A phase I dose escalation and expansion trial of the next-generation oral SERD camizestrant in women with ER-positive, HER2-negative advanced breast cancer: SERENA-1 monotherapy results.

BACKGROUND: SERENA-1 (NCT03616587) is a phase I, multi-part, open-label study of camizestrant in pre- and post-menopausal women with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer. Parts A and B aim to determine the safety and tolerability of camizestrant monotherapy and define doses for clinical evaluation. PATIENTS AND METHODS: Women aged ≥18 years with metastatic or recurrent ER+, HER2- breast cancer, refractory (or intolerant) to therapy, were assigned 25 mg up to 450 mg once daily (QD; escalation) or 75, 150, or 300 mg QD (expansion). Safety and tolerability, antitumor efficacy, pharmacokinetics, and impact on mutations in the estrogen receptor gene (ESR1m) circulating tumor (ct)DNA levels were assessed. RESULTS: By 9 March 2021, 108 patients received camizestrant monotherapy at 25-450 mg doses. Of these, 93 (86.1%) experienced treatment-related adverse events (TRAEs), 82.4% of which were grade 1 or 2. The most common TRAEs were visual effects (56%), (sinus) bradycardia (44%), fatigue (26%), and nausea (15%). There were no TRAEs grade 3 or higher, or treatment-related serious adverse events at doses ≤150 mg. Median tmax was achieved ∼2-4 h post-dose at all doses investigated, with an estimated half-life of 20-23 h. Efficacy was observed at all doses investigated, including in patients with prior cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) and/or fulvestrant treatment, with and without baseline ESR1 mutations, and with visceral disease, including liver metastases. CONCLUSIONS: Camizestrant is a next-generation oral selective ER antagonist and degrader (SERD) and pure ER antagonist with a tolerable safety profile. The pharmacokinetics profile supports once-daily dosing, with evidence of pharmacodynamic and clinical efficacy in heavily pre-treated patients, regardless of ESR1m. This study established 75-, 150-, and 300-mg QD doses for phase II testing (SERENA-2, NCT04214288 and SERENA-3, NCT04588298).

Disseminated Saksenaea infection in an immunocompromised host associated with a good clinical outcome: a case report and review of the literature.

BACKGROUND: Saksenaea species (spp.) are uncommon causes of mucormycosis but are emerging pathogens mostly associated with trauma and soil contamination often in immunocompetent hosts. Due to lack of sporulation in the laboratory, diagnosis and susceptibility testing is difficult so optimal treatment regimens are unknown. CASE PRESENTATION: A 67 year-old man from the Northern Territory in Australia, with a history of eosinophilic granulomatosis with polyangiitis, developed disseminated Saksenaea infection after initially presenting with symptoms consistent with bacterial pyelonephritis. Despite a delay in diagnosis; with aggressive surgical management and dual therapy with amphotericin B and posaconazole, he survived. CONCLUSIONS: We describe an unusual case of disseminated infection with a favourable outcome to date.

Advances in research on the impacts of anti-submarine sonar on beaked whales.

Mass stranding events (MSEs) of beaked whales (BWs) were extremely rare prior to the 1960s but increased markedly after the development of naval mid-frequency active sonar (MFAS). The temporal and spatial associations between atypical BW MSEs and naval exercises were first observed in the Canary Islands, Spain, in the mid-1980s. Further research on BWs stranded in association with naval exercises demonstrated pathological findings consistent with decompression sickness (DCS). A 2004 ban on MFASs around the Canary Islands successfully prevented additional BW MSEs in the region, but atypical MSEs have continued in other places of the world, especially in the Mediterranean Sea, with examined individuals showing DCS. A workshop held in Fuerteventura, Canary Islands, in September 2017 reviewed current knowledge on BW atypical MSEs associated with MFAS. Our review suggests that the effects of MFAS on BWs vary among individuals or populations, and predisposing factors may contribute to individual outcomes. Spatial management specific to BW habitat, such as the MFAS ban in the Canary Islands, has proven to be an effective mitigation tool and mitigation measures should be established in other areas taking into consideration known population-level information.

Mechanical Ventilation and Extracorporeal Membrane Oxygenation as a Bridging Strategy to Lung Transplantation: Significant Gains in Survival.

