MTHFR, XRCC1 and OGG1 genetic polymorphisms in breast cancer: a case-control study in a population from North Sardinia.

BACKGROUND: Despite conflicting results, considerable evidence suggests the association between single nucleotide polymorphisms in MTHFR, XRCC1 and OGG1 genes and, risk of developing breast cancer. Here a case-control study is reported, including 135 breat cancer patients and 112 healthy women, all representative of Northern Sardinian population. METHODS: Polymerase chain reaction/restriction fragment length polymorphism method was used to determine the genotypes of five polymorphisms: MTHFR C677T (rs1801133) and A1298C (rs1801131), XRCC1 Arg194Trp (rs1799782) and Arg399Gln (rs25487) and OGG1 Ser326Cys (rs1052133). Allelic, genotypic and haplotype association analyses with disease risk and clinicopathological parameters were performed. RESULTS: A nominally significant association with breast cancer risk was observed for MTHFR C677T polymorphism heterozygous genotype in the codominant model (OR: 0.57, 95% CI: 0.32-1.00, p = 0.049) and for Cys/Cys genotype of the OGG1 Ser326Cys polymorphism in the recessive model (OR: 0.23, 95% CI: 0.05-1.11, p = 0.0465). No significant differences were found at genotype-level for A1298C polymorphism of the MTHFR gene and Arg194Trp and Arg399Gln of the XRCC1 gene. Furthermore, the OGG1 and XRCC1 rs25487 polymorphisms were nominally associated with PgR, Her2 status and with sporadic breast cancer, respectively. CONCLUSIONS: Based on genetic characteristics of individuals included in this study, results suggest that MTHFR CT and OGG1 Cys/Cys genotypes have a protective effect that may have an influence on breast cancer risk in a representative Northern Sardinian population.

Blood cell count indexes as predictors of outcomes in advanced non-small-cell lung cancer patients treated with Nivolumab.

Lung cancer is the most common malignancy worldwide. Despite significant advances in diagnosis and treatment, mortality rates remain extremely high, close to incidence rates. Several targeted therapies have been recently introduced for the treatment of non-small cell lung cancer (NSCLC), the most common type of lung cancer. Nivolumab, a monoclonal antibody that targets programmed death-1 (PD-1), was the first immune checkpoint inhibitor approved for the treatment of patients with advanced/metastatic NSCLC not responding to platinum-based chemotherapy. Biomarkers predicting response to these therapies would allow early identification of non-responders and timely implementation of appropriate combination strategies, avoiding inadequate and expensive therapies. The role of the neutrophil to lymphocyte ratio and other blood cell count indexes as possible biomarkers of response has been recently investigated. We discuss the encouraging results reported on the topic, provide new data from our personal experience, and discuss opportunities for further research.

Prognostic impact of KRAS, NRAS, BRAF, and PIK3CA mutations in primary colorectal carcinomas: a population-based study.

BACKGROUND: Activation of oncogenes downstream the EGFR gene contributes to colorectal tumorigenesis and determines the sensitivity to anti-EGFR treatments. The aim of this study was to evaluate the prognostic value of KRAS, BRAF, NRAS and PIK3CA mutations in a large collection of CRC patients from genetically-homogeneous Sardinian population. METHODS: A total of 1284 Sardinian patients with histologically-proven diagnosis of colorectal carcinoma (CRC) and presenting with metastatic disease were included into the study. Genomic DNA was isolated from formalin-fixed, paraffin-embedded primary tumour tissue samples of CRC patients and screened for mutations in RAS and BRAF genes, using pyrosequencing assays, and in PIK3CA gene, using automated DNA sequencing assays. RESULTS: Overall, mutation rates were 35.6 % for KRAS, 4.1 % for NRAS, and 2.1 % for BRAF. Among available DNA samples, 114/796 (14.3 %) primary CRCs were found to carry a mutation in the PIK3CA gene. In this subset of patients analysed in all four genes, a pathogenetic mutation of at least one gene was discovered in about half (378/796; 47.5 %) of CRC cases. A mutated BRAF gene was found to steadily act as a negative prognostic factor for either time to progression as metastatic disease (from detection of primary CRC to diagnosis of first distant metastasis; p = 0.009) or partial survival (from diagnosis of advanced disease to the time of death or last control; p = 0.006) or overall survival (p < 0.001). No significant impact on prognosis was observed for mutated KRAS, NRAS, and PIK3CA genes or combined RAS mutations (all RAS). CONCLUSIONS: Our study defines both prevalence and prognostic role of main activated oncogenes in a population-based large collection of CRC patients.

