The potential of virtual triage AI to improve early detection, care acuity alignment, and emergent care referral of life-threatening conditions.

Objective: To evaluate the extent to which patient-users reporting symptoms of five severe/acute conditions requiring emergency care to an AI-based virtual triage (VT) engine had no intention to get such care, and whose acuity perception was misaligned or decoupled from actual risk of life-threatening symptoms. Methods: A dataset of 3,022,882 VT interviews conducted over 16 months was evaluated to quantify and describe patient-users reporting symptoms of five potentially life-threatening conditions whose pre-triage healthcare intention was other than seeking urgent care, including myocardial infarction, stroke, asthma exacerbation, pneumonia, and pulmonary embolism. Results: Healthcare intent data was obtained for 12,101 VT patient-user interviews. Across all five conditions a weighted mean of 38.5% of individuals whose VT indicated a condition requiring emergency care had no pre-triage intent to consult a physician. Furthermore, 61.5% intending to possibly consult a physician had no intent to seek emergency medical care. After adjustment for 13% VT safety over-triage/referral to ED, a weighted mean of 33.5% of patient-users had no intent to seek professional care, and 53.5% had no intent to seek emergency care. Conclusion: AI-based VT may offer a vehicle for early detection and care acuity alignment of severe evolving pathology by engaging patients who believe their symptoms are not serious, and for accelerating care referral and delivery for life-threatening conditions where patient misunderstanding of risk, or indecision, causes care delay. A next step will be clinical confirmation that when decoupling of patient care intent from emergent care need occurs, VT can influence patient behavior to accelerate care engagement and/or emergency care dispatch and treatment to improve clinical outcomes.

How Virtual Triage Can Improve Patient Experience and Satisfaction: A Narrative Review and Look Forward.

Objective: To complete a review of the literature on patient experience and satisfaction as relates to the potential for virtual triage (VT) or symptom checkers to enhance and enable improvements in these important health care delivery objectives. Methods: Review and synthesis of the literature on patient experience and satisfaction as informed by emerging evidence, indicating potential for VT to favorably impact these clinical care objectives and outcomes. Results/Conclusions: VT enhances potential clinical effectiveness through early detection and referral, can reduce avoidable care delivery due to late clinical presentation, and can divert primary care needs to more clinically appropriate outpatient settings rather than high-acuity emergency departments. Delivery of earlier and faster, more acuity level-appropriate care, as well as patient avoidance of excess care acuity (and associated cost), offer promise as contributors to improved patient experience and satisfaction. The application of digital triage as a front door to health care delivery organizations offers care engagement that can help reduce patient need to visit a medical facility for low-acuity conditions more suitable for self-care, thus avoiding unpleasant queues and reducing microbiological and other patient risks associated with visits to medical facilities. VT also offers an opportunity for providers to make patient health care experiences more personalized.

The Role of Virtual Triage in Improving Clinician Experience and Satisfaction: A Narrative Review.

Objective: This review examines the literature on improving clinician satisfaction with a focus on what has been most effective in improving experience from the perspective of clinicians, and the potential role that virtual triage (VT) technology can play in delivering positive clinician experiences that improve clinical care, and bring value to health care delivery organizations (HDOs). Methods: Review and synthesis of evidence on clinician satisfaction indicating a potential for VT to favorably impact clinician experience, sense of effectiveness, efficiency, and reduction of administrative task burden. Analysis considers how to conceptualize and the value of improving clinician experience, leading clinician dissatisfiers, and the potential role of VT in improving clinician experience/satisfaction. Results: Contributors to poor clinician experience/satisfaction where VT could have a beneficial impact include better managing resource limitations, administrative workload, lack of care coordination, information overload, and payer interactions. VT can improve clinician experience through the technology's ability to leverage real-time actionable data clinicians can use, streamlining patient-clinician communications, personalizing care delivery, optimizing care coordination, and better aligning digital/virtual services with clinical practice. From an organizational perspective, improvements in clinician experience and satisfaction derive from establishing an effective digital back door, increasing the clinical impact of and satisfaction derived from telemedicine and virtual care, and enhancing clinician centricity. Conclusions: By embracing digital transformation and implementing solutions such as VT that focus on improving patient and clinician experience, HDOs can address barriers to delivery of high-quality, efficient, and cost-effective care. VT is a digital health tool that can create a more streamlined and satisfying experience for clinicians and the patients they care for. VT is a technology solution that can help clinicians make faster more informed decisions, reduces avoidable care, improves communication with patients and within care teams, and lowers their administrative burden so they have more quality time to care for patients.

