Baseline MD Anderson Symptom Inventory Score is Strongly Associated With Patient-reported Acute and Late Toxicity Following (Chemo) Radiotherapy for Head and Neck Cancers.

AIMS: Patient-reported outcomes measures (PROMs) are an increasingly recognised end point of radiotherapy studies. We hypothesised that the baseline PROMs score is the strongest predictor for acute and late scores after treatment. We assessed the strength of association of baseline MD Anderson Symptom Inventory (MDASI) scores, alongside other known factors for patient- or clinician-reported toxicity, with acute (6-week) and late (12-month) scores in head and neck cancer (HNC) patients following (chemo)radiotherapy. MATERIALS AND METHODS: This was a retrospective analysis of longitudinal MDASI scores for 247 patients receiving (chemo)radiotherapy for HNC via multivariable linear regression. The factors investigated were: baseline symptom score, age, sex, concurrent chemotherapy, disease stage, radiotherapy fractionation, prior definitive surgery and performance status. Patients with a baseline score >4 in any item were defined as symptomatic in that category. RESULTS: Patients rated symptomatic for an MDASI item pre-treatment on average reported statistically (P < 0.0005) and clinically (>-1.5) significant reductions in scores 6 weeks and 12 months after (chemo)radiotherapy for all considered sub-items except taste, dryness of mouth and problems with teeth. Conversely patients asymptomatic at baseline reported a worsening of scores at both time points. Other investigated factors showed little association with changes in MDASI scores following treatment. CONCLUSIONS: Our data show that baseline MDASI scores are strongly associated with patient-reported toxicity 6 weeks and 12 months after (chemo)radiotherapy for HNC. Patients who are symptomatic at baseline can experience an early and durable benefit from treatment. This finding can inform discussions with patients before therapy and has implications for use of PROMs scores for the assessment of toxicity in randomised trials.

A Predictive Model for Reactive Tube Feeding in Head and Neck Cancer Patients Undergoing Definitive (Chemo) Radiotherapy.

AIMS: Careful management of a patient's nutritional status during and after treatment for head and neck squamous cell cancers (HNSCC) is crucial for optimal outcomes. The aim of this study was to develop a model for stratifying a patient's risk of requiring reactive enteral feeding through a nasogastric tube during radiotherapy for HNSCC, based on clinical and treatment-related factors. MATERIALS AND METHODS: A cohort of consecutive patients treated with definitive (chemo)radiotherapy for HNSCC between January 2016 and January 2018 was identified in the institutional electronic database for retrospective analysis. Patients requiring enteral feeding pretreatment were excluded. Clinical and treatment data were obtained from prospectively recorded electronic clinical notes and planning software. RESULTS: Baseline patient characteristics and tumour-related parameters were captured for 225 patients. Based on the results of the univariate analysis and using a stepwise backwards selection process, clinical and dosimetric variables were selected to optimise a clinically predictive multivariate model, fitted using logistic regression. The parameters found to affect the probability, P, of requiring a nasogastric feeding tube for >4 weeks in our clinical multivariate model were: tumour site, tumour stage (early T0/1/2 stage versus advanced T3/T4 stage), chemotherapy drug (none versus any drug) and mean dose to the contralateral parotid gland. A scoring model using the regression coefficients of the selected variables in the clinical multivariate model achieved an area under the curve (AUC) of 0.745 (95% confidence interval 0.678-0.812), indicating good discriminative performance. Internal validation of the model involved splitting the dataset 80:20 into training and test datasets 10 times and assessing differences in AUC of the model fitted to these. CONCLUSIONS: We developed an easy-to-use prediction model based on both clinical and dosimetric parameters, which, once externally validated, can lead to more personalised treatment planning and inform clinical decision-making on the appropriateness of prophylactic versus reactive enteral feeding.

Improved survival prediction for oropharyngeal cancer beyond TNMv8.

