Population-Based Analysis of Trends in Incidence and Survival of Human Papilloma Virus-Related Oropharyngeal Cancer in a Low-Burden Region of Southern Europe.

Introduction: Human papilloma virus (HPV)-related oropharyngeal carcinoma (OPC) can be considered a new subtype of cancer with different clinical characteristics and prognosis than that related to tobacco. Its incidence is increasing worldwide. Its epidemiology has been widely studied in areas such as North America and Northern Europe, but less is known in Southern Europe. Methods: We analyzed the epidemiology of OPC using the database from Girona's population-based Cancer Registry, in the North-East of Spain, from 1994 to 2018. To analyze differences between neoplasms related to human papillomavirus or not, we determined the immunohistochemical expression of p16 in cases within four time periods: 1997-1999, 2003-2005, 2009-2011, and 2016-2018. Results: Oropharyngeal cancer incidence increased significantly from 2001 to 2018 with an Annual Percentage of Change (APC) of 4.1. OPC p16-positive cases increased with an APC of 11.1. In the most recent period, 2016-2018, 38.5% of OPC cases were p16-positive. European age-standardized incidence rate was 4.18 cases/100.000 inhabitants-year for OPC cancer and 1.58 for those p16-positive. Five-year observed survival was 66.3% for p16-positive OPC and 37.7% for p16-negative. Conclusions: Although with lower burden than in other regions, p16-positive oropharyngeal cancer is increasing in our area and has a better prognosis than p16-negative OPC.

Melatonin Targets Metabolism in Head and Neck Cancer Cells by Regulating Mitochondrial Structure and Function.

Metabolic reprogramming, which is characteristic of cancer cells that rapidly adapt to the hypoxic microenvironment and is crucial for tumor growth and metastasis, is recognized as one of the major mechanisms underlying therapeutic resistance. Mitochondria, which are directly involved in metabolic reprogramming, are used to design novel mitochondria-targeted anticancer agents. Despite being targeted by melatonin, the functional role of mitochondria in melatonin's oncostatic activity remains unclear. In this study, we aim to investigate the role of melatonin in mitochondrial metabolism and its functional consequences in head and neck cancer. We analyzed the effects of melatonin on head and neck squamous cell carcinoma (HNSCC) cell lines (Cal-27 and SCC-9), which were treated with 100, 500, and 1500 µM of melatonin for 1, 3, and 5 days, and found a connection between a change of metabolism following melatonin treatment and its effects on mitochondria. Our results demonstrate that melatonin induces a shift to an aerobic mitochondrial metabolism that is associated with changes in mitochondrial morphology, function, fusion, and fission in HNSCC. We found that melatonin increases oxidative phosphorylation (OXPHOS) and inhibits glycolysis in HNSCC, resulting in increased ROS production, apoptosis, and mitophagy, and decreased cell proliferation. Our findings highlight new molecular pathways involved in melatonin's oncostatic activity, suggesting that it could act as an adjuvant agent in a potential therapy for cancer patients. We also found that high doses of melatonin, such as those used in this study for its cytotoxic impact on HNSCC cells, might lead to additional effects through melatonin receptors.

RNA sequencing and Immunohistochemistry Reveal ZFN7 as a Stronger Marker of Survival than Molecular Subtypes in G-CIMP-negative Glioblastoma.

