Application of Chromogenic In Situ Hybridization (CISH) for Human Papillomavirus (HPV) Genotyping

Obvious decreasing in cervical cancer mortality has been observed in countries with organized cervical cancer screening programs. Liquid based cytology is a technique that enables cells to be suspended in liquid medium and spread in monolayer for better morphological assessment. It includes the preparation and evaluation of cells collected in liquid fixative. It is being introduced to improve the sensitivity of the Pap test. Liquid based preparations are increasingly being used both for gynecologic and non-gynecologic cytology, including fine needle aspirations . Two technologies, ThinPrep (Hologic, Marlborough, MA, USA) and BD Sure Path (BD Diagnostics – TriPath, Burlington, NC, USA) have been more widely used. 

The advantages of liquid based cytology include improved sensitivity and specificity since fixation is better and nuclear details are well-preserved. Abnormal cells are not obscured or diluted by other epithelial or inflammatory cells. There is, therefore, a lower rate of unsatisfactory cervical cytology samples. The residual cell suspension can be used to make further cytological preparations or used for other tests like detection of human papillomavirus DNA. Other ancillary techniques like immunocytochemistry can also be performed on the residual sample . The more widely used technologies for liquid based cytology require expensive equipment.

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Chronic constipation linked to increased risk of colorectal cancer

Basal Cell Carcinoma:

Basal Cell Carcinoma or BCC is the cancer which is caused due to the unrestricted growth in the skin’s basal cells, i.e., the outermost layer of the skin. BCC appears on the skin in the form of open sores, red patches, pink growths or scars. It lacks the property of metastasis.

Benign Neoplasm:

Benign neoplasm is the mass of slow growing localized tumor. The property of metastasis, i.e., to invade surrounding tissues and spread to the distant sites is absent in the benign neoplasm. Therefore, it is said to be non- cancerous. Some kinds of benign neoplasms are adenoma, fibroma, hemangioma and lipoma.

Cancer:

Cancer is a disease in which cells at a particular site grows and proliferate in an abnormal, rapid and unsystematic manner in the body which results in the destruction of the healthy body tissues. Cancer can be Benign or Malignant depending on its property of invasion.

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Anti-VEGFR2 Driven Nuclear Translocation of VEGFR2

lioblastoma (GBM) is considered as hypervascular, hypoxic and most malignant form of glioma. GBM is most lethal during first year after initial diagnosis despite surgical resection, radiotherapy and/ or chemotherapy. Anti-Angiogenic Therapies (AAT) are being used as an adjuvant mainly against Vascular Endothelial Growth Factor and its receptors (VEGF-VEGFRs) in endothelial cells to normalize tumor vasculatures. Due to lower genetic instability in endothelial cells compared to in tumor cells, it was anticipated that targeting VEGFVEGFR pathways, primarily in endothelial cells, would decrease tumor vasculature without imposing drug resistance. However, treatments provided minimal to none effect with no change in overall patients survival.

Similar data was obtained from preclinical studies. For example, VEGFR2 blockade in GBM through vatalanib, a receptor tyrosine kinase inhibitor, increased tumor size through hypoxia mediated overexpression of VEGF, SDF-1α, HIF-1α, VEGFR2, VEGFR3 and EGFR at peripheral part of tumors compared to central part. Activation of alternative pathways of angiogenesis, vasculogenesis and involvement of stem cells were observed following AAT in GBM, which was associated with overexpression of bFGF, angiopoietin1/2, GCSF, and SDF1α. 

Conventionally, tumor vessel formation occurs through angiogenesis, which is mediated by proliferation and migration of resident ECs.However, at a cellular level, up-regulation of HIF- 1α and SDF-1α by tumor cells resulted into recruitment of CXCR4+ Bone Marrow Derived Cells (BMDCs) to the tumor. BMDCs play a pivotal role in tumor development. Endothelial Progenitor Cells (EPCs) from BM pool are recruited in Tumor Microenvironment and contributed to vasculogenesis.

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Anti-VEGFR2 Driven Nuclear Translocation of VEGFR2

lioblastoma (GBM) is considered as hypervascular, hypoxic and most malignant form of glioma. GBM is most lethal during first year after initial diagnosis despite surgical resection, radiotherapy and/ or chemotherapy. Anti-Angiogenic Therapies (AAT) are being used as an adjuvant mainly against Vascular Endothelial Growth Factor and its receptors (VEGF-VEGFRs) in endothelial cells to normalize tumor vasculatures. Due to lower genetic instability in endothelial cells compared to in tumor cells, it was anticipated that targeting VEGFVEGFR pathways, primarily in endothelial cells, would decrease tumor vasculature without imposing drug resistance. However, treatments provided minimal to none effect with no change in overall patients survival.

