Lye Mun Tho

The ATM–Chk2 and ATR–Chk1 Pathways in DNA Damage Signaling and Cancer

DNA damage is a key factor both in the evolution and treatment of cancer. Genomic instability is a common feature of cancer cells, fuelling accumulation of oncogenic mutations, while radiation and diverse genotoxic agents remain important, if imperfect, therapeutic modalities. Cellular responses to DNA damage are coordinated primarily by two distinct kinase signaling cascades, the ATM-Chk2 and ATR-Chk1 pathways, which are activated by DNA double-strand breaks (DSBs) and single-stranded DNA respectively. Historically, these pathways were thought to act in parallel with overlapping functions; however, more recently it has become apparent that their relationship is more complex. In response to DSBs, ATM is required both for ATR-Chk1 activation and to initiate DNA repair via homologous recombination (HRR) by promoting formation of single-stranded DNA at sites of damage through nucleolytic resection. Interestingly, cells and organisms survive with mutations in ATM or other components required for HRR, such as BRCA1 and BRCA2, but at the cost of genomic instability and cancer predisposition. By contrast, the ATR-Chk1 pathway is the principal direct effector of the DNA damage and replication checkpoints and, as such, is essential for the survival of many, although not all, cell types. Remarkably, deficiency for HRR in BRCA1- and BRCA2-deficient tumors confers sensitivity to cisplatin and inhibitors of poly(ADP-ribose) polymerase (PARP), an enzyme required for repair of endogenous DNA damage. In addition, suppressing DNA damage and replication checkpoint responses by inhibiting Chk1 can enhance tumor cell killing by diverse genotoxic agents. Here, we review current understanding of the organization and functions of the ATM-Chk2 and ATR-Chk1 pathways and the prospects for targeting DNA damage signaling processes for therapeutic purposes.

Systemic inflammatory response is a predictor of outcome in patients undergoing preoperative chemoradiation for locally advanced rectal cancer

Aimu2002 Current management of locally advanced rectal cancer includes neoadjuvant chemoradiation in selected patients to increase the chance of a tumour‐free circumferential resection margin. There is uncertainty over the role of and selection criteria for additional systemic therapy in this group of patients. In this retrospective study we investigate the association between markers of systemic inflammatory response (SIR) and outcome from treatment.

Chk1 is essential for chemical carcinogen-induced mouse skin tumorigenesis.

Chk1 is a key regulator of DNA damage checkpoint responses and genome stability in eukaryotes. To better understand how checkpoint proficiency relates to cancer development, we investigated the effects of genetic ablation of Chk1 in the mouse skin on tumors induced by chemical carcinogens. We found that homozygous deletion of Chk1 immediately before carcinogen exposure strongly suppressed benign tumor (papilloma) formation, and that the few, small lesions that formed in the ablated skin always retained Chk1 expression. Remarkably, Chk1 deletion rapidly triggered spontaneous cell proliferation, γ-H2AX staining and apoptosis within the hair follicle, a principal site of origin for carcinogen-induced tumors. At later times, the ablated skin was progressively repopulated by non-recombined Chk1-expressing cells and ultimately normal sensitivity to tumor induction was restored when carcinogen treatment was delayed. In marked contrast, papillomas formed normally in Chk1 hemizygous skin but showed an increased propensity to progress to carcinoma. Thus, complete loss of Chk1 is incompatible with epithelial tumorigenesis, whereas partial loss of function (haploinsufficiency) fosters benign malignant tumor progression.

THE ROLE OF IMAGING IN THE PRE-OPERATIVE STAGING AND POST- OPERATIVE FOLLOW-UP OF RECTAL CANCER

Developments in rectal cancer imaging have revolutionised the management of this condition. It has become increasingly important for oncologists and surgeons to have a working insight into radiological assessment in order to make informed clinical decisions. In this context, we discuss the role that imaging plays in the pre-operative staging, post-operative follow-up and therapy of this disease including some novel advances in the field. Rectal cancer outcomes have improved due to modern surgical techniques, namely total mesorectal excision. Meticulous pre-operative assessment remains key. Conventional TNM staging now appears less crucial compared to assessing tumour distance from the potential plane of surgical resection (particularly the circumferential margin bounded by the mesorectal fascia), and this is reliant on high-quality imaging. Those with margin threatening disease can be offered downstaging chemoradiotherapy to facilitate successful resection. Endorectal ultrasound is useful for T staging and CT for detecting metastases. Malignant lymph node identification remains a problem and the use of size and morphological criteria may lead to misdiagnosis. In the post-operative setting, intensive follow-up is associated with improved outcomes but there are many variations in protocols. Most modalities struggle to differentiate tumour from reactive or fibrotic tissue and functional imaging is being investigated as the solution. PET scanning, particularly PET/CT, has been a major recent development. It has superior utility in detecting recurrent disease, including when conventional imaging is negative, detects occult metastases and may significantly enhance our ability to deliver accurate radiotherapy. Imaging has also opened up avenues for guided therapies aimed at ablating liver metastases. Radiofrequency ablation, in particular, is being used successfully and can improve survival of stage four patients.

