Merkel cell carcinoma is an aggressive neuroendocrine skin cancer that usually affects elderly patients. Despite being uncommon, incidence has been steadily increasing over the last two decades, ...likely due to increased awareness, better diagnostic methods and aging of the population. It is currently one of the most lethal cutaneous malignancies, with a five-year overall survival of approximately 50%. With the better understanding of the molecular pathways that lead to the development of Merkel cell carcinoma, there has been an increasing excitement and optimism surrounding novel targeted therapies, in particular to immunotherapy. Some of the concepts surrounding the novel targeted therapies and currently ongoing clinical trials are reviewed here.
Summary Background The relative efficacy of the addition of induction chemotherapy to chemoradiotherapy compared with chemoradiotherapy alone for patients with head and neck cancer is unclear. The ...PARADIGM study is a multicentre open-label phase 3 study comparing the use of docetaxel, cisplatin, and fluorouracil (TPF) induction chemotherapy followed by concurrent chemoradiotherapy with cisplatin-based concurrent chemoradiotherapy alone in patients with locally advanced head and neck cancer. Methods Adult patients with previously untreated, non-metastatic, newly diagnosed head and neck cancer were eligible. Patients were eligible if their tumour was either unresectable or of low surgical curability on the basis of advanced tumour stage (3 or 4) or regional-node stage (2 or 3, except T1N2), or if they were a candidate for organ preservation. Patients were randomly assigned (in a 1:1 ratio) to receive either induction chemotherapy with three cycles of TPF followed by concurrent chemoradiotherapy with either docetaxel or carboplatin or concurrent chemoradiotherapy alone with two cycles of bolus cisplatin. A computer-generated randomisation schedule using minimisation was prepared and the treatment assignment was done centrally at one of the study sites. Patients, study staff, and investigators were not masked to group assignment. Stratification factors were WHO performance status, primary disease site, and stage. The primary endpoint was overall survival. Analysis was by intention to treat. Patient accrual was terminated in December, 2008, because of slow enrolment. The trial is registered with ClinicalTrials.gov , number NCT00095875. Findings Between Aug 24, 2004, and Dec 29, 2008, we enrolled 145 patients across 16 sites. After a median follow-up of 49 months (IQR 39–63), 41 patients had died—20 in the induction chemotherapy followed by chemoradiotherapy group and 21 in the chemoradiotherapy alone group. 3-year overall survival was 73% (95% CI 60–82) in the induction therapy followed by chemoradiotherapy group and 78% (66–86) in the chemoradiotherapy alone group (hazard ratio 1·09, 95% CI 0·59–2·03; p=0·77). More patients had febrile neutropenia in the induction chemotherapy followed by chemoradiotherapy group (16 patients) than in the chemoradiotherapy alone group (one patient). Interpretation Although survival results were good in both groups there was no difference noted between those patients treated with induction chemotherapy followed by chemoradiotherapy and those who received chemoradiotherapy alone. We cannot rule out the possibility of a difference in survival going undetected due to early termination of the trial. Clinicians should still use their best judgment, based on the available data, in the decision of how to best treat patients. The addition of induction chemotherapy remains an appropriate approach for advanced disease with high risk for local or distant failure. Funding Sanofi-Aventis.
Abstract Purpose To date, there is no screening test for lung cancer shown to affect overall mortality. MicroRNAs (miRNAs) are a class of small noncoding RNA genes found to be abnormally expressed in ...several types of cancer, suggesting a role in the pathogenesis of human cancer. Patients and Methods We evaluated the circulating levels of tumor exosomes, exosomal small RNA, and specific exosomal miRNAs in patients with and without lung adenocarcinoma, correlating the levels with the American Joint Committee on Cancer (AJCC) disease stage to validate it as an acceptable marker for diagnosis and prognosis in patients with adenocarcinoma of the lung. Results To date, 27 patients with lung adenocarcinoma AJCC stages I-IV and 9 controls, all aged 21-80 years, were enrolled in the study. Small RNA was detected in the circulating exosomes. The mean exosome concentration was 2.85 mg/mL (95% CI, 1.94–3.76) for the lung adenocarcinoma group versus 0.77 mg/mL (95% CI, 0.68–0.86) for the control group ( P < .001). The mean miRNA concentration was 158.6 ng/mL (95% CI, 145.7–171.5) for the lung adenocarcinoma group versus 68.1 ng/mL (95% CI, 57.2–78.9) for the control group ( P < .001). Comparisons between peripheral circulation miRNA-derived exosomes and miRNA-derived tumors indicated that the miRNA signatures were not significantly different. Conclusion The significant difference in total exosome and miRNA levels between lung cancer patients and controls, and the similarity between the circulating exosomal miRNA and the tumor-derived miRNA patterns, suggest that circulating exosomal miRNA might be useful as a screening test for lung adenocarcinoma. No correlation between the exosomal miRNA levels and the stage of disease can be made at this point.