Similar data was obtained from preclinical studies. For example, VEGFR2 blockade in GBM through vatalanib, a receptor tyrosine kinase inhibitor, increased tumor size through hypoxia mediated overexpression of VEGF, SDF-1α, HIF-1α, VEGFR2, VEGFR3 and EGFR at peripheral part of tumors compared to central part. Activation of alternative pathways of angiogenesis, vasculogenesis and involvement of stem cells were observed following AAT in GBM, which was associated with overexpression of bFGF, angiopoietin1/2, GCSF, and SDF1α. 

Conventionally, tumor vessel formation occurs through angiogenesis, which is mediated by proliferation and migration of resident ECs.However, at a cellular level, up-regulation of HIF- 1α and SDF-1α by tumor cells resulted into recruitment of CXCR4+ Bone Marrow Derived Cells (BMDCs) to the tumor. BMDCs play a pivotal role in tumor development. Endothelial Progenitor Cells (EPCs) from BM pool are recruited in Tumor Microenvironment and contributed to vasculogenesis.

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Chronic Constipation Linked To Increased Risk Of Colorectal Cancer

The living body is made up of cells that develop, proliferate and undergo apoptosis in a systematic manner. In certain cases, unusual behavior of cell is observed, which is termed as neoplasm. Neoplasm or neoplasia refers to the rapid, uncontrolled and abnormal growth of cells or tissues in the body. Neoplastic tumor can be benign or malignant. Benign neoplasm neither grows vigorously nor invades the surrounding body tissues. Thus, benign neoplasm is less fatal, though can kill a person depending on its size. On the other hand, malignant neoplasm has the property of invasion and metastasis. Malignant neoplasms are precisely cancerous. 

The Journal is using Editorial Manager System for quality in peer review process. Editorial Manager is an online manuscript submission and single- blind review system. Review processing is performed by the Editorial Board members of Journal of Neoplasm or outside experts; at least two independent reviewers approval followed by editor approval is required for acceptance of any citable manuscript. Authors may submit manuscripts and track their progress through the system, hopefully to publication. Reviewers can download manuscripts and submit their opinions to the editor. Editors can manage the whole submission  process. 

Benign neoplasm is the mass of slow growing localized tumor. The property of metastasis, i.e., to invade surrounding tissues and spread to the distant sites is absent in the benign neoplasm. Therefore, it is said to be non- cancerous. Some kinds of benign neoplasms are adenoma, fibroma, hemangioma and lipoma.

A Review on Pyridazinone Compounds ABT-963 as Selective Cyclooxygenase Inhibitor

Nonsteriodal anti-inflammatory drugs (NSAIDs) are efficacious for the treatment of pain associated with inflammatory disease. Selective cyclooxygenase-2 (COX-2) inhibitors (such as celecoxib, rofecoxib, and valdecoxib) have used in the treatment of inflammatory pain with an improved gastrointestinal tract (g.i.t) safety profile relative to conventional NSAIDs. These COX-2 inhibitors contain a core heterocyclic ring with two appropriately substituted phenyl rings appended to adjacent atoms.

The NSAIDs constitute an important class of drugs with therapeutic applications and used in the treatment of inflammatory conditions such as rheumatoid arthritis (RA) and osteoarthritis (OA) starting from the classic drug aspirin to the recent rise and fall of selective COX-2 inhibitors. The study their mechanism of action at the molecular level such as cyclooxygenase (COX) inhibition, development of selective COX-2 inhibitors, their adverse cardiovascular effects. The recent developments targeted to the design of effective antiinflammatory drugs with reduced side effects.

The structural basis for COX-1 and COX-2 inhibition is described along with methods used to evaluate COX-1/COX-2 inhibition. Some of the recent advances toward developing effective anti-inflammatory agents such as nitric oxide donor NO-NSAIDs, dual COX/LOX inhibitors and anti-TNF therapy. A great deal of progress has been made toward developing novel anti-inflammatory agents. The design and development of a safe, effective and economical therapy  for treating inflammatory conditions still presents a major challenge.

