphoma, version 1.2015.

Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are different manifestations of the same disease, which are managed in the same way. The advent of novel monoclonal antibodies (ofatumumab and obinutuzumab) led to the development of effective chemoimmunotherapy regimens. The recently approved small molecule kinase inhibitors (ibrutinib and idelalisib) are effective treatment options for CLL in elderly patients with decreased tolerance for aggressive regimens and in patients with poor prognostic features who do not benefit from conventional chemoimmunotherapy regimens. This portion of the NCCN Guidelines for Non-Hodgkin's Lymphomas describes the recent specific to the incorporation of recently approved targeted therapies for the management of patients with newly diagnosed and relapsed or refractory CLL/SLL.

Delayed hematopoietic recovery after auto-SCT in patients receiving arsenic trioxide-based therapy for acute promyelocytic leukemia: a multi-center analysis.

A potential link between arsenic (ATO)-based therapy and delayed hematopoietic recovery after autologous hematopoietic SCT (HSCT) for acute promyelocytic leukemia (APL) has previously been reported. We retrospectively reviewed the clinical histories of 58 patients undergoing autologous HSCT for APL at 21 institutions in the United States and Japan. Thirty-three (56%) of the patients received ATO-based therapy prior to stem cell collection. Delayed neutrophil engraftment occurred in 10 patients (17%): 9 of the 10 patients (90%) received prior ATO (representing 27% of all ATO-treated patients), compared with 1 of the 10 patients (10%) not previously treated with ATO (representing 4% of all ATO-naïve patients; P<0.001). Compared with ATO-naïve patients, ATO-treated patients experienced significantly longer times to ANC recovery (median 12 days vs 9 days, P<0.001). In multivariate analysis, the only significant independent predictor of delayed neutrophil engraftment was prior treatment with ATO (hazard ratio 4.87; P<0.001). Of the available stem cell aliquots from APL patients, the median viable post-thaw CD34+ cell recovery was significantly lower than that of cryopreserved autologous stem cell products from patients with non-APL AML. Our findings suggest that ATO exposure prior to CD34+ cell harvest has deleterious effects on hematopoietic recovery after autologous HSCT.

Non-Hodgkin's lymphomas, version 4.2014.

Non-Hodgkin's lymphomas (NHL) are a heterogeneous group of lymphoproliferative disorders originating in B lymphocytes, T lymphocytes, or natural killer cells. Mantle cell lymphoma (MCL) accounts for approximately 6% of all newly diagnosed NHL cases. Radiation therapy with or without systemic therapy is a reasonable approach for the few patients who present with early-stage disease. Rituximab-based chemoimmunotherapy followed by high-dose therapy and autologous stem cell rescue (HDT/ASCR) is recommended for patients presenting with advanced-stage disease. Induction therapy followed by rituximab maintenance may provide extended disease control for those who are not candidates for HDT/ASCR. Ibrutinib, a Bruton tyrosine kinase inhibitor, was recently approved for the treatment of relapsed or refractory disease. This manuscript discusses the recommendations outlined in the NCCN Guidelines for NHL regarding the diagnosis and management of patients with MCL.

Non-Hodgkin's lymphomas, version 2.2014.

Non-Hodgkin's lymphomas (NHLs) are a heterogeneous group of lymphoproliferative disorders originating in B lymphocytes, T lymphocytes, or natural killer cells. Follicular lymphoma (FL) is the most common subtype of indolent NHL, accounting for approximately 22% of all newly diagnosed cases of NHL. The incorporation of rituximab to chemotherapy regimens has become a widely accepted standard of care for first-line therapy for patients with FL. Maintenance and consolidation therapy with rituximab and radioimmunotherapy have also been associated with improved progression-free survival in patients experiencing response to first-line therapy. Despite therapeutic advances that have improved outcomes, FL is generally considered a chronic disease characterized by multiple recurrences with current therapies. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with FL.

Non-Hodgkin's lymphomas, version 1.2013.

These NCCN Guidelines Insights summarize several key updates to the NCCN Guidelines for Non-Hodgkin's Lymphomas (NHL) and provide a discussion of the clinical evidence that support the updates. The updates discussed in this article feature recommendations for additional treatment options in patients with chronic lymphocytic leukemia and guidance surrounding the management of hepatitis virus reactivation/infections in high-risk patients with NHL undergoing antitumor therapy.