PURPOSE: Glioblastoma is the most aggressive brain tumor in adults and has few therapeutic options. The study of molecular subtype classifications may lead to improved prognostic classification and identification of new therapeutic targets. The Cancer Genome Atlas (TCGA) subtype classification has mainly been applied in U.S. clinical trials, while the intrinsic glioma subtype (IGS) has mainly been applied in European trials. EXPERIMENTAL DESIGN: From paraffin-embedded tumor samples of 432 patients with uniformly treated, newly diagnosed glioblastoma, we built tissue microarrays for IHC analysis and applied RNA sequencing to the best samples to classify them according to TCGA and IGS subtypes. RESULTS: We obtained transcriptomic results from 124 patients. There was a lack of agreement among the three TCGA classificatory algorithms employed, which was not solely attributable to intratumoral heterogeneity. There was overlapping of TCGA mesenchymal subtype with IGS cluster 23 and of TCGA classical subtype with IGS cluster 18. Molecular subtypes were not associated with prognosis, but levels of expression of 13 novel genes were identified as independent prognostic markers in glioma-CpG island methylator phenotype-negative patients, independently of clinical factors and MGMT methylation. These findings were validated in at least one external database. Three of the 13 genes were selected for IHC validation. In particular, high ZNF7 RNA expression and low ZNF7 protein expression were strongly associated with longer survival, independently of molecular subtypes. CONCLUSIONS: TCGA and IGS molecular classifications of glioblastoma have no higher prognostic value than individual genes and should be refined before being applied to clinical trials.

Dosimetric impact of Acuros XB dose-to-water and dose-to-medium reporting modes on VMAT planning for head and neck cancer.

PURPOSE: To assess the dosimetric impact of switching from the Analytical Anisotropic Algorithm (AAA) to Acuros XB (AXB) for both dose-to-medium (Dm) and dose-to-water (Dw) in VMAT for H&N patients. To study whether it should be linked to a change in the dose prescriptions to the PTVs and in the constraints to the OARs. METHODS: 110H&N patients treated with VMAT were included. Calculations were performed with AAA and AXB. PTV54, PTV60, PTV70, spinal cord, brainstem, brain, larynx, oral cavity, cochleas, parotid glands and mandible were delineated. Clinically-relevant dose-volume parameters were compared. Paired t-tests were used to analyze the differences in mean values. The Pitman-Morgan dispersion test was computed to evaluate inter-patient variability of these differences. RESULTS: AAA overestimated all dose-volume parameters compared to AXB Dm (0.2 Gy to 2.4 Gy). No systematic trend was observed in the differences between AAA and AXB Dw (-5.3 Gy to 0.6 Gy). Dose-volume parameters were significantly higher for AXB Dw compared to AXB Dm (0.1 Gy to 6.6 Gy). In all cases, the largest absolute differences (4%-14%) were found for maximum absorbed doses to the cochleas and the mandible. The number of parameters with significant inter-patient variability was greater when switching from AAA to AXB Dw than from AAA to AXB Dm. CONCLUSIONS: There are important differences between AXB and AAA in VMAT planning for H&N cancer. The systematic differences and their inter-patient variability identified may help to facilitate decision-making about the dose prescriptions to the PTVs and the constraints to the OAR.

Pseudoprogression as an adverse event of glioblastoma therapy.

We explored predictive factors of pseudoprogression (PsP) and its impact on prognosis in a retrospective series of uniformly treated glioblastoma patients. Patients were classified as having PsP, early progression (eP) or neither (nP). We examined potential associations with clinical, molecular, and basal imaging characteristics and compared overall survival (OS), progression-free survival (PFS), post-progression survival (PPS) as well as the relationship between PFS and PPS in the three groups. Of the 256 patients studied, 56 (21.9%) were classified as PsP, 70 (27.3%) as eP, and 130 (50.8%) as nP. Only MGMT methylation status was associated to PsP. MGMT methylated patients had a 3.5-fold greater possibility of having PsP than eP (OR: 3.48; 95% CI: 1.606-7.564; P = 0.002). OS was longer for PsP than eP patients (18.9 vs. 12.3 months; P = 0.0001) but was similar for PsP and nP patients (P = 0.91). OS was shorter-though not significantly so-for PsP than nP patients (OS: 19.5 vs. 27.9 months; P = 0.63) in methylated patients. PPS was similar for patients having PsP, eP or nP (PPS: 7.2 vs. 5.4 vs. 6.7; P = 0.43). Neurological deterioration occurred in 64.3% of cases at the time they were classified as PsP and in 72.8% of cases of eP (P = 0.14). PsP confounds the evaluation of disease and does not confer a survival advantage in glioblastoma.