Complete Blood Count-Based Biomarkers as Predictors of Clinical Outcomes in Advanced Non-Small Cell Lung Cancer Patients with PD-L1 < 50% Treated with First-Line Chemoimmunotherapy.

Background: The aim of the study was to investigate a series of complete blood cell count-based biomarkers of systemic inflammation as predictors of clinical outcomes in patients who underwent first-line chemoimmunotherapy for advanced NSCLC. Methods: Consecutive patients with pathologically diagnosed stage III/IV NSCLC and PD-L1 < 50% who underwent first-line chemoimmunotherapy were retrospectively enrolled. The clinical outcomes used for biomarker evaluation were Objective Response Rate (ORR) and Overall Survival (OS). Results: Non-responders had significantly higher values of neutrophil to lymphocyte ratio (NLR, median: 5.36; IQR: 2.78-10.82 vs. 3.31; IQR: 2.15-4.12, p = 0.019), neutrophil to monocyte ratio (NMR, median: 14.00; IQR: 8.82-21.20 vs. 9.20; IQR: 7.45-11.20, p = 0.013), and systemic inflammation index (SII, median: 1395; IQR: 929-3334 vs. 945; IQR: 552-1373, p = 0.025), but only NLR and NMR remained independently associated with clinical response in multivariate logistic regression. In the univariate analysis, white blood cells (OR:1.2202; 95% CI: 1.0339-1.4400, p = 0.019), neutrophils (OR:1.2916; 95% CI: 1.0692-1.5604, p = 0.008), NLR (OR:1.3601: 95% CI: 1.0949-1.6896, p = 0.005) and NMR (OR:1.2159; 95% CI: 1.00396-1.4221, p = 0.015) were significantly associated with survival; Cox regression models confirmed that neutrophils, NLR, and MLR were independently associated with survival; NLR, at a cut-off value of 4.0, showed the better AUC (0.749) in predicting OS. Conclusions: Baseline complete blood cell count biomarkers, especially the NLR, can predict clinical outcomes in patients with advanced NSCLC treated with first-line chemoimmunotherapy.

Duration of Immunotherapy in Non-Small Cell Lung Cancer Survivors: A Lifelong Commitment?

Lung cancer is one of the most common human malignancies and the leading cause of cancer-related death worldwide. Novel therapeutic approaches, like targeted therapies against specific molecular alterations and immunotherapy, have revolutionized in the last decade the oncological outcomes in patients affected by non-small cell lung cancer (NSCLC). The advent of immunotherapy for the treatment of NSCLC has significantly improved overall and progression-free survival, as well as the patient's quality of life in comparison to traditional chemotherapy. Currently, it is estimated that long-term survival can be achieved in more than 15% of NSCLC patients treated with immunotherapy. Therefore, the optimal duration of immunotherapy in long survivors needs to be established to avoid overtreatment, side effects, and high costs and at the same time, protect them from potential disease relapse or progression. We performed a narrative review to discuss all the aspects related to the optimal duration of immunotherapy in long survivors with NSCLC. Data regarding the duration of immunotherapy in the most impacting clinical trials were collected, along with data regarding the impact of toxicities, side effects, and costs for healthcare providers. In addition, the two-year immunotherapy scheme in patients who benefit from first-line or subsequent treatment lines are examined, and the need for biomarkers that can predict outcomes during and after immunotherapy cessation in patients affected by NSCLC are discussed.

HIV Infection Indicator Disease-Based Active Case Finding in a University Hospital: Results from the SHOT Project.

