Cancer Science & Therapy

The origin of the common phrase “your name is mud” may derive from the ordeal of 19th century physician, Dr. Samuel Mudd, who was perhaps wrongly convicted of conspiracy in the assassination of President Abraham Lincoln. Mudd’s crime may have only been bad luck: Lincoln’s assassin, John Wilkes Booth, allegedly previously unknown to the doctor, had broken his leg and happened across Mudd who, unwisely, as it turned out, set the fracture, and his own subsequent fate, which included life imprisonment with hard labor, making him a potential victim of circumstance rather than the perpetrator of a crime. Mudd’s grandson, also a physician, tried unsuccessfully to clear his grandfather’s widely reviled name, which as a result has remained, both literally and figuratively, Mudd.

This historical analogy highlights the important point that radiosensitizers as a class have been ignored rather than adored due to their failed reputation. Hence, in the field of radiation oncology, the “your name is mud” expression applies to radiation sensitizers, which from hyperbaric oxygen and the nitroimidazoles, to motexafin gadolinium, tirapazamine and efaproxiral have generally overpromised and under delivered with respect to survival treatment benefits in multiple different indications. However, newer non-toxic radiosensitizers on the horizon such as the antienergetic epigenetic redox modulator, RRx-001, that will start a Phase 2 clinical trial with concurrent whole brain radiotherapy (WBRT) in subjects with brain metastases, may finally validate the underlying promise and unrealized potential of these agents. The successful treatment of brain metastases is at least a four-hurdle process involving penetration, retention, selectivity and toxicity. This article will review the mechanism of the radiosensitizers, RRx- 001, and 2-deoxyglucose, as examples or “role models” for therapies that theoretically are able to overcome these substantial in vivo obstacles to successfully treat brain metastases.

It is the thesis of this review that new radiosensitizers are urgently needed and their poor reputation should be overcome.

Medullary breast carcinomas (MBCs) represent <5% of all invasive breast carcinomas and although these tumors show aggressive pathological features they are often associated with a more favourable outcome. It is also said to be particularly common in carriers of BRCA1 mutations. They are almost invariably negative for hormone receptors as well as Her-2/neu (‘triple negative’ phenotype). The prognosis for medullary carcinoma is better than for the ordinary invasive ductal carcinoma, a fact already apparent in the early reports on this tumor. We report a similar case in a 56 year old female with cytological, histological and immunohistochemical analysis of MBC.

Objective: MicroRNAs (miRNAs) are known to play important roles in the diagnosis and prognosis of papillary thyroid cancer (PTC), and they are useful in developing targeted therapies. However, there have been no studies on the existence of racial differences in miRNAs expression that could explain differential overall survival of PTC patients. Expression analysis of miRNAs in major racial groups would be important for optimizing personalized treatment strategies. In the current study, we assessed the differential expression of 8 miRNAs between normal and tumor tissues, and also assessed racial differences between African American (AA) and Caucasian American (CA).

Methods: First, the miRNA expression profiling was performed using formalin-fixed paraffin embedded (FFPE) tissue sections of tumor containing over 70% tumor cells. Normal and tumor sections of thyroid tissues were studied from AA and CA patients. The miRNA microarray profiling was done using miRBase version 18 (LC Sciences, Houston, TX, USA). Quantitative real-time PCR (qRT-PCR) was used to validate expression of 8 selected miRNAs.

Results: Ingenuity pathway analysis showed involvement of target genes, such as Ras and NF-κB. Deregulated miRNAs such as miR-221 and miR-31 were found to be statistically significant between the two races. Using qRTPCR, we found that miR-21, miR-146b, miR-221, miR-222, miR-31, and miR-3613 were up-regulated while miR- 138 and miR-98 were down-regulated in tumors compared to normal tissues.

Conclusion: Though sample size was small, we found several deregulated miRNAs having racial differences. The differential expression of miRNAs suggest that these miRNAs and their target genes could be useful to gain further mechanistic insight of PTC and their clinical implications, including miRNA replacement therapy or their knockdown strategies.

As the major iron storage protein, ferritin has been linked with iron metabolism for many years. However, recent studies have discovered new functions for this protein. Our current review summarizes new findings suggesting the link between ferritin and many pathways related with cancer, such as cell proliferation, growth suppressor evasion, cell death inhibition, immortalization, angiogenesis, invasion and metastasis, and immunomodification. Most of the evidence revealed suggested that elevated ferritin in cancer cells may be related with cancer progression, resistance to therapies, or poor prognosis. By either directly or indirectly participating in cancer related pathways, ferritin proposes itself as a promising target for cancer therapy. Ongoing and prospective preclinical and clinical research will further explore this new strategy that is currently underappreciated. Conclusion: Ferritin is proving to be a much more versatile protein than simply iron storage. It may have signaling properties and reporter properties for some cancers. Data are mounting that ferritin may be a promising target in cancer therapy.

Aim: The main aim of our study was to compare the variation of Gamma Index (GI) in Pre-treatment Verification Procedure in Intensity Modulated Radiotherapy (IMRT) Plans with Varying Grid Sizes Using 2D Array Detectors. Choosing an optimum grid size plays a vital role for planning in radiotherapy cases especially while treating with IMRT. A minimal change of even 1 mm of grid size can result in large variation in treatment planning and is reflected in quality assurance results also.

Methods and Material: We compared IMRT plans for a total of 12 patients. Out of these 12 patients 4 were head and neck, 4 were pelvic and 4 were brain patients respectively. For each patient three plans were generated with three different grid sizes. The plan acceptance criteria were 95% of PTV to receive at least 95% of prescribed dose and dose to 1% of PTV not to exceed 107% of prescribed dose. Dose for the organs at risk were respected as per the QUANTEC guidelines. After plan acceptance corresponding Pre-treatment Verification Procedure for IMRT was executed by PTW 729 array detector. The Gamma index (GI) results of each plan were recorded for the three different grid sizes. The passing criteria were kept to be 3% Dose Difference (DD) and 3 mm Distance to Agreement (DTA) for all cases.

Results: We estimated the variations in GI quality assurance results for patients undergoing IMRT planning with varying grid sizes of 3 mm, 5 mm and 10 mm respectively. We also evaluated 2% DD and 2 mm DTA, 3% DD, 3 mm DTA and 5% DD, 5 mm DTA criteria for passing result. Stastical analysis: We have calculated the average and standard Deviations (Std. Dev.) for each passing criteria for 2% DD, 2 mm DTA, 3% DD, 3 mm DTA and 5% DD, 5 mm DTA for each IMRT plans with varying grid sizes.

Conclusions: Though the present results suggest the gamma criteria of 5% DD and 5 mm DTA as the most suitable criteria for IMRT quality assurance. This gamma criterion of 5% DD and 5 mm DTA favourably exceeds 95% in each case and grid sizes but it is not recommended for strict verification procedure in Intensity Modulated Radiotherapy (IMRT). The criteria of 2% DD and 2 mm DTA, and 3% DD and 3 mm DTA gamma values show below 90% for 5 mm and 10 mm grid sizes but exceeds 95% for the 3 mm grid sizes. Hence 3 mm or less grid sizes should be routinely used in pre-treatment verification procedure IMRT plans using 2D Array Detectors.