PURPOSE: For oropharynx squamous cell carcinoma (OPSCC) this study aimed to: (i) compare 5-year overall survival (OS) stratification by AJCC/UICC TNM versions 7 (TNMv7) and 8 (TNMv8), (ii) determine whether changes to T and N stage groupings improve prognostication and (iii) develop and validate a model incorporating additional clinical characteristics to improve 5-year OS prediction. MATERIAL AND METHODS: All OPSCC treated with curative-intent at our institution between 2011 and 2017 were included. The primary endpoint was 5-year OS. Survival curves were produced for TNMv7 and TNMv8. A three-way interaction between T, N stage and p16 status was evaluated for improved prognostication. Cox proportional hazards modelling was used to derive a new predictive model. RESULTS: Of 750 OPSCC cases, 574 (77%) were p16-positive. TNMv8 was more prognostic than TNMv7 (concordance probability estimate [CPE] ±â€¯SE = 0.72 ±â€¯0.02 vs 0.53 ±â€¯0.02). For p16-positive disease, TNMv8 discriminated stages II vs I (HR 2.32, 95% CI 1.47-3.67) and III vs II (HR 1.75, 95% CI 1.13-2.72). For p16-negative disease, TNMv7 and TNMv8 demonstrated poor hazard discrimination. Different T, N stage and p16-status combinations did not improve prognostication after adjusting for other factors (CPE = 0.79 vs 0.79, p = 0.998). A model for p16-positive and p16-negative OPSCC including additional clinical characteristics improved 5-year OS prediction beyond TNMv8 (c-index 0.76 ±â€¯0.02). CONCLUSIONS: TNMv8 is superior to TNMv7 for p16-positive OPSCC, but both performed poorly for p16-negative disease. A novel model incorporating additional clinical characteristics improved 5-year OS prediction for both p16-positive and p16-negative disease.

An evaluation of MR based deep learning auto-contouring for planning head and neck radiotherapy.

INTRODUCTION: Auto contouring models help consistently define volumes and reduce clinical workload. This study aimed to evaluate the cross acquisition of a Magnetic Resonance (MR) deep learning auto contouring model for organ at risk (OAR) delineation in head and neck radiotherapy. METHODS: Two auto contouring models were evaluated using deep learning contouring expert (DLCExpert) for OAR delineation: a CT model (modelCT) and an MR model (modelMRI). Models were trained to generate auto contours for the bilateral parotid glands and submandibular glands. Auto-contours for modelMRI were trained on diagnostic images and tested on 10 diagnostic, 10 MR radiotherapy planning (RTP), eight MR-Linac (MRL) scans and, by modelCT, on 10 CT planning scans. Goodness of fit scores, dice similarity coefficient (DSC) and distance to agreement (DTA) were calculated for comparison. RESULTS: ModelMRI contours improved the mean DSC and DTA compared with manual contours for the bilateral parotid glands and submandibular glands on the diagnostic and RTP MRs compared with the MRL sequence. There were statistically significant differences seen for modelMRI compared to modelCT for the left parotid (mean DTA 2.3 v 2.8 mm), right parotid (mean DTA 1.9 v 2.7 mm), left submandibular gland (mean DTA 2.2 v 2.4 mm) and right submandibular gland (mean DTA 1.6 v 3.2 mm). CONCLUSION: A deep learning MR auto-contouring model shows promise for OAR auto-contouring with statistically improved performance vs a CT based model. Performance is affected by the method of MR acquisition and further work is needed to improve its use with MRL images.

Assessment of liver cirrhosis for patients with Child's A classification before hepatectomy using dynamic contrast-enhanced MRI.

AIM: To determine the feasibility of semi-quantitative haemodynamic parameters derived from dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) to assess liver fibrosis. MATERIALS AND METHODS: Seventy-five patients with Child's A classification (males/females=24/51; average age, 58 years; range, 30-80 years) received DCE-MRI 3 days prior to hepatectomy. Semi-quantitative haemodynamic parameters, including the wash-in slope, wash-out slope, and time-to-peak, were calculated from DCE-MRI data. Liver fibrosis of the resected non-tumour liver was graded pathologically from F0 (no fibrosis) to F6 (cirrhosis) in the regions corresponding to those assessed by DCE-MRI. RESULTS: The wash-out slope showed higher interobserver and intra-observer reliabilities than the wash-in slope and time-to-peak. There was a significant positive correlation between the wash-out slope and pathological grade of fibrosis (Spearman's correlation coefficient: r=0.5331, p<0.0001). The area under the receiver operating characteristic curve was 0.8066 when using the wash-out slope to differentiate cirrhosis (grade F6) from non-cirrhosis (grades F0-5). Using the cut-off point that maximised specificity, the sensitivity was 62.07%, specificity was 91.30%, positive predictive value was 81.81%, negative predictive value was 79.25%, and accuracy was 80%. CONCLUSIONS: The wash-out slope derived from DCE-MRI might be potentially useful in assessing liver cirrhosis in patients with Child's A classification before hepatectomy.