In 2014, UNAIDS launched renewed global targets for HIV control to achieve by 2025, known as "the three 95": 95% of people living with HIV (PWH) diagnosed, of which 95% are receiving treatment, of which 95% are on sustained virological suppression. In Italy, new HIV diagnoses have been steadily decreasing since 2012. However, in 2020, 41% of new diagnoses presented with less than 200 CD4+ cells/µL and 60% with less than 350 CD4+ cells/µL. Implementing testing and early treatment is a key strategy to prevent AIDS, late presentation, and HIV transmission. We selected non-Infectious Diseases Units based on the European project HIDES and engaged colleagues in a condition-guided HIV screening strategy. We enrolled 300 patients, of which 202 were males (67.3%) and 98 were females (32.7%). Most of the screening was performed in Infectious Diseases (ID) and Hematologic wards. In total, we diagnosed eleven new HIV infections with a hospital prevalence in the study population of 3.7%. Five (45.4%) had a CD4 count <100/mm3, one (9.1%) <200/mm3, and one (9.1%) <300/mm3. Regarding risk factors, 81.8% declared having had unprotected sexual intercourse and 54.5% were heterosexual. All patients promptly started a combination antiretroviral regimen and 10 (90.9%) obtained an undetectable HIV-RNA status. Eight of the eleven (72.7%) patients are currently on follow-up in our outpatient clinic. A proactive indicator disease-guided screening can help avoid missed opportunities to diagnose HIV infection in a hospital setting. Implementing this kind of intervention could favor early diagnosis and access to treatment.

Clinical Outcomes of HER2-Negative Metastatic Breast Cancer Patients in Italy in the Last Decade: Results of the GIM 13-AMBRA Study.

GIM 13-AMBRA is a longitudinal cohort study aimed at describing therapeutic strategies and the relative outcome parameters in 939 HER2-ve MBC patients. Taxanes-based regimens, or taxanes + targeted agents, mainly Bevacizumab, were the preferred first choice in both Luminal (30.2%) and TNBC (33.3%) patients. The median PFS1 was 12.5 months (95% CI 16.79-19.64), without any significant difference according to subtypes, while the median Time to first Treatment Change (TTC1) was significantly lower in TNBC patients (7.7 months-95% CI 5.7-9.2) in comparison to Luminal A (13.2 months, 95% CI 11.7-15.1) and Luminal B patients (11.8 months, 95% CI 10.3-12.8). PFS2 was significantly shorter in TNBC patients (5.5 months, 95% CI 4.3-6.5 vs. Luminal A-9.4, 95% CI 8.1-10.7, and Luminal B-7.7 95% CI 6.8-8.2, F-Ratio 4.30, p = 0.014). TTC2 was significantly lower in patients with TNBC than in those with the other two subtypes. The median OS1 was 35.2 months (95% CI 30.8-37.4) for Luminal A patients, which was significantly higher than that for both Luminal B (28.9 months, 95% CI 26.2-31.2) and TNBC (18.5 months, 95% CI 16-20.1, F-ratio 7.44, p = 0.0006). The GIM 13-AMBRA study is one of the largest collections ever published in Italy and provides useful results in terms of time outcomes for first, second, and further lines of treatment in HER2- MBC patients.

Impact on breast cancer susceptibility and clinicopathological traits of common genetic polymorphisms in TP53, MDM2 and ATM genes in Sardinian women.

Common variants of genes involved in DNA damage correction [tumor protein p53 (TP53), murine double 2 homolog oncoprotein (MDM2) and ataxia-telengiectasia mutated (ATM)] may serve a role in cancer predisposition. The purpose of the present study was to investigate the association of five variants in these genes with breast cancer risk and clinicopathological traits in a cohort of 261 women from northern Sardinia. Polymorphic variants in TP53 (rs17878362, rs1042522 and rs1625895), MDM2 (rs2279744) and ATM (rs1799757) were determined by PCR and TaqMan single nucleotide polymorphism assay in patients with breast cancer (n=136) and healthy controls (n=125). Association with clinicopathological (e.g., age at diagnosis, lymph node involvement, clinical stage) and lifestyle factors (e.g., smoking status, alcohol intake, contraceptive use) was also evaluated. TP53 rs17878362 and rs1625895 polymorphisms were associated with decreased risk of BC diagnosis in patients older than 50 years (codominant and recessive models) and post-menopause (recessive model). Furthermore, there was a significant association between lymph node status (positive vs. negative) and ATM rs1799757-delT in dominant and additive models and between MDM2 rs2279744-allele and use of oral contraceptives. This analysis suggested that TP53 rs17878362 and rs1625895 may affect age of onset of breast cancer and ATM rs1799757 and MDM2 rs2279744 may be associated with lymph node status and prolonged use of oral contraceptives, respectively.

