Big Data is changing the battle against infectious diseases.

Big Data has traditionally been associated with computer geeks and commercial enterprises, but it has become entrenched in many scientific disciplines including the prevention and control of infectious diseases. The use of Big Data has allowed disease trends to be identified and outbreak origins to be tracked and even predicted. Big Data is not getting smaller. The challenges we face are to hone our analytical capacity to address the huge "signal-to-noise" ratio with adequate computing power and multidisciplinary teams that can handle ever-increasing amounts of data. Big Data will also create the opportunity for future applications of bespoke (or personalized) treatment.

Implementation of risk stratified antibiotic therapy for neutropenic fever: what are the risks?

BACKGROUND: A new national guideline for the management of febrile patients with severe neutropenia uses a risk stratification score to tailor treatment. AIMS: To evaluate the implementation of this guideline in a metropolitan teaching hospital. METHODS: A protocol was developed for implementation of the national guidelines for patients with neutropenic fever or at risk because of recent chemotherapy. Medical records of all patients presenting with fever to the haematology and oncology service for 3 months in 2011 were audited. Patients with a neutrophil count between 0.5 and 1.0 × 10(9) /L were classified as borderline neutropenia. RESULTS: Eighty-one episodes of fever were treated on the protocol. Forty-three per cent of patients were neutropenic. Uptake of the policy was low (35%) despite concerted efforts. The sensitivity and specificity of the Multinational Association for Supportive Care in Cancer score was 86% and 24% respectively. The readmission rate with fever was 19.2%. Median time to antibiotics was 60 min. Outcomes were similar for the neutropenic fever and borderline groups. Increasing treatment complexity was the major barrier to implementation. CONCLUSIONS: The majority of presentations with cancer and fever following chemotherapy do not have neutropenia but have similar outcomes when treated on the same pathway. The utility of the Multinational Association for Supportive Care in Cancer score was limited by uptake and specificity. Reducing time to antibiotics administration and readmission rates were identified as priorities. Implementation was labour-intensive and faced significant barriers. Prioritisation of evidence for translation requires attention to local priorities and implementation complexity. These results argue for a single sepsis guideline with treatment of cancer as a high-risk group.

Phase II study of gemcitabine and oxaliplatin in patients with recurrent ovarian cancer: an Australian and New Zealand Gynaecological Oncology Group study.

Gemcitabine and oxaliplatin have shown single-agent activity in relapsed ovarian cancer. This combination was used to determine response rates, time-to-event efficacy measures, and toxicity in patients with recurrent ovarian cancer. Patients with prior platinum-based chemotherapy who had measurable lesions and/or elevated CA-125 levels were identified as group A (platinum-refractory/platinum-resistant patients) and group B (platinum-sensitive patients). All patients received gemcitabine 1000 mg/m(2) on days 1 and 8 and oxaliplatin 130 mg/m(2) on day 8 every 21 days for up to eight cycles. Seventy-five patients (21 in group A and 54 in group B), with a median age of 58 years (range, 37-78), were enrolled. A median of six cycles (range, 1-8) was administered. By intent-to-treat analysis, 15 patients with measurable disease achieved partial response for an overall best response rate of 20.0% (9.5% in group A and 24.1% in group B). CA-125 response was observed in 48.4% patients (30.0% in group A and 57.1% in group B). Median time to progressive disease was 7.1 months (95% CI, 5.6-9.0 months) with 5.0 months in group A and 8.3 months in group B. Median overall survival was 17.8 months (95% CI, 12.9-21.3 months) with 9.2 months for group A and 20.0 months for group B. Major grade 3/4 toxicities were neutropenia (61.3%), leukopenia (24.0%), nausea (16.0%), and vomiting (22.7%). We conclude that the combination of oxaliplatin and gemcitabine is active in patients with recurrent ovarian cancer, but the regimen is unsatisfactory for further study due to modest response and relatively high toxicity.

Cytoreductive surgery and perioperative intraperitoneal chemotherapy for peritoneal carcinomatosis from colorectal carcinoma: non-mucinous tumour associated with an improved survival.