Non-Hodgkin's Lymphomas, version 3.2012.

These NCCN Guidelines Insights summarize several key updates to the 2012 NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Hodgkin's Lymphomas (NHL) and describe the clinical evidence supporting the updates. The featured updates include changes to the recommendations for treatment options in patients with chronic lymphocytic leukemia (including in elderly or frail patients and patients with poor-risk cytogenetics), guidance surrounding surveillance imaging for follow-up of patients with NHL, and the addition of first-line consolidation options for patients with mantle cell lymphoma.

Matrix metalloproteinases and proangiogenic factors in testicular germ cell tumors.

PURPOSE: Testicular cancer is the most frequent solid tumor in young male adults and a disease with elusive pathogenesis. The purpose of this study was to determine the role of matrix metalloproteinases and angiogenic factors in the pathogenesis of testicular germ cell tumors (GCTs). METHODS: Between 2003 and 2006 we measured the serum levels of matrix metalloproteinase 2 (MMP-2), matrix metalloproteinase 9 (MMP-9), tissue inhibitor of matrix metalloproteinase 2 (TIMP-2), vascular endothelial growth factor A (VEGF-A), basic fibroblast growth factor (bFGF), platelet derived growth factor BB (PDGF-BB) and angiopoietin 2 (Ang-2) in 50 patients with testicular GCTs, at baseline, one month after the completion of the second cycle of chemotherapy and one year after the completion of chemotherapy, and in 16 male age-matched controls at baseline. RESULTS: At baseline, mean TIMP-2 value was lower in patients than controls, mean MMP-2/TIMP-2 ratio was higher in patients than controls and MMP9/TIMP-2 ratio was also higher. Ang-2 value was higher in patients than controls and bFGF value was also higher. Comparisons of the same parameters were also made among the 3 consecutive serum samples of the patients. All parameters normalized after chemotherapy except Ang-2 which remained elevated. CONCLUSION: The present study supports the hypothesis that tumor invasion and angiogenesis play a role in testicular GCTs pathogenesis. Also an interesting hypothesis was formed, concerning the role of elevated levels of Ang-2 found in testicular GCTs patients in the pathogenesis of the increased long term cardiovascular morbidity of these patients. Larger prospective studies are needed to confirm our results.

Primary fallopian tube carcinoma: results of a retrospective analysis of 64 patients.

OBJECTIVE: The objective of this retrospective study was to determine the clinical outcomes of patients with primary fallopian tube carcinoma (PFTC) treated with paclitaxel and platinum analogue-based combination chemotherapy following primary cytoreductive surgery. METHODS: Sixty-four patients with the diagnosis of PFTC were identified through the gynecology service database and the tumor registry of 4 different institutions. The majority of patients (48/64, 75%) were treated with carboplatin AUC (area under curve) 6 and paclitaxel 175 mg/m(2) as a 3 h infusion. RESULTS: Among 28 patients with measurable disease, we observed 19 (68%) complete clinical and 7 (25%) partial responses for an overall response rate of 93%. After a median follow-up of 40 months (3+-134+ months), the 5-year survival rate of the entire population was 70% (median overall survival [mOS] not reached) and the median time to tumor progression (mTTP) was 81 months (95% CI: 53-109). Stage and residual disease were of prognostic significance. The mTTP was not reached in patients with stage I/II and was 38 months for patients with stage III/IV (p=0.004). The mOS for patients with stage I/II was not reached, whereas it was 62 months for those with stage III/IV (p=0.057). The mTTP was 86 and 23 months for patients with residual disease <2 cm and >2 cm, respectively (p<0.001). The mOS was not reached for patients with residual disease <2 cm, while it was 36 months for residual disease >2 cm (p<0.001). CONCLUSION: Optimally cytoreduced patients with PFTC treated with platinum and paclitaxel-based chemotherapy regimen have an excellent possibility of survival.

EBV PCR in the diagnosis and monitoring of posttransplant lymphoproliferative disorder: results of a two-arm prospective trial.