Activity of EGFR TKIs in Caucasian Patients With NSCLC Harboring Potentially Sensitive Uncommon EGFR Mutations.

BACKGROUND: Molecular characterization of non-small-cell lung cancer (NSCLC), defined predictive and druggable mutations that greatly modified patient prognoses. The most frequent driver mutations detected in NSCLC are epidermal growth factor receptor (EGFR) mutations, accounting for approximately 90% of exon 19 deletions and exon 21 point mutations. The other EGFR mutations are classified as uncommon or nonclassical and include exon 18 point mutations, exon 20 insertions, and combined mutations, which present different sensitivity to tyrosine kinase inhibitor (TKI) targeting. PATIENTS AND METHODS: We collected data from EGFR TKI-naive patients with metastatic NSCLC, harboring EGFR exon 18 mutations and EGFR combined mutations treated with first- or second-generation EGFR TKIs. Efficacy end points were evaluated considering the activity of EGFR TKIs in exon 18 versus double-mutation EGFR groups. RESULTS: Eighty-eight patients harboring uncommon EGFR mutations were evaluated in our analysis, and subdivided into 2 group: complex mutations (cohort A = 46 patients) and double mutations in exon 18 (cohort B = 42 patients). The results showed a median progression-free survival of 8.3 versus 12.3 months (hazard ratio [HR], 0.65; P = .06) and a median overall survival of 17.0 versus 31.0 months (HR, 0.62, P = .04) favoring the EGFR combination group. Within the combination group, no detrimental effect was associated with exon 20 mutations. CONCLUSION: Our study confirmed that EGFR exon 18 and combination mutations might be considered potentially sensitive uncommon mutations, with a similar survival compared with the well known common EGFR mutations. Comparative analysis showed that patients with complex mutations achieved longer survival compared with the exon 18 group, without correlation with the presence of exon 20 mutations.

Adjuvant zoledronic acid and letrozole plus ovarian function suppression in premenopausal breast cancer: HOBOE phase 3 randomised trial.

AIM: The aim of the study is to analyse whether letrozole (L) and zoledronic acid plus L (ZL) are more effective than tamoxifen (T) as adjuvant endocrine treatment of premenopausal patients with breast cancer with hormone receptor-positive (HR+) tumours. PATIENTS AND METHODS: In a phase 3 trial, 1065 premenopausal patients with HR + early breast cancer received triptorelin to suppress ovarian function and were randomly assigned (1:1:1) to adjuvant T, L or ZL for 5 years. Cancer recurrence, second breast or non-breast cancer and death were considered events for the intention-to-treat disease-free survival (DFS) analysis. RESULTS: With a 64-month median follow-up and 134 reported events, the disease-free rate at 5 years was 85.4%, 93.2% and 93.3% with T, L and ZL, respectively (overall P = 0.008). The hazard ratio for a DFS event was 0.52 (95% confidence interval [CI], 0.34 to 0.80; P = 0.003) with ZL vs T, 0.72 (95% CI, 0.48 to 1.07; P = 0.06) with L vs T and 0.70 (95% CI, 0.44 to 1.12; P = 0.22) with ZL vs L. With 36 deaths, there was no significant difference in overall survival (P = 0.14). Treatment was stopped for toxicity or refusal in 7.3%, 7.3% and 16.6% patients, and in the safety population, grade 3-4 side-effects were reported in 4.2%, 6.9% and 9.1% patients treated with T, L or ZL, respectively. CONCLUSION: HOBOE study shows that in premenopausal patients with early breast cancer undergoing ovarian function suppression with triptorelin, ZL significantly improves DFS, while worsening compliance and toxicity, as compared with T. (NCT00412022).

Deciduoid mesothelioma of the thorax: A comprehensive review of the scientific literature.

