Medical Oncology

Acute myeloid leukemia (AML) is a group of clonal diseases, resulting from two classes of mutation. Investigation for additional abnormalities associated with a well-recognized subtype, core-binding factor AML (CBF-AML) can provide further understanding and discrimination to this special group of leukemia. In order to better define genetic alterations in CBF-AML and identify possible cooperating lesions, a single-nucleotide polymorphism-array (SNP-array) analysis was performed, combined to KIT mutation screening, in a set of cases. Validation of SNP-array results was done by array comparative genomic hybridization and FISH. Fifteen cases were analyzed. Three cases had microscopic lesions better delineated by arrays. One case had +22 not identified by arrays. Submicroscopic abnormalities were mostly non-recurrent between samples. Of relevance, four regions were more frequently affected: 4q28, 9p11, 16q22.1, and 16q23. One case had an uncovered unbalanced inv(16) due to submicroscopic deletion of 5´MYH11 and 3´CBFB. Telomeric and large copy number neutral loss of heterozygosity (CNN-LOH) regions (>25 Mb), likely representing uniparental disomy, were detected in four out of fifteen cases. Only three cases had mutation on KIT gene, enhancing the role of abnormalities by SNP-array as presumptive cooperating alterations. Molecular karyotyping can add valuable information to metaphase karyotype analysis, emerging as an important tool to uncover and characterize microscopic, submicroscopic genomic alterations, and CNN-LOH events in the search for cooperating lesions.

Sarcomatoid features can arise in renal cell carcinoma of any subtype and are associated with a poor prognosis. Doxorubicin and gemcitabine in a limited series showed activity in aggressive renal tumors and we wished to formally assess the combination in patients with renal cell carcinoma specifically containing sarcomatoid features. The Eastern Cooperative Oncology Group (ECOG) conducted a phase II trial of doxorubicin 50 mg/m2 IV push and gemcitabine 1,500 mg/m2 IV over 30 min every 2 weeks in 39 patients with locally advanced or metastatic renal cell carcinoma with sarcomatoid features. Ten patients (26%) had grade 3 toxicity, and four patients (11%) had grade 4 toxicities. Although most toxicity was from myelosuppression, one patient died on study from cardiac dysfunction after a cumulative dose of 450 mg/m2 doxorubicin. Six (16%) patients experienced responses (5 partial responses and 1 complete response), and ten (26%) patients had stable disease. In addition, another patient had an unconfirmed partial response and an additional patient experienced over 50% decrease in her tumor burden after an initial progression. The median overall survival was 8.8 months, and the median progression-free survival was 3.5 months. We conclude that the combination of doxorubicin and gemcitabine, inactive in patients with mostly clear cell histology, demonstrated responses in patients with RCC with sarcomatoid features. We acknowledge the toxicity of this combination but note that limited treatment options exist for this aggressive histology. Only through prospective multicenter trials with comprehensive central pathology review will better treatment options be identified.

Before the development of targeted therapies, administration of cytokines (e.g., interleukin-2, interferon-α) was the primary systemic treatment option for advanced renal cell carcinoma. Sorafenib, an oral targeted, multikinase inhibitor, significantly prolonged progression-free survival and overall survival in the Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGET), a large (N = 903) phase III, double-blind, randomised, placebo-controlled study of patients with advanced renal cell carcinoma resistant to standard therapy. This analysis of a patient subgroup from TARGET evaluated the safety and efficacy of sorafenib in patients who had received prior cytokine therapy (sorafenib: n = 374; placebo: n = 368) and in patients who were cytokine-naïve (sorafenib: n = 77; placebo: n = 84). Progression-free survival was significantly prolonged with sorafenib therapy compared with placebo among patients with and without prior cytokine therapy (respectively 5.5 vs. 2.7 months; hazard ratio, 0.54; 95% confidence interval, 0.45–0.64 and 5.8 vs. 2.8 months; hazard ratio, 0.48; 95% confidence interval, 0.32–0.73). Clinical benefit rates for sorafenib-treated patients compared with placebo patients were also higher (cytokine-treated: 83 vs. 54.3%; cytokine-naïve: 85.7 vs. 56.0%). Sorafenib was well tolerated in both subgroups (grade 3/4: 20 and 22%, respectively). Sorafenib demonstrated a consistent, significant clinical benefit against advanced renal cell carcinoma, with a twofold improvement in progression-free survival and disease control rate, with similar toxicities in patients with or without prior cytokine treatment.