While EBV PCR is used in the management of PTLD, the optimal primer set, relative importance of intracellular versus free plasma EBV, and the baseline profile in an organ transplant population remains unclear. We performed a prospective 2-arm trial utilizing an EBV PCR panel measuring LMP-1, EBER-1 and EBNA-1 in both free plasma as well as intracellular whole blood. Control Arm A consisted of 31 lung transplant patients and Arm B consisted of 35 transplant patients being evaluated for possible PTLD. In Arm A, 1/31 (3%) patients developed a transient plasma EBV load. Thirteen of 31 (42%) had detectable intracellular EBV. In Arm B, 17 (49%) patients were diagnosed with PTLD. Thirteen (76%) had EBV-positive PTLD with 12/13 (92%) having detectable EBV by PCR. The EBV PCR panel had a high sensitivity (92%), specificity (72%), positive predictive value (PPV) (71%) and negative predictive value (NPV) (93%) for diagnosing EBV-positive PTLD and followed patients' clinical course well (p < 0.001). Comparing the individual PCR assays, plasma EBNA PCR was superior with high sensitivity (77%), specificity (100%), PPV (100%) and NPV (86%). We conclude that EBV PCR is a useful test for managing PTLD patients. While plasma EBNA PCR is the best single assay for diagnosing and monitoring PTLD, the complete PCR panel is superior for ruling out its presence.

Neoadjuvant chemotherapy followed by radiotherapy versus concurrent chemoradiotherapy for larynx preservation in patients with advanced laryngeal cancer.

PURPOSE: The efficacy and toxicity of neoadjuvant chemotherapy followed by radiotherapy and concurrent chemoradiotherapy and their impact on larynx preservation have been studied in patients with advanced (stage III, IVa, and IVb) squamous cell cancer of the larynx. PATIENTS AND METHODS: Fifty patients were treated with either 2-4 cycles of induction chemotherapy with cisplatin 100 mg/m(2), day 1 and infusional 5-fluorouracil (5-FU 1000 mg/m(2), days 1-5), followed by radiotherapy 70 Gy, 1.8-2 Gy per fraction, or concurrent chemoradiotherapy (the above-mentioned radiotherapy concurrently with carboplatin 300 mg/m(2) every 21 days or weekly paclitaxel 80 mg/m(2)). Patients were allocated in the 2 arms by 1:1 selection. At the end of both protocols, patients without complete response (CR) underwent laryngectomy and/or neck lymph node dissection. Assessed were response and toxicity rates, overall survival (OS) and disease-free survival (DFS). RESULTS: A total of 31 (62%) patients achieved larynx preservation with acceptable organ function. No statistically significant difference in response rate and OS was found between the two treatment arms. Patients submitted to concurrent chemoradiotherapy showed significantly longer DFS (14 vs. 10 months, p= 0.0397) and higher rates of larynx preservation (p <0.05). All grade IV side effects occurred in the concurrent chemoradiotherapy group. CONCLUSION: Concurrent compared to alternating chemoradiotherapy was more toxic, but achieved significantly longer DFS and higher rate of larynx preservation.

A phase III randomized study comparing paclitaxel and cisplatin versus cyclophosphamide and cisplatin in patients with advanced ovarian cancer.

AIM: To assess progression-free survival (PFS) and overall survival (OS) in patients with advanced epithelial ovarian cancer receiving the combination of cisplatin (75 mg/m(2) i.v.) and cyclophosphamide (700 mg/m(2) i.v.) (CP), or the combination of paclitaxel (175 mg/m2) followed by cisplatin (75 mg/m2) (TP). PATIENTS AND METHODS: One hundred and twenty patients were randomized to receive six cycles of one of the treatments every 3 weeks. If measurable, complete response (CR) or partial response (PR) was determined. RESULTS: There was a significant difference (p<0.05) in the frequency of response (CR +PR) rates between treatment groups, in favor of paclitaxel containing regimen. The median PFS was 9 months for patients in the CP group and 12 months for patients in the TP group (log-rank p=0.215). The median OS were 24 months and 20 months in TP and CP arms, respectively (log-rank p=0.350). Neutropenia and alopecia were more severe with paclitaxel-containing regimen. CONCLUSION: Although OS and PFS were similar in two arms, TP regimen yielded superior response rates relative to CP, with an acceptable toxicity profile. Therefore, the TP regimen remains the preferred initial treatment option.