A multinational survey of patient utilization of and value conveyed through virtual symptom triage and healthcare referral.

Objective: To describe the use patterns, impact and derived patient-user value of a mobile web-based virtual triage/symptom checker. Methods: Online survey of 2,113 web-based patient-users of a virtual triage/symptom checker was completed over an 8-week period. Questions focused on triage and care objectives, pre- and post-triage care intent, frequency of use, value derived and satisfaction with virtual triage. Responses were analyzed and stratified to characterize patient-user pre-triage and post-triage intent relative to triage engine output. Results: Seventy-eight percent of virtual triage users were female, and 37% were 18-24 years old or younger, 28% were 25-44, 16% were 45-54, and 19% were 55 years or older; 41.2% completed the survey from the U.S., 12.5% from the U.K., 9.1% from Canada, 5.6% from India, 3.8% from South Africa. Motivations were to determine need to consult a physician (44.2%), to secure medical advice without visiting a physician (21.0%), and to confirm a diagnosis received (14.2%). Forty-three percent were first time users of virtual triage, 36.6% utilized a triage engine at least once every few months or more often. Pre-triage, 40.5% did not know what level of healthcare they were planning to utilize, 33.9% stated they intended to seek a physician consultation, 23.7% engage self-care and 1.8% seek emergency care. Virtual triage recommended 56.8% of patient-users consult a physician, 33.8% seek emergency care and 9.4% engage self-care. In three-fourths, virtual triage helped users decide level of care to pursue. Among 74.1%, triage recommended care different than pre-triage intentions. Post-triage, those who remained uncertain of their care path decreased by 25.4%. Patient-user experience and satisfaction with virtual triage was high, with 80.1% stating that they were highly likely or likely to use it again, and interest in and willingness to use telemedicine doubled. Conclusion: Virtual triage successfully redirected patient-users who initially planned to seek an inappropriate level of care acuity, reduced patient uncertainty of care path, and doubled the percentage of patients amenable to telemedicine and virtual health engagement. Patient-users were highly satisfied with virtual triage and the virtual triage patient experience, and a large majority will use virtual triage recurrently in the future.

Anti-Cancer Effects of an Optimised Combination of Ginsenoside Rg3 Epimers on Triple Negative Breast Cancer Models.

Key problems of chemotherapies, as the mainstay of treatment for triple-negative breast cancer (TNBC), are toxicity and development of tumour resistance. Using response surface methodology, we previously optimised the combination of epimers of ginsenoside Rg3 (Rg3) for anti-angiogenic action. Here, we show that the optimised combination of 50 µM SRg3 and 25 µM RRg3 (C3), derived from an RSM model of migration of TNBC cell line MDA-MB-231, inhibited migration of MDA-MB-231 and HCC1143, in 2D and 3D migration assays (p < 0.0001). C3 inhibited mammosphere formation efficiency in both cell lines and decreased the CD44+ stem cell marker in the mammospheres. Molecular docking predicted that Rg3 epimers had a better binding score with IGF-1R than with EGFR, HER-2 or PDGFR, and predicted an mTOR inhibitory function of Rg3. C3 affected the signalling of AKT in MDA-MB-231 and HCC1143 mammospheres. In a mouse model of metastatic TNBC, an equivalent dose of C3 (23 mg/kg SRg3 + 11 mg/kg RRg3) or an escalated dose of 46 mg/kg SRg3 + 23 mg/kg RRg3 was administered to NSG mice bearing MDA-MB-231-Luc cells. Calliper and IVIS spectrum measurement of the primary and secondary tumour showed that the treatment shrunk the primary tumour and decreased the load of metastasis in mice. In conclusion, this combination of Rg3 epimers showed promising results as a potential treatment option for TNBC patients.