Brain metastases from radioresistant histologies are perceived to be less responsive to WBRT compared to other histologies, and stereotactic radiosurgery (SRS) may provide better local control. The aim of this study was to examine the outcomes of patients with 1–4 brain metastasis from radioresistant histologies (renal cell carcinoma and melanoma) treated with SRS alone. Thirty-eight patients with 1–4 radioresistant brain metastases (66 lesions) were treated with SRS alone. The median age was 55 years. Fourteen and 24 patients had renal cell carcinoma (RCC) and melanoma brain metastases, respectively. Distribution of number of lesions was as follows: one lesion, 22 patients; 2 lesions, 8 patients; 3 lesions, 5 patients; and 4 lesions, 3 patients. Distribution of RTOG recursive partitioning analysis (RPA) classes was as follows: II, 37 patients and III, 1 patient. The median marginal dose was 20 Gy. The median follow-up was 6.1 months. The 3-, 6-, 9-, 12-, and 18-month local control (LC) rates were 87.9, 81.4, 67.9, 67.9, and 60.3%, respectively. The corresponding free-from-distant-brain failure (FFDBF) rates were 71.3, 58.1, 49.8, 40.2, and 27.6%. The corresponding progression-free survival (PFS) rates were 55.3, 41.9, 33, 23.3, and 13.3%. RCC histology was associated with better LC (P = 0.0055). Although SRS alone could yield reasonable LC in patients with 1–4 radioresistant brain metastases, the risk of distant brain failure was substantial. The approach of routine omission of WBRT outside of a trial setting should be used judiciously.

Even though ipilimumab is a promising antibody used for stage IV melanoma therapy, the response varies and is difficult to predict. We here report on a case of successful treatment with ipilimumab in dacarbazine-resistant metastatic malignant melanoma, including a review of the literature on the long-term treatment results. A 62-year-old patient with a history of a resected lentigo-maligna melanoma 5 years earlier and parotideal metastasis 1 year before was admitted with a newly detected 3.5 cm liver metastasis. Atypical liver resection was performed (R1). Immunohistochemically, CD3+ T-lymphocytes and CD68+ macrophages were detected at the tumour margins and within the parotideal and hepatic melanoma metastases. A sub-analysis of the liver metastasis showed scattered FOX-P3+ regulatory T-lymphocytes as well as multiple CD8+ effector T-cells. Chemotherapy with dacarbazine 1,000 mg/m2/day was administered at 4-weeks intervals for 3 months. A follow-up positron-emission computed tomography and liver biopsy revealed melanoma metastases in the liver, lungs, and mediastinum. Compassionate use of ipilimumab was administered at 3 mg/kg every 3 weeks for a total of four doses. After an initial increase in tumour size, most lesions responded, but progressive axillary and cervical lymphadenopathy was observed before complete remission was achieved. Side effects included fatigue, dyspnoea, cough, upper abdominal pain with diarrhoea, and gingival hyperplasia. Now, 36 months after ipilimumab therapy and 8 years after the initial melanoma diagnosis, the tumour did not recur. It would be challenging to hypothesize that long intervals between diagnosis and need for treatment, clinical side effects, an initial increase in tumour size and the presence of intra-tumoural T-cells and macrophages might predict tumour response.