The influence of MRI scan position on patients with oropharyngeal cancer undergoing radical radiotherapy.

BackgroundThe purpose of this study was to demonstrate how magnetic resonance imaging (MRI) patient position protocols influence registration quality in patients with oropharyngeal cancer undergoing radical radiotherapy and the consequences for gross tumour volume (GTV) definition and radiotherapy planning.Methods and materialsTwenty-two oropharyngeal patients underwent a computed tomography (CT), a diagnostic MRI (MRID) and an MRI in the radiotherapy position within an immobilization mask (MRIRT). Clinicians delineated the GTV on the CT viewing the MRID separately (GTVC); on the CT registered to MRID (GTVD) and on the CT registered to MRIRT (GTVRT). Planning target volumes (PTVs) were denoted similarly. Registration quality was assessed by measuring disparity between structures in the three set-ups. Volumetric modulated arc therapy (VMAT) radiotherapy planning was performed for PTVC, PTVD and PTVRT. To determine the dose received by the reference PTVRT, we optimized for PTVC and PTVD while calculating the dose to PTVRT. Statistical significance was determined using the two-tailed Mann–Whitney or two-tailed paired student t-tests.ResultsA significant improvement in registration accuracy was found between CT and MRIRT versus the MRID measuring distances from the centre of structures (geometric mean error of 2.2xa0mm versus 6.6xa0mm). The mean GTVC (44.1xa0cm3) was significantly larger than GTVD (33.7xa0cm3, p valueu2009=u20090.027) or GTVRT (30.5xa0cm3, p valueu2009=u20090.014). When optimizing the VMAT plans for PTVC and investigating the mean dose to PTVRT neither the dose to 99% (58.8%) nor 95% of the PTV (84.7%) were found to meet the required clinical dose constraints of 90% and 95% respectively. Similarly, when optimizing for PTVD the mean dose to PTVRT did not meet clinical dose constraints for 99% (14.9%) nor 95% of the PTV (66.2%). Only by optimizing for PTVRT were all clinical dose constraints achieved.ConclusionsWhen oropharyngeal patients MRI scans are performed in the radiotherapy position there are significant improvements in CT-MR image registration, target definition and PTV dose coverage.

Efficacy of temsirolimus in metastatic chromophobe renal cell carcinoma

BackgroundRenal cell carcinoma (RCC) is a histopathologically and molecularly heterogeneous disease with the chromophobe subtype (chRCC) accounting for approximately 5% of all cases. The median overall survival of advanced RCC has improved significantly since the advent of tyrosine kinase inhibitors and mammalian target of rapamycin (mTOR) inhibitors. However, high-quality evidence for the use of new generation tyrosine kinase inhibitors in patients with advanced chRCC is lacking. Few published case reports have highlighted the use of temsirolimus in chRCC.Case presentationHere, we report the case of a 36-year-old Caucasian woman with metastatic chRCC with predominantly skeletal metastases who was refractory to sunitinib who demonstrated a durable clinical response to temsirolimus lasting 20 months. We review the available evidence pertaining to the use of new generation molecularly targeted agents, in particular mTOR inhibitors in chRCC and discuss their emerging role in the management of this disease which would aid the oncologists faced with the challenge of treating this rare type of RCC.ConclusionConducting randomised clinical trials in this rarer sub-group of patients would be challenging and our case report and the evidence reviewed would guide the physicians to make informed decision regarding the management of these patients.

Treatment outcome for nasopharyngeal carcinoma in University Malaya Medical Centre from 2004-2008.