Ninety Day Mortality After Radical Radiotherapy for Head and Neck Cancer.

AIMS: Treatment for head and neck cancers using definitive radiotherapy, with or without chemotherapy, is associated with significant acute toxicity. Our aim was to assess 90 day mortality after radical radiotherapy. A further aim was to identify patient, tumour or treatment factors associated with early death after treatment and whether these could be used to predict outcomes. MATERIALS AND METHODS: In total, 1116 patients with squamous cell pharyngeal and larynx cancer between January 2011 and December 2015 were included. Patients with T1 larynx cancer were excluded. Patients were treated using radical radiotherapy, with or without chemotherapy. Ninety day mortality was calculated using survival of less than 135 days from the planned start date for radical radiotherapy, to include early deaths during and up to 90 days after treatment. RESULTS: Overall, 90 day mortality was 4.7%. Among the subgroup of patients treated with concurrent platinum chemotherapy, the 90 day mortality rate was 0.4%. Overall survival at 1, 3 and 5 years was 84%, 62% and 53%, respectively. Factors associated with a higher risk of early death included performance status > 1, haemoglobin <100 g/l, weight < 60 kg, age > 80 years and presence of multiple comorbidities. CONCLUSION: We report excellent crude overall survival rates among our radically treated cohort of head and neck cancer patients. Several factors were associated with an increased risk of death within 90 days of completion of radical head and neck radiotherapy. Given the potential severe acute effects and the impact on patient quality of life associated with radical head and neck radiotherapy, this information is helpful to inform treatment-related discussions with patients.

Phase 2, open-label, 1:1 randomized controlled trial exploring the efficacy of EMD 1201081 in combination with cetuximab in second-line cetuximab-naïve patients with recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN).

AIM: To determine whether EMD 1201081, a TLR9 agonist, added to cetuximab had antitumor activity in second-line recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). METHODS: This was a phase 2, open-label, randomized trial of EMD 1201081 0.32 mg/kg subcutaneously weekly plus cetuximab (combination) vs cetuximab monotherapy (control) in cetuximab-naïve patients with R/M SCCHN who progressed on 1 cytotoxic regimen. Crossover to combination was permitted after progression. RESULTS: Objective response rate in both arms was 5.7% (95% CI 1.2-15.7%) by independent assessment. Disease control was 37.7% for patients on combination (24.8-52.1%) and 43.4% on control (29.8-57.7%). Neither independent nor investigator assessments showed significant differences between study arms. Median progression-free survival was 1.5 months (1.3-2.6) for patients on combination, and 1.9 months (1.5-2.9) on control. The most frequent adverse events in the combination arm were rash (29.6%), acneiform dermatitis (22.2%), and injection site reactions (20.4%). Grade 3/4 dyspnea and hypokalemia were more frequent with cetuximab monotherapy (7.5% and 5.7% vs 1.9% each, respectively), and grade 3/4 respiratory failure and disease progression were more frequent with combination (5.6% each vs 1.9% each). CONCLUSION: EMD 1201081 was well tolerated combined with cetuximab, but there was no incremental clinical efficacy.

Mutation of a Nopp140 gene dao-5 alters rDNA transcription and increases germ cell apoptosis in C. elegans.