AIMS: Cytoreductive surgery combined with perioperative intraperitoneal chemotherapy has been reported as a treatment option for patients with peritoneal carcinomatosis from colorectal carcinoma. METHODS: Thirty patients with colorectal peritoneal carcinomatosis underwent cytoreductive surgery and perioperative intraperitoneal chemotherapy. All appendiceal cancers were excluded. All patients were followed until January 2006 or death. Univariate analysis was performed to evaluate significant prognostic factors for overall survival, defined from the time of surgery. RESULTS: There were 13 male patients. The mean age at the time of surgery was 54years. There was no hospital mortality. The mean duration of hospital stay was 27days. The overall median survival was 29months, with 1- and 2-year survival of 72% and 64%, respectively. Twenty-one patients had complete cytoreduction and their 1- and 2-year survival rates were 85% and 71%, respectively. Univariate analysis demonstrated that patients with non-mucinous colorectal adenocarcinoma, Peritoneal Cancer Index (PCI) < or =13, and complete cytoreduction were associated with an improved survival. CONCLUSIONS: This study reported on 30 patients who underwent cytoreductive surgery and perioperative intraperitoneal chemotherapy for colorectal peritoneal carcinomatosis. Patients with mucinous tumour had relatively more extensive intraperitoneal disease. Non-mucinous colorectal adenocarcinoma, PCI < or =13, and complete cytoreduction were associated with an improved survival.

Concurrent end-phase boost high-dose radiation therapy for non-small-cell lung cancer with or without cisplatin chemotherapy.

The aim of this study was to audit the results of a high-dose, combined-modality prospective protocol for non-small-cell lung cancer in terms of survival, disease-specific survival and toxicity. One hundred and twenty-one patients with non-small-cell lung cancer were treated with a concurrent, end-phase, boost, high-dose radiotherapy protocol with 65 Gy in 35 fractions for more than 5 weeks. Sixty-six patients received radiotherapy alone (group 1), 29 received concurrent chemoradiation (group 2) and 26 received neoadjuvant and concurrent chemotherapy (group 3). Thirty-four patients had stage I disease, six had stage II and 81 had stage III. Overall median survival was 23 months: 75% at 1 year and 23% at 5 years. Median survivals for patients with stage I and stages II and III disease were 43 and 19 months, respectively. For stages II and III patients by groups 1-3, median survivals were 18, 25 and 18 months, respectively, and 2-year survivals were 36, 52 and 38%, respectively. Toxicity was acceptable. Overall, 9% had symptomatic pneumonitis and 7% had grades 3 and 4 oesophagitis. For those who had the mediastinum included in the volume, grade > or = 3 oesophagitis occurred in 0, 11 and 22% (n = 110, P = 0.001), respectively, for treatment groups 1-3. Overall treatment-related mortality was 3%, consisting of two septic deaths, one pneumonitis and possibly one late cardiac event, all occurring in patients who had chemotherapy (7% of 55 patients). Treatment-related mortality declined over the study period. Accelerated radiotherapy was well tolerated, with only moderate increased acute toxicity when combined with concurrent platinum chemotherapy. Toxicity was enhanced by induction chemotherapy. Overall survival outcomes were excellent for this condition. Continued use of this radiotherapy schedule is recommended as the platform for assessment of other chemotherapy schedules.

Cytoreductive surgery and perioperative intraperitoneal chemotherapy for pseudomyxoma peritonei from appendiceal mucinous neoplasms.