BACKGROUNDnNasopharyngeal carcinoma (NPC) is the commonest radiocurable cancer in Malaysia. This study aimed to determine the treatment outcomes and late effects of radiotherapy for NPC patients treated in University Malaya Medical Centre (UMMC).nnnMATERIALS AND METHODSnAll newly diagnosed patients with NPC referred for treatment to the Oncology unit at UMMC from 2004-2008 were retrospectively analyzed. Treatment outcomes were 5 years overall survival (OS), disease free survival (DFS), cause-specific survival (CSS), loco- regional control (LRC) and radiotherapy-related late effects. The Kaplan-Meier method was used for survival analysis and differences in survival according to AJCC stage was compared using the log-rank test.nnnRESULTSnA total of 176 patients with newly diagnosed NPC were treated in UMMC during this period. Late presentation was common, with 33.5% presenting with T3-4 disease, 84.7% with N1-3 disease and 75.6% with AJCC stage 3-4 disease. Radical RT was given to 162 patients with 22.7% having RT alone and 69.3% having CCRT. The stipulated OTT was 7 weeks and 72.2% managed to complete their RT within this time period. Neoadjuvant chemotherapy was given to 14.8% while adjuvant chemotherapy was administered to 16.5%. The 5 years OS was 51.6% with a median follow up of 58 months. The 5 years OS according to stage were 81.8% for stage I, 77.9% for stage II, 47.4% for stage III and 25.9% for stage IV. The 5 years overall CSS, DFS and LRC were 54.4%, 48.4% and 70.6%, respectively. RT related late effects were documented in 80.2%. The commonest was xerostomia (66.7%). Other documented late effects were hearing deficit (17.3%), visual deficit (3.1%), neck stiffness (3.1%) , dysphagia (3.4%), cranial nerve palsy (2.5%), pneumonitis (0.6%) and hypothyroidism (1.2%).nnnCONCLUSIONSnThe 5 years OS and LRC in this study are low compared to the latest studies especially those utilizing IMRT. Implementation of IMRT for NPC treatment should be strongly encouraged.

Defining Optimal Cut-off Values and Research Methodology for Evaluating Systemic Inflammatory Markers in Clinical Outcome Prediction

To the Editor, We read with interest the article by Sato et al. [1], who have elegantly demonstrated the utility of a simple measure of systemic inflammation, the neutrophil to lymphocyte ratio (NLR), in response prediction for esophageal cancer patients undergoing neoadjuvant chemotherapy. As they say, it is a readily available, non-cumbersome test that neither depends on sophisticated analytic methods nor poses an excessive burden on resources. Despite a number of studies in esophageal cancer demonstrating the usefulness of NLR measurements, in our opinion, there remain important issues still to be addressed. One is the somewhat confusing variance in optimal NLR cut-off levels which separate favorable from poor prognostic/predictive groupings. Sato et al. [1] must be congratulated as they have performed receiver operating characteristics (ROC) curve analysis to objectively define the optimal cut-off point within their data set, producing a discriminatory NLR of 2.2. Previous studies, however, have used different cut-off levels. For example, Rashid et al. [2] used NLR 3.5, Sharaiha et al. [3] used NLR 5.0, and Dutta et al. [4] used NLR 2.5 and 5.0. In our center, a review of pretreatment NLR values for 127 patients being staged for potentially radically treatable esophageal carcinoma revealed that NLR is significantly associated with the robust endpoint of overall survival by Cox regression analysis (p = 0.01). Interestingly ROC curve analysis showed an optimal NLR cut-off value of 2.2, similar to the findings of Sato et al. In the wider literature, it is often unclear which, if any, methodology is used to define NLR cut-off points. Also, it is also not always clear if confounding factors are accounted for; for example, if patients suffer from ongoing systemic inflammatory disease or if there was concurrent use of immune modulators (e.g., steroids). Finally, where chemotherapy has been delivered prior to NLR measurements, albeit weeks beforehand, this can still potentially influence white cell production and constitution. Taken together, further standardization of the methodology involved in the study of systemic inflammatory markers is urgently required. Nevertheless, the study by Sato et al. [1] emphasizes the utility of a simple, uncomplicated test that could have important implications for clinical practice. There appears to be enough preliminary evidence for the research community to take forward the investigation of systemic inflammatory markers in a coordinated and rigorous fashion [5]. Ideally, confirmatory analysis in esophageal cancer patients will be done on prospective trial data with robust clinical outcome endpoints, and the community should also consider the role of pooled data analyses.