Human diseases of impaired ribosome biogenesis resulting from disruption of rRNA biosynthesis or loss of ribosomal components are collectively described as 'ribosomopathies'. Treacher Collins syndrome (TCS), a representative human ribosomopathy with craniofacial abnormalities, is attributed to mutations in the tcof1 gene that has a homologous gene called nopp140. Previous studies demonstrated that the dao-5 (dauer and aged animal overexpression gene 5) of Caenorhabditis elegans is a member of nopp140 gene family and plays a role in nucleogenesis in the early embryo. Here, we established a C. elegans model for studying Nopp140-associated ribosomopathy. A null dao-5 mutant ok542 with a semi-infertile phenotype showed a delay in gonadogenesis, as well as a higher incidence of germline apoptosis. These phenotypes in dao-5(ok542) are likely resulted from inefficient rDNA transcription that was observed by run-on analyses and chromatin immunoprecipitation (ChIP) assays measuring the RNA Pol I occupancy on the rDNA promoter. ChIP assays further showed that the modifications of acetylated histone 4 (H4Ac) and dimethylation at the lysine 9 of histone 3 (H3K9me2) around the rDNA promoter were altered in dao-5 mutants compared with the N2 wild type. In addition, activated CEP-1 (a C. elegans p53 homolog) activity was also linked to the loss of DAO-5 in terms of the transcriptional upregulation of two CEP-1 downstream effectors, EGL-1 and CED-13. We propose that the dao-5 mutant of C. elegans can be a valuable model for studying human Nopp140-associated ribosomopathy at the cellular and molecular levels.

Carotid dosimetry for T1 glottic cancer radiotherapy.

OBJECTIVE: Radiotherapy for T1 glottic cancer is commonly delivered using a lateral parallel opposed pair of megavoltage photon fields. There is increasing reported evidence of cerebrovascular events due to radiation-induced carotid stenosis. An alternative field arrangement is to use an anterior oblique technique. This study compares the carotid dosimetry between the two techniques and reviews the evidence for the risk of radiation-induced vascular events. METHODS: The radiotherapy plans of 10 patients with T1 glottic cancer treated with an anterior oblique technique were examined for carotid dose. Alternative plans were then created using a parallel opposed pair of fields and the dose to the carotids compared. All patients received 50 Gy in 16 fractions treating once daily, for 5 days in a week. RESULTS: The average of the mean dose to the carotids with the anterior oblique technique was 21 Gy compared with 37 Gy using the lateral parallel opposed pair arrangement (p < 0.0001). CONCLUSION: An anterior oblique field arrangement for the treatment of T1 glottic cancer results in a significantly lower radiation dose to the carotid arteries, which may be clinically important in terms of reducing the risk of cerebrovascular events in long-term survivors. ADVANCES IN KNOWLEDGE: Although the anterior oblique technique for treating early glottic cancers is well described, and it is predictable that the dose received by the carotid arteries should be lower with this technique, to our knowledge this is the first study to quantify that reduction in dose with a series of patients.

Nasopharyngeal carcinoma: a retrospective review of demographics, treatment and patient outcome in a single centre.

AIMS: Nasopharyngeal cancer (NPC) is relatively uncommon, especially in the Western world. We report our single institution experience of 20 years of data in 128 patients with NPC, including responses to different treatment modalities and outcomes by histological subtype. MATERIALS AND METHODS: NPC patients presenting from 1992 to 2005 were located on the cancer registry database. Demographic data included age, gender, length of presenting symptoms and stage. World Health Organization classification (2005) was used for histological subtyping. The date of recurrence and survival outcomes were analysed using Kaplan-Meier curves. RESULTS: Presentation data were analysed from 128 patients; the survival analysis included 123 patients. The median age at presentation was 57.7 years. Stage III and IV presentation rates were 34 and 38%, respectively. The most common presenting symptom was a palpable neck lump (55%) and the median duration of symptoms was 16 weeks. Forty-eight patients received radiotherapy alone and 75 received chemoradiotherapy. The median overall survival in chemoradiotherapy patients was 80.3 months versus 28.5 months with radiotherapy alone (P = 0.003). A significant difference was also seen with recurrence-free survival (RFS) (P = 0.017). Type 1 keratinising carcinoma had a significantly worse overall survival (P = 0.04) and a similar but non-statistically significant trend was seen for RFS (P = 0.051). The multivariate analysis for overall survival showed that histological subtype (hazard ratio 2.7, 95% confidence interval 1.3-5.5, P = 0.034), age (hazard ratio 2.3, 95% confidence interval 1.1-4.9, P = 0.018) and N stage (hazard ratio 3.7, 95% confidence interval 1.4-9.4, P = 0.024) were prognostic factors. CONCLUSIONS: We present the first large-scale, single-centre retrospective review of NPC in a UK-based population. Demographic data were similar to that in other Western populations, with a significantly worse survival outcome in the keratinising group. Further prospective study of outcome in Western populations accounting for newer radiotherapy techniques such as intensity-modulated radiotherapy and dose escalation, particularly in the keratinising population who were more likely to present with an isolated local recurrence, is recommended.