OBJECTIVE: Deciduoid mesothelioma is a rare variant of malignant epithelioid mesothelioma. It often involves the peritoneum, but also thoracic cases have been reported. The aim of the present review is to describe the demographic, clinical, radiological, and pathological features of such a rare variant of thoracic mesothelioma, and the state of the art regarding the therapeutic approaches currently available. DATA SOURCE: English-language articles published from 1985 to June 2016, and related to thoracic deciduoid mesothelioma cases were retrieved using the Pubmed database. STUDY SELECTION: The search terms were "mesothelioma," "thoracic mesothelioma," "epithelial mesothelioma," "pleural mesothelioma," and "deciduoid mesothelioma." RESULTS: Forty-four cases included in 16 articles, published in the period under investigation, were analyzed in detail. CONCLUSIONS: The mean age of the patients was 63 years, and the male to female ratio 1.7:1. Approximately 58% had exposure to asbestos, and 73% had a smoking history; familiarity was rarely reported. The most common anatomical site of origin was the right pleura, and the most frequent clinical manifestations were chest pain, dyspnea, cough, and weight loss. Thoracic X-ray and computed tomography were the imaging techniques most employed for diagnosis and surgical planning. The pathological diagnosis was obtained by examination of surgical or biopsy specimens in most cases. The best treatment strategy of deciduoid mesothelioma is a matter of debate; nevertheless a multidisciplinary approach is currently the best option for the choice of the adequate therapeutic scheme.

Intra-patient alternated dose escalation of paclitaxel and gemcitabine versus paclitaxel followed by fixed dose rate infusion of gemcitabine in fit elderly non-small cell lung cancer patients. A Southern Italy Cooperative Oncology Group randomised phase II trial.

PURPOSE: This study was undertaken to select the best schedule of administration for the paclitaxel plus gemcitabine combination in fit elderly patients affected by locally advanced or metastatic non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Ninety-eight patients in stage III or IV NSCLC, aged 70 years or more and in ECOG performance status (PS)

Bronchial mucoepidermoid carcinoma: A case report.

INTRODUCTION: Bronchial localization of Mucoepidermoid carcinoma (MEC) is rare. The precise nature of these neoplasms is not yet clear and little is known on the histogenesis and pathogenesis of the disease. Here we present a case of a bronchial MEC with a detailed pathological, immunohistochemical, and molecular analysis. PRESENTATION OF A CASE: A 46 years old Caucasian male patient was referred to our Unit for fever, non productive cough and dyspnea lasting for two months. The chest CT scan evidenced an 8-mm intraluminal lesion in the left main bronchus, in correspondence of the origin of the lingular segmental bronchus. Multiple biopsies were performed through bronchoscopy, and the diagnosis of a mucoepidermoid carcinoma of the lung was obtained. A left upper lobectomy was performed. The histopathological examination confirmed the preoperative diagnosis and stage (pT1N0M0). No further therapies were employed, given the stage of the disease. The patient is presently free of disease, approximately three years after surgery. DISCUSSION: The treatment of MECs is usually surgical by traditional or sleeve lobectomy, performed with an open or video-assisted technique, with the aim of an R0 resection. In this stage the prognosis is excellent. Conversely, high grade tumors seems to be particularly aggressive, even more than other NSCLC. CONCLUSIONS: Low grade type of Bronchial MEC, as our case, is often characterized by an optimal clinical management and prognosis. The lack of EGFR sensitizing mutations does not preclude the use of TKIs, which may be extremely useful in patients non responsive to other therapies.

A proper schedule of weekly paclitaxel and gemcitabine combination is highly active and very well tolerated in NSCLC patients.

BACKGROUND: In a previous phase I dose-escalation study, we showed a weekly administration of paclitaxel (TAX) and gemcitabine (GEM) to be active and very well tolerated in non-small-cell lung cancer (NSCLC) patients, with the lack of interaction between drugs. The dose of GEM 1500 mg/m(2) and TAX 100 mg/m(2) was selected for phase II studies due to its predictable kinetic behaviour and less severe thrombocytopenia. PATIENTS AND METHODS: Fifty-four chemo-naïve patients with advanced NSCLC (53 patients: stage IV) received TAX (100mg/m(2) i.v. infusion over 1h) followed by GEM 1500 mg/m(2) over 30 min) on days 1, 8, 15 and 21 of a 28-day cycle. RESULTS: The objective response rate was 46% (95% CI 32-61), median OS of 10.4 ms (95% CI 6.5-4.3), and a 1-year survival rate of 53%. Grades 3 and 4 haematological toxicity consisted of non-febrile neutropenia and thrombocytopenia in 13 and 4% of the cycles, respectively. Grade 3 non-haematological toxicities were observed in three patients (asthenia, diarrhoea and neuropathy), and were always reversible. CONCLUSIONS: This weekly schedule of TAX and GEM is highly active in chemo-naïve NSCLC patients and confirms the low toxicity profile already observed in a previous phase I study.