BACKGROUND: Cytoreductive surgery (CRS) combined with perioperative intraperitoneal chemotherapy (PIC) has been used to treat pseudomyxoma peritonei. The aim of this prospective study was to evaluate survival outcome and treatment-related prognostic markers in patients who underwent CRS and PIC for pseudomyxoma peritonei from appendiceal mucinous neoplasms. METHODS: Survival data and 12 clinicopathological and treatment-related prognostic variables for survival were obtained prospectively in 50 consecutive patients (23 men). Univariate analysis was used to determine their prognostic significance for overall survival, determined from the time of CRS. RESULTS: The mean(s.d.) age was 52(12) years. Eighteen patients had moderate complications, and six patients had severe complications that required operation or intensive care support. Two patients died after surgery. The actuarial 5-year survival rate was 69 per cent. Univariate analysis demonstrated that the extent of previous surgery (P = 0.045) and Ronnett's histopathological classification (P < 0.001) were significantly related to overall survival. CONCLUSION: CRS combined with PIC was associated with improved survival in patients with less extensive previous surgery and diffuse peritoneal adenomucinosis histopathological type.

Vinblastine pharmacokinetics in patients with non-small cell lung cancer given cisplatin.

The pharmacokinetics of vinblastine were studied in 16 patients with non-small cell lung cancer after a bolus intravenous dose of 3 mg/m2 given before or after cisplatin (100 mg/m2). Venous blood was collected at 0, 10, and 36 hr for analysis by radioimmunoassay. The mean plasma vinblastine concentration at 10 hr was similar when vinblastine was given before (4.8 ng/ml; 95% CI, 3.2-6.3) or after cisplatin (4.9 ng/ml; 95% CI, 2.7-7.1). Plasma vinblastine concentrations in patients given cisplatin were higher than previously reported in patients given vinblastine alone. Patients with plasma vinblastine concentrations less than 2.75 ng/ml at 10 hr experienced less severe neutropenia (37% fall in neutrophil count; 95% CI, 18-55) than those with levels greater than 2.75 ng/ml (69% fall in neutrophil count; 95% CI, 62-77). In conclusion, the pharmacokinetics of vinblastine predict the severity of neutropenia and may be altered when given in conjunction with cisplatin.

Chemoprotectants: a review of their clinical pharmacology and therapeutic efficacy.

Dose-limiting toxicity secondary to antineoplastic chemotherapy is due to the inability of cytotoxic drugs to differentiate between normal and malignant cells. The consequences of this may include impairment of patient quality of life, because of toxicity, and reduced tumour control because of the inability to deliver adequate dose-intensive therapy against the cancer. Specific examples of toxicity against normal tissues include cisplatin-related neurotoxicity and nephrotoxicity, myelotoxicity secondary to treatment with alkylating agents and carboplatin, oxazaphosphorine-induced haemorrhagic cystitis, and cumulative dose-related cardiac toxicity secondary to anthracycline treatment. Chemoprotectants have been developed as a means of ameliorating the toxicity associated with cytotoxic agents by providing site-specific protection for normal tissues, without compromising antitumour efficacy. Clinical trials with toxicity protectors must include sufficient dose-limiting events for study, and assessment of both toxicity (allowing for measurement of efficacy of protection) and antitumour effect. Several chemoprotective compounds have now been extensively investigated, including dexrazoxane, amifostine, glutathione, mesna and ORG 2766. Dexrazoxane appears to complex with metal co-factors including iron, to reduce the incidence of anthracycline-induced cardiotoxicity, allowing the delivery of higher cumulative doses of anthracyclines without the expected consequence of cardiomyopathy. Numerous studies have demonstrated that sulfur-containing nucleophiles, including amifostine, glutathione, and mesna can specifically bind cisplatin- or alkylating agent-generated free radicals or alkylating agent metabolites to reduce the incidence of cisplatin-associated neurotoxicity and nephrotoxicity, or alkylating agent-associated myelosuppression and urothelial toxicity. These studies, in the majority of instances, have not revealed any evidence of reduction in antitumour efficacy. Further randomised trials are required to identify the optimal role of chemoprotectants when used alone or in combination with other toxicity modifiers including haemopoietic growth factors.

Caffeine-increased radiosensitivity is not dependent on a loss of G2/M arrest or apoptosis in bladder cancer cell lines.

