The Evolving Role of Taxanes in Combination With Cetuximab for the Treatment of Recurrent and/or Metastatic Squamous Cell Carcinoma of the Head and Neck : Evidence, Advantages, and Future Directions

The addition of cetuximab to platinum-based chemotherapy (cisplatin or carboplatin plus 5-fluorouracil [5-FU]), followed by maintenance cetuximab until disease progression (EXTREME), resulted in the first regimen to yield significantly improved survival outcomes in the first-line treatment of patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) in over 30 years. Currently, the EXTREME regimen is a guideline-recommended treatment in the first-line R/M setting, and, therefore, it is used as a control arm in all new first-line, phase 3 immunotherapy trials. More recently, new checkpoint inhibitor approaches have emerged and are changing the treatment landscape for PD-L1\u2013positive patients with R/M SCCHN. Additionally, alternative chemotherapy backbones in R/M SCCHN are continually investigated. Replacing 5-FU with a taxane in the EXTREME regimen seeks to take advantage of the potential immunogenic and proapoptotic synergy between cetuximab and docetaxel or paclitaxel. These cetuximab-, platinum-, and taxane-based treatments have demonstrated promising survival results and cytoreductive properties in single-arm studies. Thus, these combination treatments may be of importance to patients with high tumor burden and dangerous site involvements (e.g., causing bleeding, suffocation, dysphagia, or ulceration), in whom symptom relief is a key treatment goal. TPExtreme is the first large, randomized trial comparing a cetuximab, platinum, and taxane combination regimen with EXTREME. Currently, the substitution of 5-FU with a taxane is a feasible and clinically beneficial option for patients with contraindications to 5-FU. The TPEx regimen appears to be a new option in first-line R/M SCCHN, with a shorter time on CT and significantly lower toxicity than the EXTREME regimen. For patients with R/M disease in whom further cisplatin- or carboplatin-based treatment is unsuitable, or whose disease has already progressed on first-line R/M therapy, treatment options such as cetuximab plus a taxane, which capitalize on the combinative ability of the 2 agents, can be considered. Notably, it is as of yet unknown what second-line treatments may be suitable to follow a checkpoint inhibitor-based first-line therapy

Using local and historical data to enhance understanding of spatial and temporal rainfall patterns

Farmers face uncertainty in their businesses from many factors, but rainfall is a key determinant of both the nature of the production system and variation in financial returns. Currently, various weather forecasting services are available from the Australian Bureau of Meteorology (BoM) based on about 7000 stations covering all of Australia. Seasonal Climate Forecasts are seen as another tool that can help to improve farm productivity. It is well known that many farmers keep their own rainfall records, and likely that the farmers have a high degree of confidence in their own records. Australian Bureau of Statistics figures indicate that there were possibly 7000 grain related ‘agricultural businesses’ in NSW alone in 2009/10 indicating that there is the potential to increase data density by up to an order of magnitude. This project is part of a broader study to improve rainfall predictions for grain farmers using data collected locally to the users (crowd sourcing). The data is collected directly on farm, and from other sources which may be available. The focus is on the historical data, its collection and analysis, in terms of discerning patterns in time and space which may help provide a local framework, within which coarser scale forecasts can be interpreted and understood. Data will be stored on secure database systems at the University of Sydney. Results indicate that farm data does provide more local detail, temporally and spatially. Deficit and surplus analysis demonstrates the predictive capacity of the local temporal data, despite limited data precluding the definition of ideal criteria and parameters for predictive ‘similar year’ selection. The spatial data demonstrates quantifiable site specific differences from institutional data. Testing across more climate types may allow these differences to be defined within and across regions. Tests for an indicator time period show that farm rainfall in the early part of the growing season (April and May) may indeed be indicative of seasonal condtions, while more data is needed to confirm this. The use of southern oscillation life cycle information to select appropriate years considerably improved the relationships revealed, with a doubling of relationship strength across all climatic types, although the strength of the relationships differed across the climatic types, and the strongest relationships were split between the months of April and May. More extensive analysis, with more data across more BoM districts (and therefore climate classes) will be required to confirm this conclusion, but it appears that farm rainfall records and SOI information can provide an indicator time period to help farmers interpret, refine and utilise seasonal forecasts

Improved methods using the reverse transcriptase polymerase chain reaction to detect tumour cells

Reverse transcriptase polymerase chain reaction (RT-PCR) is increasingly used to detect small numbers of circulating tumour cells, though the clinical benefit remains controversial. The largest single contributing factor to the controversy of its value is the different approaches to sample processing. The aim of this study was to compare the sensitivity and reproducibility of RT-PCR for the detection of tumour cells after four commonly used different methods of sample processing. Using RT-PCR, one tumour cell spiked in 2 ml of whole blood was detected after analysis of separated mononuclear cell RNA, whole blood total or poly-A+RNA. No false positives were identified with any method. However, the reproducibility of tumour cell detection was reduced after isolation of the mononuclear cell fraction. Only analysis of poly-A+RNA had a sensitivity of 100% in all the cell spiking experiments. In patient blood samples, analysis of poly-A+RNA increased the number of blood samples positive for tyrosine hydroxylase (TH) mRNA compared with those positive after analysis of total RNA. This may reflect high levels of cDNA reducing the efficiency of the PCR. Isolation of poly-A+RNA increases the sensitivity and reproducibility of tumour cell detection in peripheral blood. © 1999 Cancer Research Campaig

Assessment of patient-derived tumour xenografts (PDXs) as a discovery tool for cancer epigenomics