Evaluation of gadolinium-enhanced T1-weighted magnetic resonance imaging in the preoperative assessment of local staging in rectal cancer.

AIM: The aim of this study was to determine whether gadolinium-enhanced T1-weighted magnetic resonance (MR) sequence is beneficial in the preoperative assessment of tumour and nodal staging in patients with primary rectal cancer. METHOD: Eighty-eight patients with primary rectal cancer underwent preoperative MR imaging, followed by surgical resection. Two radiologists independently reviewed (i) T2-weighted MR images (T2WI); (ii) gadolinium-enhanced T1-weighted MR images (T1 + Gd); (iii) MR combined with T2WI and T1 + Gd for the prediction of tumour and nodal stage compared with histopathologic findings as the end point. Differences in the diagnostic performance of T2WI only, T1 + Gd image only and combined T2WI and T1 + Gd MR images were analyzed by comparing areas under receiver operating characteristic curves (Az) for each reader. Interobserver agreement was also calculated. RESULTS: There was no significant difference in the Az values of T2WI only, T1 + Gd image only and combined T2WI and T1 + Gd images for the prediction of tumour staging (Az of T2WI, T1 + Gd and combined MR images for reader 1, 0.80, 0.76 and 0.85; reader 2, 0.83, 0.82 and 0.87) and nodal staging (Az for reader 1, 0.73, 0.73 and 0.81; reader 2, 0.79, 0.80 and 0.83). Interobserver agreement for the prediction of tumour staging was moderate to substantial, while only fair agreement was noted for the prediction of nodal staging. CONCLUSION: Gadolinium-enhanced T1-weighted MRI did not increase the diagnostic yield for tumour and nodal staging, and may be omitted in the MR protocol for preoperative assessment of primary rectal cancer.

Thoracic radiotherapy for limited-stage small-cell lung cancer: controversies and future developments.

Thoracic radiotherapy has an established role in the management of limited-disease small-cell lung cancer (LD SCLC). However, essential questions relating to the optimisation of thoracic radiotherapy remain unanswered, including volume of irradiation, optimal total dose, fractionation, timing and sequencing of radiation. This review highlights the need for well-designed multi-national trials aimed at the optimisation and standardisation of radiotherapy for LD SCLC.

Adjuvant and salvage treatment after radical prostatectomy: current practice in the UK.

OBJECTIVE: To survey UK urologists and radiation oncologists in the evaluation and treatment of localised prostate cancer in the adjuvant and salvage setting. METHODS: Postal questionnaires were mailed to 292 urologists and 98 radiation oncologists in the UK. RESULTS: In all, 188 (48%) questionnaires were returned. In total, 72/128 (56%) of the urologist respondents and 58/60 (97%) of the oncologist respondents perform routine radical prostate treatment. Among 43 (60%) of the urologist, 40 (69%) recommended adjuvant treatment, which could be radiotherapy, hormonal treatment or combined hormonal and radiation treatment. There is no significant difference between the modality of treatment recommended. The poor prognostic factors that would influence the decision to offer adjuvant treatment include a detectable postoperative PSA, seminal vesicle involvement, positive margins, Gleason score>8 and pathological T3. With regard to the choice of hormonal treatment, most urologists preferred antiandrogens, whereas most oncologists prefer lutienising hormone releasing hormone (LHRH) analogue (P=0.03). Regarding salvage treatment, there is a wide variation in the PSA threshold and number of PSA rises before initiation of investigations and treatment. Significantly more urologists recommended salvage radiotherapy (P=0.02), whereas oncologists recommended combined hormonal radiation therapy (P=0.03). There is a wide variation of practice regarding the duration of hormonal treatment, the type of investigations initiated, range of radiotherapy doses and treatment volumes. CONCLUSION: There is a wide variation in practice among UK clinicians.