Anti-Angiogenic Properties of Ginsenoside Rg3 Epimers: In Vitro Assessment of Single and Combination Treatments.

Tumour angiogenesis plays a key role in tumour growth and progression. The application of current anti-angiogenic drugs is accompanied by adverse effects and drug resistance. Therefore, finding safer effective treatments is needed. Ginsenoside Rg3 (Rg3) has two epimers, 20(S)-Rg3 (SRg3) and 20(R)-Rg3 (RRg3), with stereoselective activities. Using response surface methodology, we optimised a combination of these two epimers for the loop formation of human umbilical vein endothelial cell (HUVEC). The optimised combination (C3) was tested on HUVEC and two murine endothelial cell lines. C3 significantly inhibited the loop formation, migration, and proliferation of these cells, inducing apoptosis in HUVEC and cell cycle arrest in all of the cell lines tested. Using molecular docking and vascular endothelial growth factor (VEGF) bioassay, we showed that Rg3 has an allosteric modulatory effect on vascular endothelial growth factor receptor 2 (VEGFR2). C3 also decreased the VEGF expression in hypoxic conditions, decreased the expression of aquaporin 1 and affected AKT signaling. The proteins that were mostly affected after C3 treatment were those related to mammalian target of rapamycin (mTOR). Eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1) was one of the important targets of C3, which was affected in both hypoxic and normoxic conditions. In conclusion, these results show the potential of C3 as a novel anti-angiogenic drug.

Perceptions diverge on aspects related to substance use disorder: An analysis of individuals in recovery, physicians, nurses, and medical students.

Background: Interactions with healthcare workers can provide effective entrance into treatment, ensuring retention and lifelong recovery for individuals with Substance Use Disorder (SUD). Healthcare providers approach the challenges of patient management with different skills, comfort levels, and viewpoints. Individuals in recovery also provide crucial perspectives relevant to the complex aspects of the drug epidemic. The purpose of this study was to determine if perceptions of SUD diverge among individuals in recovery, physicians, nurses and medical students. Methods: A survey consisting of 29 Likert statements was deployed to physicians, nurses, medical students, and persons with SUD in recovery. Respondents were asked to rate their level of agreement on statements about SUD such as treatment, stigma, medications for opioid use disorder (MOUD), naloxone kits, safe injection sites, and methamphetamine usage. Separate Welch's analysis of variances (ANOVAs) were conducted to determine differences between the respondent groups and each statement. For any statistically significant findings, Games-Howell post-hoc analyses were employed. Results: A total of 523 individuals provided survey responses: individuals in recovery (n = 111), physicians (n = 113), nurses (n = 206), and medical students (n = 93). Survey results revealed the majority of items had statistically significant differences in respondent groups. Perceptions diverged on items related to treatment, stigma, MOUD, take-home naloxone kits, safe injection sites, needle exchange programs, and methamphetamine. Conclusion: As healthcare providers and policymakers develop treatment strategies to engage those with SUD in quality treatment, they will benefit from understanding how different viewpoints on SUD affect treatment for these individuals. These attitudes impact stigma, willingness to prescribe new treatments, and development of clinical relationships. The insight from this study allows for important discussions on the substance use health crisis and further inquiry on why these differences exist and how the diverging viewpoints may impact the lives of persons with SUD.

North-South surgical training partnerships: a systematic review.