PURPOSE: Bladder cancer cell lines UCRU-BL-13, UCRU-BL-17/2 and UCRU-BL-28, with differing p53 status and molecular responses to irradiation, were used to investigate possible mechanisms for caffeine-induced radiosensitization. MATERIALS AND METHODS: After treatment with caffeine and exposure to X-radiation, radiosensitivity was determined by clonogenic assay. Cell-cycle arrest and apoptosis were measured by flow cytometry. RESULTS: Both BL-13 and BL-28 cells (each expressing p53 with a wild-type sequence) fail to arrest at the G2 checkpoint after radiation, but nevertheless caffeine did induce radiosensitization. In contrast, in BL-17/2 cells (expressing p53 with a point mutation in codon 280), caffeine treatment abrogated the radiation-induced G2 arrest but was not accompanied by radiosensitization. No effects on radiosensitivity were seen in RT112 cells (expressing a functionally defective p53) at low caffeine doses (2 mM), but at higher doses (4 mM and 10 mM) caffeine caused both abrogation of radiation-induced G2 arrest and radiosensitization. In none of the cell lines examined did caffeine treatment and/or irradiation result in apoptosis. CONCLUSIONS: In contrast with previous studies, the data suggest that radiosensitization induced by caffeine is not dependent on abrogation of G2 arrest or the induction of apoptosis, and is not selective for cells expressing p53 proteins with mutations.

Clinical relevance of the molecular mechanisms of resistance to anti-cancer drugs.

Resistance to anti-cancer drugs (drug resistance) can be defined in the laboratory by the amount of anti-cancer drug that is required to produce a given level of cell death (drug response). Clinical drug resistance can be defined either as a lack of reduction of the size of a tumour following chemotherapy or as the occurrence of clinical relapse after an initial 'positive' response to anti-tumour treatment. Many studies of tumour samples do not directly measure drug resistance in the laboratory (because it is difficult to perform functional assays on tumour tissue); instead, key proteins or genes that are involved in particular mechanisms of drug resistance have been proposed as 'markers' of drug resistance. In this review, we have focused on the problems that can arise when attempts are made to relate the relevance of laboratory-identified molecular mechanisms of drug resistance to anti-cancer drug resistance that occurs in patients.

Regulation and deregulation of G2 checkpoint proteins with cisplatin.

BACKGROUND: The G2 checkpoint has a key role in the response to DNA damage. G2 arrest following DNA damage is associated with inactivation of the protein kinase cyclin B-cdc2. The role of changes in protein expression in enzyme inhibition is controversial. METHODS: Expression of cyclin B1, cdc2, cdc25c, total protein and DNA content were examined by flow cytometry in two lung cancer cell lines. Changes in protein expression were compared to cell cycle matched controls under conditions associated with and without G2 arrest. RESULTS: Total protein increased with G2 arrest and decreased with cell death. Changes in cdc2, cdc25c and p16 paralleled changes in total protein. A larger increase in cyclin B1 was seen which was due to cell cycle redistribution. Deregulation of cyclin B1 was seen with a sublethal dose of cisplatin. CONCLUSIONS: Our results do not support the model that changes in expression of cyclin B1 or other checkpoint proteins mediate G2 arrest after cisplatin.

A randomized trial of cimetidine with 5-fluorouracil and folinic acid in metastatic colorectal cancer.

Cimetidine has demonstrated a survival benefit in a randomized trial as adjuvant therapy for gastric cancer. We have demonstrated expression of histamine receptors on colon cancer cell lines and inhibition of their growth with cimetidine. Cimetidine also activates suppressor T cells and stimulates cell-mediated immunity. We therefore performed a randomized controlled clinical trial to determine the effect of cimetidine 400 mg given twice daily in conjunction with chemotherapy vs chemotherapy alone. Thirty-eight patients were randomized and 35 patients were eligible for further analysis. Both groups were well matched for pre-treatment characteristics. There was no difference in overall response. There was, however, a significantly increased rate of CEA response in the cimetidine group. Four of 11 patients (36%) in the cimetidine group had a CEA response compared to none of eight in the control. Meaningful comparisons of overall survival cannot yet be made. This study demonstrates that cimetidine has encouraging activity in increasing CEA response in patients with metastatic colorectal cancer treated with chemotherapy. This observation needs to be extended in a larger randomized study, which is currently underway.