Phase III trial of liposomal doxorubicin and cyclophosphamide compared with epirubicin and cyclophosphamide as first-line therapy for metastatic breast cancer.

OBJECTIVE: To ascertain the efficacy and tolerability of non-pegylated liposomal doxorubicin (Myocet) and epirubicin combined with cyclophosphamide in the first-line treatment of patients with metastatic breast cancer. METHODS: One hundred and sixty anthracycline-naïve metastatic breast cancer patients were randomised to receive Myocet (M; 75 mg/m(2)) or epirubicin (E; 75 mg/m(2)) in combination with cyclophosphamide (C; 600 mg/m(2)), every 3 weeks for up to eight cycles. OUTCOME MEASURES: Response (overall response = complete + partial response rates), time to disease progression, overall survival and cardiac function (left ventricular ejection fraction). RESULTS: Overall response rates were 46% and 39% for MC and EC treatment, respectively (P=0.42). MC was superior to EC with respect to median time to treatment failure (5.7 versus 4.4 months; P=0.01) and median time to disease progression (7.7 versus 5.6 months; P=0.02). Median survival times were 18.3 and 16.0 months for MC and EC, respectively (P=0.504). Unsurprisingly, given an equimolar comparison, neutropenia and stomatitis/mucositis were significantly more common in patients who received MC. However, there was less injection site toxicity with MC. Both treatments showed a low incidence of cardiotoxicity. CONCLUSION: Myocet appears to be an acceptable alternative to epirubicin as a first-line treatment for patients with metastatic breast cancer because it combines the dose-effect reliability of doxorubicin with the level of safety provided by epirubicin.

Hypofractionated radiotherapy as salvage for rising prostate-specific antigen after radical prostatectomy.

AIMS: To review the outcome of men receiving hypofractionated salvage radiotherapy for rising prostate-specific antigen (PSA) after radical prostatectomy. MATERIALS AND METHODS: A retrospective analysis of 61 men referred for salvage radiotherapy for biochemical relapse after radical prostatectomy was conducted. Twenty-four men receiving hormonal therapy or with follow-up of less than 12 months were excluded. Thirty-seven men were identified, median age 64 years, median preoperative PSA 11 ng/ml (5.6-60 ng/ml), Gleason scores <7: 70%, Gleason scores > or = 7: 30%. Twenty-seven men had positive surgical resection margins, eight had seminal-vesicle involvement and one had lymph-node involvement. Diagnosis of failure after radical prostatectomy was made on rising PSA in all cases; 19 men also had positive magnetic resonance imaging, 11 abnormal digital rectal examination and nine positive biopsy. Radiotherapy was delivered conformally to the prostatic fossa, 50-52.5 Gy in 20 fractions over 4 weeks. Date of failure after radiotherapy was defined by the American Society for Therapeutic Radiology and Oncology (ASTRO) consensus criteria or as date of commencement of hormonal therapy for rising PSA. RESULTS: Median time from radical prostatectomy to radiotherapy was 30.6 months (8-68 months); median pre-radiotherapy PSA was 2.9 ng/ml (0.5-11.4 ng/ml). PSA response after radiotherapy was seen in 33 out of 37 (89%) patients. At median follow-up of 36 months (20-85 months), 28 out of 37 remained disease-free. Thirteen more patients have had two consecutive PSA rises. Actuarial 3-year disease-free survival is 74%. No patient has developed metastases or died of prostate cancer. Pre-radiotherapy PSA less than 2 ng/ml predicted disease-free survival (P = 0.027). No acute toxicity greater than Radiation Therapy Oncology Group (RTOG) G2 was observed. CONCLUSIONS: Salvage radiotherapy after radical prostatectomy achieved durable biochemical control in most patients. Outcome is improved if radiotherapy is delivered when PSA is less than 2 ng/ml. A policy of close monitoring after radical prostatectomy with early referral for salvage radiotherapy is advocated.

Reduced cardiotoxicity and preserved antitumor efficacy of liposome-encapsulated doxorubicin and cyclophosphamide compared with conventional doxorubicin and cyclophosphamide in a randomized, multicenter trial of metastatic breast cancer.