Cetuximab as treatment for head and neck cancer patients with a previous liver transplant: report of two cases.

Cetuximab is a monoclonal antibody against epidermal growth factor receptor useful in the treatment of patients with Head and Neck Squamous Cell Carcinoma combined with radiotherapy or chemotherapy. Its pharmacokinetics are not influenced by hepatic status and there are no specific warnings concerning its indication in patients with impaired hepatic function. Patients with a previous liver transplant are at risk for hepatic toxicity and use immunosupressants to avoid rejection that can interact with other drugs. We present two cases of patients with a previous liver transplant in which cetuximab was administered to treat head and neck cancer.

Response of brain metastasis from lung cancer patients to an oral nutraceutical product containing silibinin.

Despite multimodal treatment approaches, the prognosis of brain metastases (BM) from non-small cell lung cancer (NSCLC) remains poor. Untreated patients with BM have a median survival of about 1 month, with almost all patients dying from neurological causes. We herein present the first report describing the response of BM from NSCLC patients to an oral nutraceutical product containing silibinin, a flavonoid extracted from the seeds of the milk thistle. We present evidence of how the use of the silibinin-based nutraceutical Legasil® resulted in significant clinical and radiological improvement of BM from NSCLC patients with poor performance status that progressed after whole brain radiotherapy and chemotherapy. The suppressive effects of silibinin on progressive BM, which involved a marked reduction of the peritumoral brain edema, occurred without affecting the primary lung tumor outgrowth in NSCLC patients. Because BM patients have an impaired survival prognosis and are in need for an immediate tumor control, the combination of brain radiotherapy with silibinin-based nutraceuticals might not only alleviate BM edema but also prove local control and time for either classical chemotherapeutics with immunostimulatory effects or new immunotherapeutic agents such as checkpoint blockers to reveal their full therapeutic potential in NSCLC BM patients. New studies aimed to illuminate the mechanistic aspects underlying the regulatory effects of silibinin on the cellular and molecular pathobiology of BM might expedite the entry of new formulations of silibinin into clinical testing for progressive BM from lung cancer patients.

Brain nodules with lung mass: are they always metastases?

In a smoking adult with a lung mass, brain masses are usually diagnosed as brain metastases of lung origin. Nevertheless, differential diagnosis between cerebral abscesses cannot be performed based on clinical symptoms or imaging technologies, and histological diagnosis is essential. This case illustrates the advisability of always obtaining histological diagnosis of the primary tumor and/or cerebral lesion before introducing any oncological treatment.

Diagnostic efficacy of bone scintigraphy, magnetic resonance imaging, and positron emission tomography in bone metastases of myxoid liposarcoma.

Myxoid liposarcomas (MLS) have a tendency to metastasize to unusual sites. We report an unusual case of bone metastases not detected by bone scan and neither by fluorodeoxyglucose positron emission tomography (PET-FDG) and successfully identified with magnetic resonance imaging (MRI) in a patient with metachronic MLS. Histopathological examination of the primary tumor evidenced a tumor with unfavorable prognostic markers, and the biopsy of an iliac bone lesion confirmed the diagnosis of metastatic disease. On histological grounds, the tumor showed features of a more differentiated neoplasm without foci of round cells or necrosis in the latter. MRI allowed the identification of disseminated disease compared to computed tomography (CT) and PET scans. Thus, because of the heterogeneous histological features of MLS and the biological behavior of the disease, a combined approach of FDGPET-CT and MRI, may allow a more accurate staging of soft tissue sarcomas.

Toxicity of combined treatment of adjuvant irradiation and interferon alpha2b in high-risk melanoma patients.