Background: Fostering the success of surgical trainees from low- and middle-income countries (LMICs) plausibly addresses the existing workforce deficit in a sustainable manner, but it is unclear whether and how these trainees are targeted as strategic learners for educational exchanges. The purpose of this review was to assess the quality and outcomes of existing literature on exchanges of surgical trainees between high-income countries (HICs) and LMICs. Methods: We conducted a systematic review of reported instances of surgical training exchanges between HICs and LMICs. After database searching, 2 independent reviewers evaluated titles, abstracts and manuscripts. Selected studies were critically appraised with the use the Critical Assessment Skills Programme Qualitative Checklist and analyzed for trainee level, institutions, countries and subspecialties, as well as reported outcomes of the exchange. Results: Twenty-eight reports met the inclusion criteria and were analyzed. Most publications (18 [64%]) detailed North-to-South exchanges; 1 exchange was bidirectional. General surgery was the most common discipline identified, with 9 other subspecialties described involving learners at all phases of training. Reports were generally of good quality, although outcomes were reported variably, and most authors failed to acknowledge the ethical implications of their study. Conclusion: The articles identified described a variety of surgical exchanges across disciplines, learner types and host/home countries. Few of the exchanges prioritized the learning of surgical trainees from LMICs. There is an increasing need to formalize these exchanges via clear goals and objectives, as well as to prioritize the proper matching of educational goals with local clinical needs. Level of evidence: V - Evidence from systematic reviews of descriptive and qualitative studies.

Contexte: Le soutien à la réussite des chirurgiens en formation des pays à revenu faible ou moyen (PRFM) pourrait concrètement aider à remédier au manque d'effectifs actuel de façon durable. On ignore toutefois si ces apprenants sont ciblés par les programmes d'échanges en tant que candidats stratégiques et quelles sont les méthodes de recrutement employées. La présente revue vise à évaluer la qualité et les résultats des publications sur les échanges entre pays à revenu élevé (PRE) et PRFM auxquels participent des chirurgiens en formation. Méthodes: Nous avons procédé à une revue systématique des cas rapportés d'échanges étudiants en chirurgie entre PRE et PRFM. Après une recherche dans les bases de données, 2 évaluateurs indépendants ont passé en revue les titres, les résumés et les manuscrits retenus. Les études sélectionnées ont fait l'objet d'une évaluation critique d'après la liste de contrôle pour la recherche qualitative CASP (Critical Assessment Skills Programme Qualitative Checklist); les critères d'analyse comprenaient le niveau de scolarité des apprenants, les établissements, les pays et les surspécialités, ainsi que les résultats rapportés pour l'échange. Résultats: Au total, 28 rapports répondaient aux critères d'inclusion et ont donc été analysés. La plupart d'entre eux (18 [64%]) traitaient d'échanges du nord au sud; un échange était bidirectionnel. La chirurgie générale était la discipline la plus souvent recensée; on a aussi décrit la participation d'apprenants à différentes étapes de leur formation pour 9 autres surspécialités. Les rapports étaient en général de bonne qualité, mais la présentation des résultats variait, et la majorité des auteurs ont omis de rendre compte des considérations éthiques de leur étude. Conclusion: Les articles évalués décrivaient des échanges étudiants en chirurgie se rapportant à une multitude de disciplines, de types d'apprenants et de pays d'origine et d'accueil. Peu de programmes d'échanges priorisaient l'apprentissage des chirurgiens en formation issus des PRFM. Il est de plus en plus pressant de baliser les échanges étudiants en établissant des buts et des objectifs clairs, et de faire une priorité de la juste correspondance des objectifs pédagogiques et des besoins cliniques locaux. Niveau de preuve: V ­ Preuve issue de revues systématiques d'études descriptives et qualitatives.

Management of early-stage gastro-esophageal cancers: expert perspectives from the Australasian Gastrointestinal Trials Group (AGITG) with invited international faculty.

Introduction: A multimodal approach in operable early-stage oesophago-gastric (OG) cancer has evolved in the last decade, leading to improvement in overall outcomes.Areas covered: A review of the published literature and conference abstracts was undertaken on the topic of optimal adjunctive chemotherapy or chemoradiotherapy in early-stage OG cancers. This review article focuses on the current evidence pertaining to neoadjuvant and perioperative strategies in curable OG cancers including the evolving landscape of immunotherapy and targeted drugs in this setting.Expert commentary: Adjunctive therapies in the form of preoperative chemo-radiotherapy (CRT) or chemotherapy and perioperative chemotherapy over surgery alone improve outcomes in patients with operable OG cancer. Although there are variations in practice around the world, a multi-disciplinary approach to patient care is of paramount importance. Immunotherapy and on treatment functional imaging are two examples of emerging strategies to improve the outcome for early-stage patients. A better understanding of the molecular biology of this disease may help overcome the problem of tumor heterogeneity and enable more rationally designed and targeted therapeutic interventions in the future.