Prostaglandins (PG) play a significant role in the maintenance of homeostasis and in the body’s response to the environment. Two isozymes of cyclooxygenase (COX) are responsible for the biosynthesis of these mediators commonly called COX-1 and COX-2. Xie et al.and Smith have proposed that COX-2-generated PGs are mediators of inflammation, cellular proliferation, and pain, whereas COX-1-generated PG are involved in homeostasis in the stomach, kidney, and blood coagulation.

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Epithelial-Mesenchymal Transition Models

Kidney cancer originating from the renal tubular epithelium system is one of the most common cancers of the urinary system. It accounts for approximately 3% of all malignant tumors. The incidence of newly diagnosed patients has increased by approximately 2.5-3% annually from 2001-2010. Metastatic renal cell carcinoma is detected in approximately 30% of patients at the time of diagnosis. The overall distribution of metastatic sites is the lung, bone, lymph nodes, liver, adrenal gland and brain.

Metastatic renal cell carcinoma has a poor prognosis with a median overall survival of 12 months and a 5-year survival rate of less than 10%, which seriously affects patients’ quality of life. Invasion and metastasis, the major characteristics of malignant tumors, lead to the poor prognosis and death of patients. At present, the intrinsic molecular mechanisms and the extrinsic microenvironment that enhance the metastatic potential of primary tumor cells are still hot topics in the field of cancer research.

During the EMT, cellular morphology and adhering capacity will change and the expression of epithelial molecular markers will down-regulate while that of mesenchymal molecular markers will increase. Hypoxia, one of the various factors that can induce EMT in cancer cells, exists in many regions of solid tumors  because angiogenesis in tumors is heterogeneous, and cancer cells grow rapidly.

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Women Aged 35-55 Suffering from Breast Cancer

The span of mortality rate is significantly smaller (about 6-19 in 100.000), due to breast cancer survivals in developed regions (high incidence). As a result, breast cancer is the fifth cause of deaths in the total number of deaths (458 000 deaths), and in spite of that, it is still the leading cause of death in women from all types of cancer locations, and in countries in development (269 000 deaths, 12.7% of overall mortality) and developed regions, with an estimated number of 189 000 deaths, which is almost equal to the estimated number of deaths by lung cancer (188 000 deaths).

Breast cancer was the leading cancer with women in Bosnia and Herzegovina in the year 2008, with an incidence 1100 (25.9%) with the standardized world rate ASR (W) on 100 000 inhabitants, 36.5 and mortality 399 (17%) with the standardized world rate ASR (W) 22.7.

Breast cancer as a disease effects on financial expenses and presents an economic burden for reasons that, next to the direct costs, come the costs of treatment and mortality rates. During a longer period, the expenses grow according to a similar rate for total health costs. According to the American National Institute for Health, it is estimated that breast cancer will cost 209.9 billion dollars in the year 2005, 118.4 billion of which due to mortality expenses (loss of productivity due to patient's death), 74 billion due to direct medical expenses (money spent on medical care), which used to be 17.5 billion dollars due to morbidity expenses (costs of loss of productivity due to disease.

Robert Cummins is the founder of international group of scientist and researchers (International Well-Being Group), which advocates the understanding that  life quality is a multi-dimensional construct made from: life standard, health, productivity, the ability to make close connections, security, the sense of belonging to a community, and the sense of security in the future.

Putative Status of Actively Operative Performance Attributes as Determinants of Minimal Platform Oncogenesis in C-Myc Amplification

The combinatorial complex-action of amplified c-Myc in inducing both increased proliferation and also apoptosis of target cells implicates a derivative dysfunctional relationship of intrinsic tumor suppressor function within the dysfunctional mediating actions of a master oncogene. Increased proline biosynthesis in carcinogenesis by MYC, links the reprogramming of glucose, glutamine and pyridine nucleotides. In such manner, promotional effects of increased cell proliferation must be interpreted within the substantial dysregulation and loss of terminal differentiation of these induced cells. Microarray gene expression profiling in osteosarcoma has revealed relationships of this tumor type and of recurrent medulloblastoma with c-Myc.

Realization of essential dynamics of turnover of proliferating cells appears to promote the emergence both of “escapers” of such proliferative clones of cells and also of “dormant” cells, that is, cells that are non-proliferative but still capable, in future, to resume increased proliferative activity. Nuclear factor, erythroid 2-like 2 (NFE2L2)- associated molecular signature is a robust prognostic gene signature independent of MYC level and lung cancer stage.