Summary Head and neck squamous cell carcinoma (HNSCC) affects over half a million people worldwide. Despite advances in therapy, only half of the patients are alive in 5 years. Epidermal growth ...factor receptor (EGFR) is overexpressed in approximately 90% of the tumors, and it is correlated with poor response to treatment and worse outcome. Multiple therapies targeting this pathway have been tested. Cetuximab is the only EGFR inhibitor approved in HNSCC, but response rates are low. More recently, significant interest has focus on identifying mechanisms of acquired and de novo EGFR blockage resistance. Here we review some of these mechanisms and describe strategies to overcome that resistance.
Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine carcinoma of the skin caused by either the integration of Merkel cell polyomavirus (MCPyV) and expression of viral T antigens or by ...ultraviolet-induced damage to the tumor genome from excessive sunlight exposure. An increasing number of deep sequencing studies of MCC have identified significant differences between the number and types of point mutations, copy number alterations, and structural variants between virus-positive and virus-negative tumors. However, it has been challenging to reliably distinguish between virus positive and UV damaged MCC.
In this study, we assembled a cohort of 71 MCC patients and performed deep sequencing with OncoPanel, a clinically implemented, next-generation sequencing assay targeting over 400 cancer-associated genes. To improve the accuracy and sensitivity for virus detection compared to traditional PCR and IHC methods, we developed a hybrid capture baitset against the entire MCPyV genome and software to detect integration sites and structure.
Sequencing from this approach revealed distinct integration junctions in the tumor genome and generated assemblies that strongly support a model of microhomology-initiated hybrid, virus-host, circular DNA intermediate that promotes focal amplification of host and viral DNA. Using the clear delineation between virus-positive and virus-negative tumors from this method, we identified recurrent somatic alterations common across MCC and alterations specific to each class of tumor, associated with differences in overall survival. Finally, comparing the molecular and clinical data from these patients revealed a surprising association of immunosuppression with virus-negative MCC and significantly shortened overall survival.
These results demonstrate the value of high-confidence virus detection for identifying molecular mechanisms of UV and viral oncogenesis in MCC. Furthermore, integrating these data with clinical data revealed features that could impact patient outcome and improve our understanding of MCC risk factors.
Preclinical and clinical studies suggest potential synergy between high dose per fraction focal radiation and immunotherapy. However, conventionally fractionated radiation regimens in combination ...with concurrent chemotherapy are more commonly administered to patients as definitive treatment and may have both immune-stimulating and -suppressive effects.
We prospectively collected longitudinal samples from head and neck squamous cell carcinoma patients receiving definitive radiation therapy. We quantified changes in populations of circulating immune cells and chemokines CXCL9, 10, and 16. Analyses of humoral and cellular immune responses were conducted in select patients via proteomic analysis and T-cell receptor sequencing.
Treatment not only increased circulating CD-8+ T-effector cells, but also myeloid-derived suppressor cells, regulatory T cells, and checkpoint receptor-expressing T cells, particularly PD-1+ T cells. Significant decreases in CXCL10 and increases in CXLC16 were noted. Treatment also increased the percentage of unique and dominant TCR clones, and increased humoral responses as measured by proteomic array.
Our results suggest that fractionated chemoradiation leads to quantifiable effects in circulating immune mediators, including a balance of stimulatory and suppressive mechanisms. These results suggest future combinations with immune checkpoint blockade.
Merkel cell polyomavirus is the primary etiological agent of the aggressive skin cancer Merkel cell carcinoma (MCC). Recent studies have revealed that UV radiation is the primary mechanism for ...somatic mutagenesis in nonviral forms of MCC. Here, we analyze the whole transcriptomes and genomes of primary MCC tumors. Our study reveals that virus-associated tumors have minimally altered genomes compared to non-virus-associated tumors, which are dominated by UV-mediated mutations. Although virus-associated tumors contain relatively small mutation burdens, they exhibit a distinct mutation signature with observable transcriptionally biased kataegic events. In addition, viral integration sites overlap focal genome amplifications in virus-associated tumors, suggesting a potential mechanism for these events. Collectively, our studies indicate that Merkel cell polyomavirus is capable of hijacking cellular processes and driving tumorigenesis to the same severity as tens of thousands of somatic genome alterations.