Druggable Molecular Targets for the Treatment of Triple Negative Breast Cancer.

Breast cancer (BC) is still the most common cancer among women worldwide. Amongst the subtypes of BC, triple negative breast cancer (TNBC) is characterized by deficient expression of estrogen, progesterone, and human epidermal growth factor receptor 2 receptors. These patients are therefore not given the option of targeted therapy and have worse prognosis as a result. Consequently, much research has been devoted to identifying specific molecular targets that can be utilized for targeted cancer therapy, thereby limiting the progression and metastasis of this invasive tumor, and improving patient outcomes. In this review, we have focused on the molecular targets in TNBC, categorizing these into targets within the immune system such as immune checkpoint modulators, intra-nuclear targets, intracellular targets, and cell surface targets. The aim of this review is to introduce and summarize the known targets and drugs under investigation in phase II or III clinical trials, while introducing additional possible targets for future drug development. This review brings a tangible benefit to cancer researchers who seek a comprehensive comparison of TNBC treatment options.

Ginsenoside Rg3: Potential Molecular Targets and Therapeutic Indication in Metastatic Breast Cancer.

Breast cancer is still one of the most prevalent cancers and a leading cause of cancer death worldwide. The key challenge with cancer treatment is the choice of the best therapeutic agents with the least possible toxicities on the patient. Recently, attention has been drawn to herbal compounds, in particular ginsenosides, extracted from the root of the Ginseng plant. In various studies, significant anti-cancer properties of ginsenosides have been reported in different cancers. The mode of action of ginsenoside Rg3 (Rg3) in in vitro and in vivo breast cancer models and its value as an anti-cancer treatment for breast cancer will be reviewed.

Pressure dressings in mastoid and middle ear surgery: are they necessary? A retrospective review of patient outcomes.

BACKGROUND: The application of mastoid pressure dressings following mastoid and middle ear surgery is widely practised to reduce the risk of haematoma and seroma. There are a number of minor morbidities associated with use of the dressings, as well as a financial cost associated with an overnight stay in hospital or a return appointment for removal of the dressings. The benefit of having these dressings in situ overnight is questionable. METHODS: A retrospective review of 133 patients who had their mastoid dressing removed 2 h after their procedure was undertaken at our Hospital. The patient records were scanned for procedure-related morbidities, and perioperative data were analysed. RESULTS: No haematomas or seromas occurred in any of the 133 patients studied. Minor morbidities associated with prolonged use of mastoid pressure dressings were avoided. CONCLUSION: Removal of mastoid pressure dressings 2 h following ear surgery is safe and effective. Furthermore, a mastoid dressing should not be a factor in the decision as to whether to treat a patient as a day case or overnight admission.

Health-related quality of life associated with regorafenib treatment in refractory advanced gastric adenocarcinoma.

BACKGROUND: The INTEGRATE phase II multinational randomized controlled trial demonstrated the activity of regorafenib on progression-free survival (PFS) in patients with refractory advanced gastric adenocarcinoma. We sought to evaluate whether these PFS gains had the potential to be offset by quality of life (QoL) impacts from treatment side effects and to thereby determine the appropriateness of continuing development to phase III. METHODS: QoL was assessed in INTEGRATE at baseline and at each 4 weeks thereafter, until discontinuation of study treatment, using the QLQ-C30, STO22, and EQ-5D questionnaires. The patient disease and treatment assessment (PTDATA) form was also provided to English-speaking participants. Randomized groups were compared on the QLQ-C30, STO22, and EQ-5D scales using a repeated-measures model; the frequency of troublesome symptoms and side effects measured by the PTDATA form; and deterioration-free survival (DFS). The prognostic value of baseline QoL information was also evaluated. RESULTS: Of the 147 eligible randomized patients, 142 consented to participate in the QoL substudy, 136 completed a baseline QoL assessment, and 95 completed at least one post-baseline QoL assessment. The DFS rate was significantly improved with regorafenib, and there was no compelling statistical evidence that regorafenib had a broad negative effect across the spectrum of QoL indices evaluated. Fatigue, anxiety, appetite loss, and pain were among the issues most commonly reported for both randomized groups. Baseline levels of pain, appetite, constipation, and physical functioning were prognostic factors for survival. CONCLUSIONS: Regorafenib improved DFS without an excessively negative effect on QoL. Progressing development to the phase III setting is warranted.