Background: The use of tumour xenografts is a well-established research tool in cancer genomics but has not yet been comprehensively evaluated for cancer epigenomics. Methods: In this study, we assessed the suitability of patient-derived tumour xenografts (PDXs) for methylome analysis using Infinium 450 K Beadchips and MeDIP-seq. Results: Controlled for confounding host (mouse) sequences, comparison of primary PDXs and matching patient tumours in a rare (osteosarcoma) and common (colon) cancer revealed that an average 2.7% of the assayed CpG sites undergo major (Δβ ≥ 0.51) methylation changes in a cancer-specific manner as a result of the xenografting procedure. No significant subsequent methylation changes were observed after a second round of xenografting between primary and secondary PDXs. Based on computational simulation using publically available methylation data, we additionally show that future studies comparing two groups of PDXs should use 15 or more samples in each group to minimise the impact of xenografting-associated changes in methylation on comparison results. Conclusions: Our results from rare and common cancers indicate that PDXs are a suitable discovery tool for cancer epigenomics and we provide guidance on how to overcome the observed limitations

Primitive neuroectodermal tumor of the cervix: a case report

<p>Abstract</p> <p>Introduction</p> <p>Peripheral primitive neuroectodermal tumor of the cervix uteri is extremely rare. Between 1987 and 2010, there were only nine cases reported in the English literature, with considerably different management policies.</p> <p>Case presentation</p> <p>A 45-year-old Iranian woman presented to our facility with a primitive neuroectodermal tumor of the cervix uteri. Her clinical stage IB2 tumor was treated successfully with chemotherapy. Our patient underwent radical hysterectomy. There was no trace of the tumor after four years of follow-up.</p> <p>Conclusions</p> <p>According to current knowledge, primitive neuroectodermal tumors belong to the Ewing's sarcoma family, and the improvement of treatment outcome in our patient was due to dose-intensive neoadjuvant chemotherapy, surgery and consolidation chemotherapy in accordance with the protocol for bony Ewing's sarcoma.</p

Elevated neutrophil and monocyte counts in peripheral blood are associated with poor survival in patients with metastatic melanoma: a prognostic model

We aimed to create a prognostic model in metastatic melanoma based on independent prognostic factors in 321 patients receiving interleukin-2 (IL-2)-based immunotherapy with a median follow-up time for patients currently alive of 52 months (range 15–189 months). The patients were treated as part of several phase II protocols and the majority received treatment with intermediate dose subcutaneous IL-2 and interferon-α. Neutrophil and monocyte counts, lactate dehydrogenase (LDH), number of metastatic sites, location of metastases and performance status were all statistically significant prognostic factors in univariate analyses. Subsequently, a multivariate Cox's regression analysis identified elevated LDH (P<0.001, hazard ratio 2.8), elevated neutrophil counts (P=0.02, hazard ratio 1.4) and a performance status of 2 (P=0.008, hazard ratio 1.6) as independent prognostic factors for poor survival. An elevated monocyte count could replace an elevated neutrophil count. Patients were assigned to one of three risk groups according to the cumulative risk defined as the sum of simplified risk scores of the three independent prognostic factors. Low-, intermediate- and high-risk patients achieved a median survival of 12.6 months (95% confidence interval (CI), 11.4–13.8), 6.0 months (95% CI, 4.8–7.2) and 3.4 months (95% CI, 1.2–5.6), respectively. The low-risk group encompassed the majority of long-term survivors, whereas the patients in the high-risk group with a very poor prognosis should probably not be offered IL-2-based immunotherapy

Reproducibility of detection of tyrosinase and MART-1 transcripts in the peripheral blood of melanoma patients: a quality control study using real-time quantitative RT-PCR

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Targeted treatment in a case series of AR+, HRAS/PIK3CA co-mutated salivary duct carcinoma

BACKGROUND AND PURPOSE: A subgroup of salivary duct carcinoma (SDC) harbor overexpression of the androgen receptor (AR), and co-occurring mutations in the HRAS- and PIK3CA-genes. The impact of genomic complexity on targeted treatment strategies in advanced cancer is unknown. MATERIALS AND METHODS: We analyzed molecular and clinical data from an institutional molecular tumor board (MTB) to identify AR+, HRAS/PIK3CA co-mutated SDC. Follow-up was performed within the MTB registrational study or retrospective chart review after approval by the local ethics committee. Response was assessed by the investigator. A systematic literature search was performed in MEDLINE to identify additional clinically annotated cases. RESULTS: 4 patients with AR+ HRAS/PIK3CA co-mutated SDC and clinical follow-up data were identified from the MTB. An additional 9 patients with clinical follow-up were identified from the literature. In addition to AR overexpression and HRAS and PIK3CA-alterations, PD-L1 expression and Tumor Mutational Burden > 10 Mutations per Megabase were identified as additional potentially targetable alterations. Among evaluable patients, androgen deprivation therapy (ADT) was initiated in 7 patients (1 Partial Response (PR), 2 Stable Disease (SD), 3 Progressive Disease (PD), 2 not evaluable), tipifarnib was initiated in 6 patients (1 PR, 4 SD, 1 PD). One patient each was treated with immune checkpoint inhibition (Mixed Response) and combination therapies of tipifarnib and ADT (SD) and alpelisib and ADT (PR). CONCLUSION: Available data further support comprehensive molecular profiling of SDC. Combination therapies, PI3K-inhibitors and immune therapy warrant further investigation, ideally in clinical trials. Future research should consider this rare subgroup of SDC