Surgically resected stage III melanoma patients commonly receive adjuvant therapy with interferon (IFN) alpha2b. For those patients with high-risk features of draining node recurrence, radiation therapy can also be considered as a treatment option. The purpose of this retrospective study was to assess the efficacy and radiation-related toxicity of this combined therapy. Eighteen patients receiving adjuvant IFNalpha2b therapy during radiation therapy, or within 1 month of its completion, were reviewed retrospectively and analysed for outcome. Radiation was delivered at 600 cGy dose per fraction, in 16 out of 18 patients, twice a week, and at 200 cGy dose per fraction in two patients five times a week. Total radiation dose and number of fractions were as follows: 30 Gy/5 fr (n=8), 36 Gy/6 fr (n=8) and 50 Gy/25 fr (n=2). The percentage of disease-free patients, with no local recurrence, at 3 years was 88%. In 10 patients, IFNalpha2b was administered concurrently with radiotherapy; in three, within 30 days before or after radiation; and in five, more than 30 days after radiation. All the patients experienced acute skin reactions, grade I on the Radiation Therapy Oncology Group (RTOG) scale. Late radiation-related toxicity was seen in one patient with grade III (RTOG) skin reaction and two with grade IV (RTOG) radiation-induced myelitis. Concurrent use of adjuvant radiotherapy and IFNalpha2b might enhance radiation-induced toxicity, and special care should be taken when the spinal cord is included in the radiation field.

Clinical outcome after surgical resection of lung metastases from melanoma.

BACKGROUND: Surgical therapy plays an important role in the management of selected patients with metastatic melanoma. PURPOSE: A retrospective review of 13 patients who underwent surgical resection of lung metastases from melanoma from 1996 to 2003 was performed. The aim of the study was to analyze the clinical outcome and survival time. MATERIALS AND METHODS: Mean age was 45 years old (range: 31-64). Complete tumour resection was confirmed histologically. Nine patients presented one single pulmonary lesion, two lesions (n = 3) and three lesions (n = 1) but in all cases confined in the same pulmonary lobe. RESULTS: Median survival time (MST) for the entire group was 20 months (95% confidence interval (CI): 16-24 months). The median time to disease progression after lung metastasectomy was 5 months (95% CI: 3-7 months). MST, according to the prognostic groups proposed by the International Registry of Lung Metastases, was 17 months (95% CI: 6-28 months) for group I (n = 6), MST of 20 months (95% CI: 16-24 months) for group II (n = 5) and MST of 4 months for group III (n = 2), without differences statistically significant (log-rank p = 0.423). MST regarding the time of disease free interval from diagnostic of primary tumour and lung metastases (< 36 months [n = 5] vs > 36 months [n = 8]) was 20 months and 17 months respectively, without differences statistically significant (log rank p = 0.222). CONCLUSIONS: Surgical resection when feasible provides survival rates superior to any available nonsurgical therapy. In carefully selected patients, when the resection is performed with curative intent, it may result in improved survival.

Spanish patterns of care for 3D radiotherapy in non-small-cell lung cancer.

PURPOSE: Curative radiotherapy for non-small-cell lung cancer is a difficult challenge, despite the use of conformal radiotherapy. Optimal three-dimensional delineation of treatment volumes is essential for improvement of local control and for limiting of tissue toxicity. MATERIAL AND METHODS: A planning course on clinical practice of lung cancer was held in Barcelona. A questionnaire was given concerning (1) patient positioning, (2) planning-computed tomography scan, (3) accounting for tumor mobility, (4) investigative-procedure respiration-gated radiotherapy and breath-holding maneuvers, (5) generation of target volumes, (6) treatment planning, and (7) treatment delivery. This questionnaire was made to determine the Spanish application of European recommendations. RESULTS: On the negative side, 1 hospital did not use three-dimensional tools, less than 50% used immobilization devices, and 55.6% used computed tomography slices of greater than 5 mm. On the positive side, 70.4% did not use standard margins for gross target volume derived from a computed tomography scan, 92.6% agreed with the inclusion of Naruke anatomic criteria of 1 cm or more in gross target volume planning, and 75% used V20 to estimate the risk of pneumonitis. CONCLUSIONS: This study is the first validation of European recommendations for treatment planning and execution of radiotherapy in lung cancer. The main conclusion is the need to improve the negative aspects determined.