Ampullary cancer of intestinal origin and duodenal cancer - A logical clinical and therapeutic subgroup in periampullary cancer.

Periampullary cancers include pancreatic, ampullary, biliary and duodenal cancers. At presentation, the majority of periampullary tumours have grown to involve the pancreas, bile duct, ampulla and duodenum. This can result in difficulty in defining the primary site of origin in all but the smallest tumors due to anatomical proximity and architectural distortion. This has led to variation in the reported proportions of resected periampullary cancers. Pancreatic cancer is the most common cancer resected with a pancreaticoduodenectomy followed by ampullary (16%-50%), bile duct (5%-39%), and duodenal cancer (3%-17%). Patients with resected duodenal and ampullary cancers have a better reported median survival (29-47 mo and 22-54 mo) compared to pancreatic cancer (13-19 mo). The poorer survival with pancreatic cancer relates to differences in tumour characteristics such as a higher incidence of nodal, neural and vascular invasion. While small ampullary cancers can present early with biliary obstruction, pancreatic cancers need to reach a certain size before biliary obstruction ensues. This larger size at presentation contributes to a higher incidence of resection margin involvement in pancreatic cancer. Ampullary cancers can be subdivided into intestinal or pancreatobiliary subtype cancers with histomolecular staining. This avoids relying on histomorphology alone, as even some poorly differentiated cancers preserve the histomolecular profile of their mucosa of origin. Histomolecular profiling is superior to anatomic location in prognosticating survival. Ampullary cancers of intestinal subtype and duodenal cancers are similar in their intestinal origin and form a logical clinical and therapeutic subgroup of periampullary cancers. They respond to 5-FU based chemotherapeutic regimens such as capecitabine-oxaliplatin. Unlike pancreatic cancers, KRAS mutation occurs in only approximately a third of ampullary and duodenal cancers. Future clinical trials should group ampullary cancers of intestinal origin and duodenal cancers together given their similarities and their response to fluoropyrimidine therapy in combination with oxaliplatin. The addition of anti-epidermal growth factor receptor therapy in this group warrants study.

Circulating tumor DNA analysis detects minimal residual disease and predicts recurrence in patients with stage II colon cancer.

Detection of circulating tumor DNA (ctDNA) after resection of stage II colon cancer may identify patients at the highest risk of recurrence and help inform adjuvant treatment decisions. We used massively parallel sequencing-based assays to evaluate the ability of ctDNA to detect minimal residual disease in 1046 plasma samples from a prospective cohort of 230 patients with resected stage II colon cancer. In patients not treated with adjuvant chemotherapy, ctDNA was detected postoperatively in 14 of 178 (7.9%) patients, 11 (79%) of whom had recurred at a median follow-up of 27 months; recurrence occurred in only 16 (9.8 %) of 164 patients with negative ctDNA [hazard ratio (HR), 18; 95% confidence interval (CI), 7.9 to 40; P < 0.001]. In patients treated with chemotherapy, the presence of ctDNA after completion of chemotherapy was also associated with an inferior recurrence-free survival (HR, 11; 95% CI, 1.8 to 68; P = 0.001). ctDNA detection after stage II colon cancer resection provides direct evidence of residual disease and identifies patients at very high risk of recurrence.

ICECREAM: randomised phase II study of cetuximab alone or in combination with irinotecan in patients with metastatic colorectal cancer with either KRAS, NRAS, BRAF and PI3KCA wild type, or G13D mutated tumours.