A variety of mutagenic processes that shape the evolution of tumors are critical determinants of disease outcome. Here, we sequenced the entire genome of virus-positive and virus-negative primary Merkel cell carcinomas (MCCs), revealing distinct mutation spectra and corresponding expression profiles. Our studies highlight the strong effect that Merkel cell polyomavirus has on the divergent development of viral MCC compared to the somatic alterations that typically drive nonviral tumorigenesis. A more comprehensive understanding of the distinct mutagenic processes operative in viral and nonviral MCCs has implications for the effective treatment of these tumors.
Background
Osteoradionecrosis of the jaw (ORN) is an infrequent yet potentially devastating complication of radiation therapy to the head and neck region. Treatment options include antimicrobial ...therapy, local sequestrectomy, resection, and the use of hyperbaric oxygen (HBO). Published data on ORN are difficult to compare because of the lack of a universally accepted classification and staging system, and the literature on the use of HBO to either prevent or successfully manage ORN is controversial and inconclusive. Therefore, we aimed to establish a standard approach for using HBO at our institution.
Materials and Methods
A literature search was conducted of articles published in the English language between January 1980 and January 2016. Retrieved articles were evaluated by two independent reviewers. Isolated case reports, s, case series, review articles, and cohort studies without a control group were excluded; summary data were extracted from the remaining studies. A panel of experts from Head and Neck Oncology and Oral Medicine from the Dana‐Farber Cancer Institute and Brigham and Women's Hospital reviewed the summary data and established multidisciplinary guidelines on the use of HBO for the prevention and management of ORN.
Results
Seven studies were evaluated and reviewed by the multidisciplinary panel. There was no consistent evidence in support of HBO for either the prevention or management of ORN.
Conclusion
Based on the available evidence and expert opinion, routine use of HBO for the prevention or management of ORN is not recommended and is rarely used at our institution.
Implications for Practice
The Division of Head and Neck Oncology of Dana‐Farber/Brigham and Women's Cancer Center does not recommend the routine use of HBO for the prevention or management of ORN. Adjunctive HBO may be considered for use on a case‐by‐case basis in patients considered to be at exceptionally high risk who have failed conservative therapy and subsequent surgical resection.
Osteoradionecrosis of the jaw is a complication of radiation therapy to the head and neck region. Many preventive strategies for osteoradionecrosis have been proposed that have yet to be validated by high‐level evidence. The use of hyperbaric oxygen has been suggested as a means for prevention and treatment, and this study aimed to establish a standard approach for using hyperbaric oxygen at one institution.
Recurrent meningiomas remain a substantial treatment challenge given the lack of effective therapeutic options aside from surgery and radiation therapy, which yield limited results in the retreatment ...situation. Systemic therapies have little effect, and responses are rare; the search for effective systemic therapeutics remains elusive. In this case report, we provide data regarding significant responses in two radiographically diagnosed intracranial meningiomas in a patient with concurrent thyroid carcinoma treated with cabozantinib, an oral multitarget tyrosine kinase inhibitor with potent activity against MET and VEGF receptor 2. Given the clinical experience supporting the role of VEGF agents as experimental therapeutics in meningioma and the current understanding of the biological pathways underlying meningioma growth, this may represent a new oral therapeutic alternative, warranting prospective evaluation.
Background Although percutaneous endoscopic gastrostomy (PEG) is widely performed for nutrition or palliation, PEG-associated outcomes in cancer patients remain poorly described. We examined the ...safety and benefits of PEG placement in this population at our institution. Study Design A 5-year retrospective review of patients with malignancy (excluding head/neck and thoracic malignancy) who underwent PEG at our institution was performed. Results One hundred and eighty-nine patients with malignancy underwent PEG; 33.9% had hematologic malignancy, 66.1% had nonhematologic malignancy, and 44.4% had metastatic disease. Indications for PEG were enteral access (73%) and gastric decompression/management of obstructive symptoms (27%). Few patients achieved independence from total parenteral nutrition (22%) or diet advancement (24.6%). Overall rates of major complications (eg, aspiration, tube dislodgement/leakage, bleeding, visceral injury, respiratory failure after procedure, and cardiac arrest) and minor complications (eg, superficial infection and ileus) were 10.2% and 11.3%, respectively. All-cause in-hospital mortality was high (19.6%) and was associated with ICU admission (p = 0.018), earlier bone marrow transplantation (p = 0.022), steroid treatment (p = 0.024), and lower preoperative albumin (p = 0.003). Code status was changed after PEG in 44 patients from full code to DNR/do no intubate or comfort measures only. Conclusions Percutaneous endoscopic gastrostomy placement in this study population was associated with major procedure-related complications. The majority of patients failed to achieve total parenteral nutrition independence or advancement of diet. Nearly 25% of patients declined aggressive resuscitation strategies after undergoing surgery for PEG. This study cautions to carefully weigh the risks and benefits of PEG placement in this patient population. Prospective studies are needed to uncover factors affecting the decision process and patient selection.
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