Trastuzumab-related Palmar Plantar Erythrodysaesthesia

Sird Trastuzumab (Herceptin ) is a licensedmonoclonal antibody used as adjuvant therapy for breast cancer patients [1] where HER2 over-expression or gene amplification can be demonstrated. This case describes the occurrence of palmar plantar erythrodysaesthesia (PPE) as an extremely rare drug-related complication. A 66-year-old postmenopausal woman presented with a 5 3 cm left breast mass. She had a history of hypertension and hypercholesterolaemia for which she was on amlodipine and atorvastatin (both more than 5 years). A mammogram, ultrasound and biopsy revealed two discrete oestrogen receptorand progesterone receptorpositive lesions, one being HER2 1þ on immunohistochemistry and another HER2 3þ. Fine needle aspiration of a single palpable axillary lymph node confirmed regional spread. Neoadjuvant chemotherapy was offered, but was declined by the patient in favour of endocrine therapy and letrozole was initiated instead. The patient proceeded to mastectomy and axillary node clearance. Histopathology revealed two separate grade 3 infiltrating ductal carcinomas with clear surgical margins, both associated with lymphovascular space invasion with six of 12 lymph nodes involved with malignancy. Adjuvant adriamycin and cyclophosphamide chemotherapy was delivered followed by adjuvant radiotherapy, exemestane and trastuzumab, at a loading dose of 8 mg/kg followed by 6 mg/kg every 3 weeks. Trastuzumab administration proceeded uneventfully until the eighth cycle (of 18) when she presented with erythema, discomfort and superficial dry desquamation of the palms of her hands and soles of her feet, which was interfering with function (Figure 1). This was diagnosed as a grade 3 PPE reaction. Topical emollients and steroids were prescribed and she was advised to avoid tight clothing and heat exposure. At her next pre-assessment visit, the PPE reaction had improved to grade 1 and the decision to proceed with further trastuzumab therapy with intravenous chlorpheniramine and hydrocortisone prophylaxis, was made. Subsequent cycles of trastuzumab proceeded without the recurrence of PPE in excess of grade 1 toxicity. Previous documentation of PPE or hand and foot syndrome in patients receiving trastuzumab has been

Delivering cancer services: a multi-disciplinary approach.

The article by Lim [1] on the development of oncology services in Malaysia was both insightful and comprehensive. It is interesting to read that cancer services are growing from strength to strength, with a national cancer institute planned. The field of oncology has been transformed over the last few decades with a proliferation in technological advances and a revolution occurring in molecular medicine. Interestingly, the thinking surrounding cancer service delivery has also been changing. Cancer care is increasingly being delivered within a multidisciplinary team environment, involving a host of highly skilled professionals. As oncologists, despite our unique skills in the diagnosis and treatment of cancer [2] we are, but a cog (albeit a necessary one), in a big wheel that is required to manage this complex disease. Therefore, it is arguable that oncology might actually be considered a multidisciplinary specialty. Every oncology department relies on a team of highly trained radiographers, physicists, pharmacists, nurses, and support staff for everyday functioning. With the resurgence of radiation research and development, intensity modulated and image guided radiotherapy [3] being prime examples, our reliance on our physicist and radiographer colleagues has never been greater. This includes all aspects of radiotherapy delivery, machine commissioning, quality assurance, treatment planning, and research. It has also been recognized that cancer centres benefit from taking an active role in public education and outreach, as this often leads to drastic improvements in patient satisfaction and overall perceptions. The concept of teamwork extends far beyond our own departments. One of our inseparable partners is radiology, which has evolved into a vast and multifaceted discipline. Different forms of imaging are used during a patients clinical course to diagnose, stage, plan, deliver intervention, and detect recurrence. Standard workhorses such as plain radiography and computed tomography (CT) are invaluable, but more specialized imaging is also important, including magnetic resonance imaging for detecting spinal cord lesions or imaging pelvic anatomy, bone scans for detecting skeletal metastases, and radiofrequency ablation for treating liver metastases. Even the most subtle of radiological features may predict a patients outcome, for example, the presence of rectal tumour found within 1 mm of the mesorectal fascia on a T2 weighted MRI scan could signify a substantial increase in the chance of local recurrence and warrant aggressive downstaging by preoperative chemoradiotherapy [4]. An emergent technology is CT-positron emission tomography (CT-PET). It offers undeniably superior imaging quality and evidence of its efficacy is …