Dimensions of a minimal platform for the induction and progression of transformation per se would implicate the potentiality for further evolutionary pathways through dysregulation and enhanced activity of abnormal c-Myc homeostasis. Micro-R675 appears involved in epigenetic regulation of histones for gene expression during hepatocarcinogenesis including that of c-Myc

Medical Education in the Global Arena: The Impact of Cross-cultural Learning

A North American Obstetrician speaks through Skype to a classroom in Mbarara, Uganda while simultaneously lecturing inperson to a Boston, USA classroom on the topic of postpartum hemorrhage. The medical students and residents in Mbarara are quietly listening and diligently taking notes. The American-based students do not take notes but occasionally raise their hands to interject and ask questions. The same lecture seems to be received differently from two groups of students and the Boston-based lecturer wonders if these different forms of engagement impact the lessons taught. Are both groups gaining the same level of knowledge from the lecture despite these differences  Why are these differences occurring  Perhaps due to the barriers of distance and Internet, or do cultural differences have implications for the learning.

Types of Pedagogy

Traditional medical graduate education combines passive didactic learning in a classroom setting and participatory learning. As advances in the science of teaching have been made, education in the preclinical years has evolved from a purely classroom-based venue to the participatory and group-based learning of Problem-Based Learning (PBL). PBL fosters understanding, knowledge retention, and social and group work. Postgraduate medical education traditionally relies on an apprenticeship model of students learning during active participation in medical care. 

Whether in the classroom or by the bedside, teaching requires interaction between student and teacher; these are often influenced by social norms and relationships that guide behavior. Western post-graduate medical training for example, relies heavily on the Osler-derived model of participatory, service-oriented and work-based learning. A set of both implicit and explicit social relationships between ‘master’ and ‘apprentice’ or teacher and learner are required for this model to work. Learners are required to speak up, participate, engage and interact with the teacher. One observational study of clinical medical education identified seven important pedagogical strategies for learning: 1- questions and answers, 2- lecturing, 3- piloting, 4- prompting, 5- supplementing, 6- demonstrating, and 7- intervening.

Neoadjuvant Chemotherapy of Three Cycles or More Improve Survival of Patients with N2-3 Nasopharyngeal Carcinoma

Nasopharyngeal carcinoma (NPC) is the most common cancer originating from the epithelial cells that cover the surface of nasopharynx. It is a rare malignancy with an average incidence under 1 per 100,000 person-years except certain regions of East Asia and Africa, where the incidence may reach 80 per 100,000 personyears. Due to anatomical complexity of NPC and its tendency to metastasize,radiotherapy instead of surgery is the mainstay of treatment. Since advent of intensity-modulated radiation therapys (IMRT) and concurrent chemotherapy (CCT), the 5-year overall survival of NPC has reached 83.0% now. Unfortunately, distant metastases remain the major causes of failure. More than 30% of patients with advanced loco-regional disease eventually died of distant failure. 

Although meta-analysis showed neoadjuvant chemotherapy (NACT) could significantly reduce distant failures in head and neck squamous cell carcinoma and improve prognosis [7]. The roles of NACT in NPC remain uncertain though a series of phase II clinical trials have recently indicated that patients with 2-3 cycles of NACT before concurrent chemo-radiation had a trend of better survival than those without NACT. It is known that the metastasis risk of NPC correlates with both T and N stage, but N stage is by far the most significant predicting factor. Even after multimodality treatment based on IMRT plus CCT, stage N2-3 disease was proved to be an independent factor predicting a greater risk of distant failure and poor overall survival (5-year distant-metastasis rate, 35.2%). Clinical outcome of these patients might be further improved through eradicating metastases. However, the previous studies on NACT of NPC almost enrolled patients with Stage III-IVB diseases. There was no published study focusing on N2-3 NPC patients, or appropriate cycle number of NACT for them. Therefore, we performed a casecontrol pilot study to evaluate the impact of NACT of different cycles on survival of patients with N2-3 NPC.

Patients with pathologically diagnosed and previously untreated NPC in our hospital from January 1st 2008 to December 31st 2009 were initially considered. The ones would be included if they had age younger than 70 years old and T1-4N2-3M0 NPC. Stage of all patients was determined through magnetic resonance imaging of head and neck (HN-MRI), whole-body bone scan and thoraco-abdominal computed tomography (or chest radiograph plus abdominal ultrasonography) and according to the Union Internationale Contre le Cancer/American Joint Cancer Committee TNM classification version 2002. After staging, 593 consecutive patients with N2-3 disease were enrolled into our study.