BACKGROUND: Patients with metastatic colorectal cancer whose disease has progressed on oxaliplatin- and irinotecan-containing regimens may benefit from EGFR-inhibiting monoclonal antibodies if they do not contain mutations in the KRAS gene (are "wild type"). It is unknown whether these antibodies, such as cetuximab, are more efficacious in refractory metastatic colorectal cancer as monotherapy, or in combination with irinotecan. Lack of mutation in KRAS, BRAF and PIK3CA predicts response to EFGR-inhibitors. The ICECREAM trial examines the question of monotherapy versus combination with chemotherapy in two groups of patients: those with a "quadruple wild type" tumour genotype (no mutations in KRAS, NRAS, PI3KCA or BRAF genes) and those with the specific KRAS mutation in codon G13D, for whom possibly EGFR-inhibitor efficacy may be equivalent. METHODS AND DESIGN: ICECREAM is a randomised, phase II, open-label, controlled trial comparing the efficacy of cetuximab alone or with irinotecan in patients with "quadruple wild type" or G13D-mutated metastatic colorectal cancer, whose disease has progressed on, or who are intolerant of oxaliplatin- and fluoropyrimidine-based chemotherapy. The primary endpoint is the 6-month progression-free survival benefit of the treatment regimen. Secondary endpoints are response rate, overall survival, and quality of life. The tertiary endpoint is prediction of outcome with further biological markers. International collaboration has facilitated recruitment in this prospective trial of treatment in these infrequently found molecular subsets of colorectal cancer. DISCUSSION: This unique trial will yield prospective information on the efficacy of cetuximab and whether this is further enhanced with chemotherapy in two distinct populations of patients with metastatic colorectal cancer: the "quadruple wild type", which may 'superselect' for tumours sensitive to EGFR-inhibition, and the rare KRAS G13D mutated tumours, which are also postulated to be sensitive to the drug. The focus on establishing both positive and negative predictive factors for the response to targeted therapy is an attempt to improve outcomes, reduce toxicity and contain treatment costs. Tissue and blood will yield a resource for molecular studies. Recruitment, particularly of patients with the rare G13D mutation, will demonstrate the ability for international collaboration to run prospective trials in small colorectal cancer molecular subgroups. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry: ACTRN12612000901808 , registered 16 August 2012.

Overview of biomarkers in metastatic colorectal cancer: tumour, blood and patient-related factors.

During the last 20 years there have been major therapeutic developments in colorectal cancer (CRC) with the introduction of multiple novel therapeutic agents into routine clinical practice. This has improved survival in both the adjuvant and advanced disease settings. However, improvements have come with substantial increases in expense to the community and potential toxicity to the patient. There has been substantial research to identify tumour factors in CRC that predict treatment response and survival outcomes. This research has identified clinically useful predictive biomarkers to aid clinical decision making, such as the presence or absence of KRAS gene mutations which can determine the benefit of using epidermal growth factor receptor (EGFR) inhibiting antibodies. However, less attention has been paid to the identification and impact of predictive patient-derived factors such as age, gender and the presence of comorbid conditions or evidence of a systemic inflammatory response. In this article, the current concepts of tumour and patient-related predictive factors in CRC management are reviewed.

Dual targeting of the epidermal growth factor receptor using the combination of cetuximab and erlotinib: preclinical evaluation and results of the phase II DUX study in chemotherapy-refractory, advanced colorectal cancer.