Successful outcome after combined chemotherapeutic and surgical management in a case of esophageal cancer with breast and brain relapse.

Esophageal cancer (EC) is a highly lethal disease. Approximately 50% of patients present with metastatic EC and most patients with localized EC will have local recurrence or develop metastases, despite potentially curative local therapy. The most common sites of distant recurrence are represented by lung, liver and bone while brain and breast metastases are rare. Usually patients with advanced disease are not treated aggressively and their median survival is six months. We report a woman patient who developed breast and brain metastases after curative surgery. We treated her with a highly aggressive chemotherapeutic and surgical combination resulting in a complete remission of the disease even after 11-year follow-up. We think that in super selected patients with more than one metastasis, when functional status is good and metastases are technically resectable, a surgical excision may be considered as a salvage option and chemotherapy should be delivered to allow a systemic control.

Small cell lung cancer in a young patient with osteopetrosis.

BACKGROUND: Osteopetrosis or Albers-Schönberg's disease is a heterogeneous group of rare hereditary troubles of the bone characterized by bone sclerosis due to an alteration of the bone reabsorption mediated by osteoclasts. The defect in the osteoclastic activity is responsible for complete or partial medullary cavities occlusion, with consequent reduced hemopoiesis, and for the excessive fragility of the affected bone segments. CASE REPORT: We reported the case of a young man of 31 years affected by osteopetrosis in which a small cell lung cancer developed. RESULTS: Small cell lung cancer is a particularly rare neoplasm in the young, and even though it is highly sensitive to chemotherapeutic treatment its prognosis remains poor. The greatest clinical problem connected with chemotherapeutic treatment of patients affected by osteopetrosis is the variability of the reduction of their bone marrow reserve, which could expose them to an excessive hematological toxicity caused by the therapy. CONCLUSIONS: The adoption of suitable prophylactic measures, such as the use of growth factors and drugs selected in relation to their toxicity or given in reduced doses, should be appropriately considered in these subjects.

Atypical primary pulmonary meningioma: a report of a case suspected of being a lung metastasis.

Primary extracranial and extraspinal meningiomas are very rare tumours, and primary pulmonary ones are even more uncommon. They present as a solitary pulmonary nodule, and most of them are benign, except for three cases. We describe a primitive atypical pulmonary meningioma first suspected of being a metastasis in a patient during follow-up ten years after therapy for breast cancer.

Efficacy and tolerability of biweekly bevacizumab, irinotecan, folinic acid and fluorouracil intravenous bolus (BIFF Regimen) in patients with metastatic colorectal cancer: the southern Italy cooperative oncology group experience.

BACKGROUND: We have extensively assessed a biweekly regimen of irinotecan plus folinic acid and fluorouracil bolus (IRIFAFU) in metastatic colorectal cancer (MCRC). Here, we report on the safety and activity of BIFF (bevacizumab plus IRIFAFU) regimen in 94 mCRC patients. PATIENTS AND METHODS: Bevacizumab 5 mg/kg (1 hour), and irinotecan 180 mg/m(2) (1 hour) were given intravenously on day 1, 6S-folinic acid 250 mg/m(2) (2 hours), and fluorouracil 850 mg/m(2) (bolus) were given intravenously on day 2 every 2 weeks for a median of 9 cycles per patient (range, 1-12), and maintenance bevacizumab alone was delivered in 16 cases. RESULTS: Grade ≥ 3 hematologic toxicities were neutropenia (50%) and febrile neutropenia (5%). Most common grade 3 nonhematologic side effects were diarrhea (20%), vomiting (7%), nausea (4%), and stomatitis (4%). Severe hypertension (1%) and epistaxis (1%) rarely occurred. Six complete responses and 44 partial responses were registered, giving a response rate of 53% (95% CI, 43%-64%). Median progression-free survival was 11.5 months (95% CI, 9.0-14.0 months). Forty-three (46%) patients eventually died, and the median overall survival was 24.0 months (95% CI, 20.2-27.8 months). CONCLUSION: Bevacizumab appeared to increase the activity of the IRIFAFU regimen without worsening its tolerability. Efficacy of BIFF was comparable with that reported with other bevacizumab plus irinotecan-based combinations.