The exclusion criteria included: (i) Karnofsky performance score <80; (ii)severe dysfunction of heart, lung, liver or kidney; (iii) history of other malignancies; (iv) prior chemotherapy or radiotherapy; (v) distant metastases before or during radiotherapy. 40 patients were excluded for distant metastases before or during radiotherapy. Then a total of 553 patients with N2-3 non-metastatic NPC were eligible for this study. Among these patients, 102 cases received NACT of 3 cycles or more (NACT≥3 group) and were defined as the experimental group. 185 did not receive NACT (NACT=0 group) and 266 received NACT of 2 cycles (NACT=2 group). Through the frequency-matching technique, patients of the NACT≥3 group were then matched in a ratio of 1:2:1 to those of the NACT=2 group and the NACT=0 group, which were defined as the control groups. Patients were matched when they had the same histological subtype (squamous cell carcinoma vs. non-keratinizing carcinoma vs. undifferentiated carcinoma), the same N stage (N2 vs. N3), the same NACT regimen (docetaxel plus cisplatin vs. cisplatin plus 5-fluorouracil) and the closet age. If there were several cases fit for matching to the same patient, selection was made randomly.

Limb Salvage Strategy by Intra-Arterial Chemotherapy for Local Recurrent Osteosarcoma in Extremities

Osteosarcoma is the most common bone primary malignant tumor with high fatality rate. Since 1970’s, the survival rate of osteosarcoma increased significantly after the application of chemotherapy, and neo-adjuvant chemotherapy is not only effective in tiny metastases but also minimize the primary foci and clarify its boundary. To a large extent, the recent progress on the treatment of osteosarcoma results from the application of neo-adjuvant chemotherapy, and the limb salvage treatment of osteosarcoma has become the mainstream with the progress of neo-adjuvant chemotherapy, surgical techniques, and bone reconstruction, in which prosthesis replacement is one of the most commonly applied strategies. It is considered that limb salvage surgery should meet the following 3 prerequisites The primary osteosarcoma should be sensitive to chemotherapy on clinical and imaging indexes.

Enough tumor removal boundaries. Limb is reconstructed with enough function through simple, effective, and low risk mode to facilitate the recovery of postoperative chemotherapy as soon as possible. The main taboo of limb salvage surgery includes patients at too young age, and patients with huge tumor, soft tissue in terrible conditions, progressively enlarged tumor after chemotherapy, and local infection and failure in limb salvage therapy.

 The factors of local recurrence

No matter limb salvage surgery or amputation is applied, there is certain rate of metastasis and local recurrence, and it is commonly accepted that local recurrence would happen on 10% to 20% cases after limb salvage surgery. It is demonstrated that three factors are related to local recurrence, including the surgical margin, tumor necrotic degree after chemotherapy, and the anatomical relationship between tumor and neurovascular bundle. It is generally accepted that wide range excision is the primary principle of limb salvage surgery, which means soft tissue should be beyond tumor boundary for 2 to 3 cm under naked eyes, and bone is beyond tumor boundary for 3 to 5 cm, or operation should be ensured in normal tissues according to tumor free principle based on Enneking staging. It is controversial in clinic between limb salvage surgery and wide excision, as tumor usually affects nearby vessels and nerves which make it difficult to keep vessels, nerves, and enough soft tissues to enable both limb salvage surgery and wide excision at the same time. It is indicated that local recurrence is related to patients’ reactivity to chemotherapy, namely, local recurrence is more common in patients who has enough surgery excision scope but with poor reactivity to chemotherapy than the contrary. According to Grimer, no local recurrence happens even with marginal excision when tumor necrosis is more than 90% after chemotherapy, on the contrary, local recurrence happens in more than 36% patients who are insensitive to chemotherapy, and 4% in patients under wide excision margin but insensitive to chemotherapy.

Neuropeptides in the Development of Colon Cancer

The American neuro-gastroenterologist Gershon has precisely nicknamed the intestines as ‘The second brain’, taking into account the size and complexity of the enteric nervous system (ENS). Enterochromaffin cells (EC) are functionally connected with the ENS and can also synthesize neuropeptides to control intestinal functions. Novel evidence has shown that EC indeed differentiates from the intestinal cryptal stem cell niche. Besides, mammalian bombesinlike peptides, cholecystokinin (CCK), gastrin, and neurotensin are gastrointestinal neuropeptides that impact on the body development, inflammation, tissue regeneration, and neoplastic transformation.