Sorafenib is an oral multikinase inhibitor approved for the treatment of hepatocellular carcinoma (HCC). In two randomized trials, sorafenib was reported to be safe without a significant impact on quality of life (QoL). The aim of this study was to evaluate the occurrence of adverse events, QoL variations, and treatment discontinuations in HCC patients treated with sorafenib. Between November 2009 and March 2011, all patients evaluated as suitable for sorafenib treatment were enrolled. Every patient was invited to complete the Functional Assessment of Cancer Therapy–Hepatobiliary Questionnaire before starting therapy, at week 1, and at months 1 and 2. QoL scores were analyzed by the Wilcoxon matched-pairs test. Side effects were classified according to the Common Terminology Criteria for Adverse Events v.3.0. Thirty-six patients were enrolled. The cumulative incidence of therapy discontinuation for drug-related adverse events was 33 % (95 % confidence interval, 20.2–49.7). The most common adverse event was fatigue (66.7 %). The worst score decrease was detected from baseline to week 1 in physical well-being, with a median reduction of −8.3 (range −60.1 to 17.9; P = 0.0003). Treatment withdrawal from adverse events was higher than previously reported, significant QoL decrease occurred, and estimated feasibility was 66.7 %.

Neutrophils are the predominant white blood cells (WBC) that are recruited to the sites of inflammation and infection. They are acknowledged to perform dual roles by promoting (pro-tumor) or by exhibiting anti-cancer properties (anti-tumor). Neutrophils are characterized based on the changes in phenotype and functional properties. To this context, circulating polymorphonuclear neutrophils (cPMN) and tumor-associated neutrophils (TANs) in cancer biology has been well explored but limited to oral polymorphonuclear neutrophils (oPMNs) in oral squamous cell carcinoma (OSCC). However, oPMNs are eminent in maintaining the healthy oral ecosystem by neutralizing microorganisms. Neutralization process enhances the expression of cell surface markers (CD11b, CD63, CD66, CD66b, CD66c, and CD66e) and inflammatory cytokines (TNF-α, IFN-γ, GM-CSF, and IL-8) and increases the recruitment of neutrophils. Along with the inflammation, it has been reported that CEACAM1 and chemerin also favors the infiltration of neutrophils to the cancer site. This indicates that oPMN might contribute to the aetiology of OSCC. The main objective of this review is to explore, the production and migration of oPMNs to the oral cavity, their phenotypes and possible role in OSCC.

CD20 is a receptor expressed on B cells with anonymous functions. The receptor is the target of some food and drug administration (FDA) approved monoclonal antibodies (mAb), such as Rituximab and Obinutuzumab. Blocking CD20 using the aforementioned mAbs has improved Non-Hodgkin Lymphoma (NHL) therapy. All commercial mAbs on the market were raised in non-human animal models. Antibody humanization is inevitable to mitigate immune response. In order to keep the affinity of antibody intact, humanizations are only applied to frameworks which do not eliminate immune response to foreign CDRs sequences. To address this issue, human monoclonal antibody deemed imperative. Herein, we report the isolation and characterization of a fully human single-chain variable fragment (scFv) against the large loop of CD20 from naïve human antibody library. After three rounds of phage display, a library of enriched anti-CD20 scFv was obtained. The polyclonal phage ELISA demonstrated that after each round of phage display, the population of anti-CD20 scFv became dominant. The scFv, G7, with the most robust interaction with CD20 was selected for further characterization. The specificity of G7 scFv was evaluated by ELISA, western blot, and flow cytometry. Detecting CD20 in western blot showed that G7 binds to a linear epitope on CD20 large loop. Next, G7 scFv was also bound to Raji cell (CD20+) while no interaction was recorded with K562 cell line (CD20—). This data attested that the epitope recognized by G7 scFv is accessible on the cell membrane. The affinity of G7 scFv was estimated to be 63.41 ± 3.9 nM. Next, the sensitivity was evaluated to be 2 ng/ml. Finally, G7 scFv tertiary structure was modeled using Graylab software. The 3D structure illustrated two domains of variable heavy (VH) and variable light (VL) connected through a linker. Afterward, G7 scFv and CD20 were applied to in-silico docking using ClusPro to illustrate the interaction of G7 with the large loop of CD20. As the selected scFv from the human antibody library is devoid of interspecies immunogenic amino acids sequences, no humanization or any other modifications are required prior to clinical applications.