High-dose chemotherapy in gynaecological cancers: does more mean better?

Evidence of the potential importance of planned dose intensity and its effect on patient outcome is based predominantly on the retrospective analysis of randomized trials. These have been subject to criticism on methodological grounds and should be considered as hypothesis-generating rather than proof of the importance of dose intensity. The relationship between chemotherapeutic dose and outcome of patients with gynaecological cancers has been investigated mainly in patients with advanced ovarian cancer. The literature is made up predominantly of small phase I-II studies demonstrating the feasibility of dose intensification strategies, but there is a paucity of large randomized trials. Although the 'more is better' approach may be intuitively appealing and is supported by some data, it must be demonstrated to translate into increased survival.

Hypercalcaemia in a patient with fatal adenosquamous carcinoma of the colon.

OBJECTIVE: To report a rare manifestation of metastatic adenosquamous carcinoma of the colon in a patient presenting with humoral hypercalcaemia of malignancy mediated by parathyroid hormone related peptide (PTHrP). CLINICAL FEATURES: A 58-year-old man with metastatic adenosquamous carcinoma of the colon presented with hypercalcaemia. A technetium bone scan excluded osteolytic bone secondaries. A negative parathyroid subtraction scan and a low serum immunoreactive parathyroid hormone level (1-34 [amino acid fragment]) made the diagnosis of primary hyperparathyroidism unlikely. The diagnosis of humoral hypercalcaemia of malignancy was considered on the basis of an elevated serum PTHrP level and positive tumour immunoreactivity to PTHrP antiserum. INTERVENTION AND OUTCOME: The hypercalcaemia was effectively treated on two occasions with intravenous administration of aminohydroxy propilidene diphosphonate. Despite interventional chemotherapy, the patient died of progressive carcinomatosis. CONCLUSION: Hypercalcaemia is an extremely rare occurrence in carcinoma of the colon. This is the first documented case of humoral hypercalcaemia of malignancy associated with adenosquamous carcinoma of the colon mediated by PTHrP.

Breaking bad news: realistic versus unrealistic hopes.

Hope is an essential aspect of the therapeutic relationship between cancer patients and their carers. Realistic hopes provide considerable support, whereas unrealistic hopes can be destructive by impairing the ability to make appropriate decisions about future plans, treatment, and issues of personal importance. Realistic hopes exist for cancer patients at all stages of their illness. Provision of realistic hope facilities the process of breaking bad news. In this article, the role of hope is explored. Appropriate hopes are identified from the time of pre-diagnostic work-up throughout the phase of definitive treatment and into the transition to palliative and supportive care. A practical approach is developed, which emphasises communication and listening skills, the importance of providing time and the benefits of intermediate goals that facilitate a gradual adjustment in hopes as the disease progresses.

Single dose pefloxacin compared with multiple dose co-trimoxazole in cystitis.

In a double-blind multicentre study the efficacy and safety of a single-dose treatment with pefloxacin (800 mg) was compared with a five-day treatment regimen of 960 mg co-trimoxazole twice daily in the therapy of acute uncomplicated cystitis in women. In order to maintain blindness, patients in the pefloxacin group received placebo to complement the full number of tablets. Nine centres were involved; 155 patients received pefloxacin and 161 patients received co-trimoxazole. Of these, 140 patients treated with pefloxacin and 145 with co-trimoxazole were considered valid for efficacy and safety analysis. At the first follow-up, after seven to ten days, 97.1% of the pefloxacin group and 95.2% of the co-trimoxazole group were bacteriologically cured. At the second follow-up visit, after 28 to 42 days, the urine culture was negative in 95.0% of the pefloxacin group and 90.3% of the co-trimoxazole group. A single dose of 800 mg pefloxacin was demonstrated to be as safe and at least as effective as a five-day regimen of co-trimoxazole in the treatment of uncomplicated cystitis.