These molecules signal through their receptors that are highly expressed in the human colon but have, however, a differentiated pattern of expression for each one of them, which might illustrate their specific physiological roles. Hence, GRP receptors, Y2 receptors, PACAP type1-receptors, cholecystokinin-A receptors, neurotensin1 and somatostatin st2 receptors were abundantly expressed in the myenteric plexus, whereas VIP/PACAP and sst2 receptors were found in lymphoid follicles, and Y2, VIP type1 and sst2 receptors were present in the colonic mucosa. Specific binding sites for VIP, have been characterized in isolated human colonic epithelial cells in the early 80s. Given that the intestinal neuro-immune axis plays a significant role in regulating the severity of inflammation, it possibly has a pivotal role in the colon cancer development. For instance, neuropeptides might have either anti-inflammatory (VIP and galanin) or pro-inflammatory effects (NPY, substance P, serotonin, and neurotensin). The activation of specific immune signaling pathways might be the key to understanding the complex and controversial effects of these neuropeptides, from which inflammatory signals increase in a cascade of events. Corticotropin-releasing factor (CRF), which is a stress peptide, has been shown to control the colonic IL-6 release and neuronal activation, a fact that helps to clarify the effects of stressful conditions on the development of colonic inflammation.

Whether colitis increases the expression of neuropeptide Y (NPY) in the enteric nervous system, NPY knockout mice showed reduced intestinal inflammation. Pharmacological inhibition of vasoactive intestinal peptide (VIP), which is a neurotransmitter and vasodilator, protected experimental models from colitis. VIP-deficient mice, authors have also found reduced inflammation in trinitrobenzene sulfonic acid-induced colitis. Then, glucagon-like peptide 2 (GLP-2), which is an enteroendocrine hormone trophic for intestinal mucosa, has been shown to increase enteric neuronal expression of VIP. Sigalet et al. suggested that GLP-2 acts on enteric neurons and glial cells via a PI3Kγ/Akt pathway, stimulating neuronal differentiation via mTOR and ERK pathways, as well as the expression of receptors and ligands for IGF-I and ErbB pathways. Conversely, the anti-inflammatory and blood flow effects of GLP-2 are related to VIP and nitric oxide synthesizes and release from submucosal enteric neurons.

Medico-legal Aspects of Delay in Diagnosis of Breast Cancer

As a capricious and heterogeneous disease breast cancer may be difficult to diagnose and despite being appropriately treated may relapse unexpectedly. Governmental pressure to reduce waiting for women with breast cancer may lead some patients to suspect that very short delays may impact adversely on their prognosis. In this supercharged atmosphere of anxiety, communicational skills of breast surgeons may be constantly tested so that minor solecisms may translate into major patient dissatisfaction. With this background it is unsurprising that more patients are turning to litigation in an attempt to obtain satisfaction for what they perceive as medical negligence.

Requirements

In order for a case alleging medical negligence to be successful the claimant has to successfully negotiate at least 3 hurdles. Firstly, did the doctor  have a duty of care Thus, was the defendant the claimant’s general practitioner or a member of a hospital team to which a GP referral had been made? Incorrect advice given by a doctor to a friend or acquaintance does not make that individual liable since they do not have a duty of care.

Secondly were the history-taking/ clinical examination/ advice/ procedure negligent? Negligence is defined as an action which no responsible doctor would have taken. Under the normal circumstances where there are various courses of action, provided that there is a sensible body of medial opinion for a particular approach that is not negligent even though a medical expert might not agree with the defendant’s allegedly negligent advice. An example of this is sentinel node biopsy where one body of opinion advocates a combination of tadio-isotope and dye whereas others use one or the other.

If the medical expert deems that negligence has occurred, such as failing to obtain a tissue diagnosis on a solid breast mass the next hurdle is determination of causation. For causation to be established it must be shown that as a result of the negligence the claimant has suffered an injury, that is, a significant worsening of prognosis, and/or a need for more extensive surgery or radiotherapy and or a requirement for more toxic systemic therapy and/or psychological damage. At present, in claims for delay in diagnosis of breast cancer it is necessary to prove that the claimants 10-year survival has changed from being >51% to <49%. Hence a reduction from 95% to 60% or from 45% to 25% will not meet the criteria for causation. Proportional damages are not granted at present.