PURPOSE: This preclinical and phase II study evaluated the efficacy and safety of the combination of cetuximab and erlotinib in metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: The activity and mechanism of action of the combination of cetuximab plus erlotinib were investigated in vitro in colorectal cancer cell lines. In the clinical study, patients with chemotherapy-refractory mCRC were treated with cetuximab 400 mg/m(2) as a loading dose and then weekly cetuximab 250 mg/m(2) with erlotinib 100 mg orally daily. The primary end point was response rate (RR), which was evaluated separately in KRAS wild-type (WT) versus KRAS mutant tumors. Secondary end points included toxicity, progression-free survival (PFS), and overall survival. Target accrual was 50 patients, with a one-stage design. RESULTS: Preclinical studies demonstrated synergistic activity of cetuximab and erlotinib cotreatment on growth inhibition of colon cancer cell lines both as a result of enhanced inhibition of the epidermal growth factor receptor pathway and differential effects on STAT3. In the clinical study, 50 patients were enrolled, with 48 patients evaluable for response. The overall RR was 31% (95% CI, 26% to 57%), with a median PFS of 4.6 months (95% CI, 2.8 to 5.6 months). RR was 41% (95% CI, 26% to 57%) in KRAS WT tumors, with a median PFS of 5.6 months (95% CI, 2.9 to 5.6 months). There was no response in 11 patients with KRAS mutations. Frequent grade 3 and 4 toxicities were rash (48%), hypomagnesaemia (18%), and fatigue (10%). CONCLUSION: The combination of cetuximab and erlotinib synergistically inhibits growth of colon cancer cell lines, achieves promising efficacy in patients with KRAS WT mCRC, and merits evaluation in further randomized studies.

Epidemiology of cancers of the kidney in an Australian population.

BACKGROUND: Kidney cancer has a high incidence in Australia by world standards but has attracted little public health attention because of its low ranking among other cancers as a cause of death. Incidence, mortality and survival trends were investigated in this study for an Australian population and cancer control opportunities considered. DESIGN: Age-standardized incidence and mortality rates were analyzed by broad age category using data from an Australian cancer registry. Disease-specific survivals were analyzed using the Kaplan-Meier product limit estimate and multivariable Cox proportional hazards regression. RESULTS: Incidence rates approximately doubled during 1980-2008, with large increases affecting both sexes. Increases were more evident for renal cell and other histology types occurring predominantly in adulthood than childhood nephroblastomas. The male to female incidence ratio approximated 2:1 but decreased over time and was lower in younger than older age groups. The increase in mortality rate was smaller (at 25%) and higher in males (at 36%) than females (at 7%). Mortality increases were restricted to the age range of 70 years and over. Five-year survivals increased from 47% for 1980-84 to 66% for 2000-08 and multivariate predictors of high case fatality were older age at diagnosis and less recent diagnostic period. Country cases had lower survivals than metropolitan cases, although the difference was small. CONCLUSIONS: Increases in mortality were smaller than incidence increases, evidently due to offsetting increases in case survival, and did not affect the younger age groups. Further reductions in tobacco smoking and reducing the prevalence of obesity will be important to prevent renal cell carcinomas. Molecular research is advocated to develop targeted therapies and potentially, an effective screening technology. Cancer registries need to routinely publish their data by histology type to enable more detailed global trend analyses. Population registries also need to record stage of cancer at diagnosis to facilitate interpretation of changes in survival.

Metastatic carcinoid tumor: changing patterns of care over two decades.

BACKGROUND: Metastatic carcinoid tumors (MCTs), an important subgroup of neuroendocrine tumors, occur infrequently and often have an indolent course, limiting data on long-term treatment outcomes. We aimed to assess treatment trends at a single center over time and the impact on the outcome. STUDY: Patients diagnosed with carcinoid tumors in the North West Adelaide Health Service between January 1, 1985 and March 1, 2007 were identified from the South Australian Cancer Registry. RESULTS: We identified 92 patients with carcinoid tumors; 49 had MCT. Although treatment options increased over time, the most significant change was to access octreotide therapy, with 24 receiving long-acting somatostatin analogs. Survival improved over time and the median overall survival for patients receiving long-acting somatostatin analogs was 112 months compared with 53 months for those who did not (P=0.021, hazard ratio: 2.46). Ten year survival was 40% and 22%, respectively. About 75% of evaluable patients had a biochemical response to initial therapy and a measurable response occurred in 3 of 24 (13%) patients. CONCLUSIONS: This single center experience has provided insight into current treatment options for MCT, and suggests the use of long-acting somatostatin analogs may impact on disease control and survival. However, the uptake of other treatment options seems limited and there is a need for agents that target tumor progression.