PURPOSE: To determine whether Myocet (liposome-encapsulated doxorubicin; The Liposome Company, Elan Corporation, Princeton, NJ) in combination with cyclophosphamide significantly reduces doxorubicin cardiotoxicity while providing comparable antitumor efficacy in first-line treatment of metastatic breast cancer (MBC). PATIENTS AND METHODS: Two hundred ninety-seven patients with MBC and no prior chemotherapy for metastatic disease were randomized to receive either 60 mg/m(2) of Myocet (M) or conventional doxorubicin (A), in combination with 600 mg/m(2) of cyclophosphamide (C), every 3 weeks until disease progression or unacceptable toxicity. Cardiotoxicity was defined by reductions in left-ventricular ejection fraction, assessed by serial multigated radionuclide angiography scans, or congestive heart failure (CHF). Antitumor efficacy was assessed by objective tumor response rates (World Health Organization criteria), time to progression, and survival. RESULTS: Six percent of MC patients versus 21% (including five cases of CHF) of AC patients developed cardiotoxicity (P =.0002). Median cumulative doxorubicin dose at onset was more than 2,220 mg/m(2) for MC versus 480 mg/m(2) for AC (P =.0001, hazard ratio, 5.04). MC patients also experienced less grade 4 neutropenia. Antitumor efficacy of MC versus AC was comparable: objective response rates, 43% versus 43%; median time to progression, 5.1% versus 5.5 months; median time to treatment failure, 4.6 versus 4.4 months; and median survival, 19 versus 16 months. CONCLUSION: Myocet improves the therapeutic index of doxorubicin by significantly reducing cardiotoxicity and grade 4 neutropenia and provides comparable antitumor efficacy, when used in combination with cyclophosphamide as first-line therapy for MBC.

Antiplatelet activity of Staphylococcus aureus lipoteichoic acid is mediated through a cyclic AMP pathway.

In this study, Gram-positive Staphylococcus aureus lipoteichoic acid (LTA) dose dependently (0.1-1.0 microg/mL) and time dependently (10-60 min) inhibited platelet aggregation in human platelets stimulated by agonists (i.e., thrombin and collagen). LTA also dose dependently inhibited intracellular Ca(2+) mobilization in human platelets stimulated by collagen. In addition, LTA (0.5 and 1.0 microg/mL) dose dependently increased the formation of cyclic AMP but not cyclic GMP in platelets. LTA (0.5 and 1.0 microg/mL) did not significantly increase the production of nitrate within a 10-min incubation period. Rapid phosphorylation of a platelet protein of M(r) 47,000, a marker of protein kinase C activation, was triggered by PDBu (0.03 microM). This phosphorylation was dose dependently inhibited by LTA (0.5 and 1.0 microg/mL) within a 10-min incubation period. Furthermore, LTA (0.5 and 1.0 microg/mL) also inhibited platelet aggregation induced by PDBu (0.03 microM) in human platelets. These results indicate that the antiplatelet activity of LTA may be involved in the increase of cyclic AMP, leading to inhibition of intracellular Ca(2+) mobilization and protein kinase C activity. Therefore, LTA-mediated alteration of platelet function may contribute to bleeding diathesis in septicemic and endotoxemic patients.

Adrenal insufficiency masquerading as sepsis in a patient with tetraparesis: a case report.

Several endocrine changes have been reported in patients with tetraplegia after spinal cord injury (SCI). These changes should be considered when prescribing medications that influence the endocrine pathways. Megestrol acetate has gained acceptance as a way to promote weight gain in cachectic patients without significant adverse effects. We present a case of a 51-year-old man with C5-C6 tetraparesis who was only 67% of his ideal body weight and was placed on megestrol acetate 5 months before admission for a urologic procedure. Postoperatively, the patient had severe hypotension and tachycardia that was interpreted as a septic or cardiac event. Further workup revealed subnormal levels of 8AM cortisol. An adrenocorticotrophic hormone stimulation test demonstrated results consistent with adrenal suppression. Hydrocortisone supplementation was started, and 6 months later cortisol levels were within normal limits. Cachexia, hypotension, and mild tachycardia are not uncommon in patients with SCI. When severe hypotension and tachycardia are seen in patients with tetraplegia, the diagnosis of adrenal insufficiency should be considered.