Mechanical ventilation (MV) and extracorporeal membrane oxygenation (ECMO) are increasingly used to bridge patients to lung transplantation. We investigated the impact of using MV, with or without ECMO, before lung transplantation on survival after transplantation by performing a retrospective analysis of 826 patients who underwent transplantation at our high-volume center. Recipient characteristics and posttransplant outcomes were analyzed. Most lung transplant recipients (729 patients) did not require bridging; 194 of these patients were propensity matched with patients who were bridged using MV alone (48 patients) or MV and ECMO (49 patients). There was no difference in overall survival between the MV and MV+ECMO groups (p = 0.07). The MV+ECMO group had significantly higher survival conditioned on surviving to 1 year (median 1,811 days ([MV] vs. not reached ([MV+ECMO], p = 0.01). Recipients in the MV+ECMO group, however, were more likely to require ECMO after lung transplantation (16.7% MV vs. 57.1% MV+ECMO, p < 0.001). There were no differences in duration of postoperative MV, hospital stay, graft survival, or the incidence of acute rejection, renal failure, bleeding requiring reoperation, or airway complications. In this contemporary series, the combination of MV and ECMO was a viable bridging strategy to lung transplantation that led to acceptable patient outcomes.

The incidence of bent dorsal fins in free-ranging cetaceans.

Laterally bent dorsal fins are rarely observed in free-ranging populations of cetaceans, contrary to captivity, where most killer whale Orcinus orca adult males have laterally collapsed fins. This topic has been poorly explored, and data/information on its occurrence and possible causes are limited. The present study: (i) undertakes a review of the available information on bent dorsal fins in free-ranging cetaceans, and updates it with new records, (ii) reports on the proportion of bent fins in different study populations, and (iii) discusses possible causes. An empirical approach based on bibliographic research and compilation of 52 new records collected worldwide resulted in a total of 17 species of cetaceans displaying bent dorsal fins. The species with the highest number of records (64%) and from most locations was O. orca. On average, individuals with bent dorsal fins represent < 1% of their populations, with the exception of false killer whales Pseudorca crassidens and O. orca. While line injuries associated with fisheries interactions may be the main cause for P. crassidens, and the vulnerability to health issues caused by the evolutionary enlargement of the fin may be the cause for O. orca adult males, factors contributing to this abnormality for other species are still unclear. The occurrence of bent dorsals could be influenced by a set of variables rather than by a single factor but, irrespective of the cause, it is suggested that it does not directly affect the animals' survivorship. While still rare in nature, this incident is more common (at least 101 known cases) and widespread (geographically and in species diversity) than hypothesized, and is not confined only to animals in captive environments. Investigation into the occurrence of bent fins may be an interesting avenue of research.

Changes in the clinical and epidemiological features of group A streptococcal bacteraemia in Australia's Northern Territory.

OBJECTIVE: Invasive group A streptococcus (iGAS) disease is an important cause of mortality globally. The incidence of iGAS in Australia's tropical Northern Territory (NT) has been previously reported as 32.2/100 000 in Indigenous people for the period 1991-1996. We aimed to measure the incidence and severity of iGAS disease in the NT since this time. METHODS: We collected demographic data for all GAS blood culture isolates over a 12-year period (1998-2009) from the three hospital laboratories serving the tropical NT. We then collected detailed clinical information from hospital records and databases for the subset of these patients who were admitted to Royal Darwin Hospital during 2005-2009. RESULTS: There were 295 confirmed cases of GAS bacteraemia over the study period, with a mean (SD) age of 42.1 (22.0) years, and 163 (55.0%) were male. The annual age-adjusted incidence was 15.2 (95% CI 13.4-16.9)/100 000 overall and 59.4 (95% CI 51.2-67.6) in Indigenous Australians. For 2005-2009, there were 123 cases with the most common focus of infection being skin/soft tissue [44 (35.6%)]; 29 patients (23.6%) required intensive care unit admission and 20 (16.3%) had streptococcal toxic shock syndrome. Antecedent sore throat or use of non-steroidal anti-inflammatory drugs was rare, but current or recent scabies, pyoderma and trauma were common. CONCLUSION: The incidence and severity of iGAS are high and increasing in tropical northern Australia, and urgent attention is needed to improve surveillance and the social determinants of health in this population. This study adds to emerging data suggesting increasing importance of iGAS in low- and middle-income settings globally.

A pilot investigation of feeding problems in children with esophageal atresia.

While many long-term complications of esophageal atresia (EA) have been well investigated, little is known about feeding difficulties in children after surgical correction of EA and its impact on caregivers. This study investigates the feeding behaviors of children with EA through a validated feeding questionnaire. The Montreal Children's Hospital Feeding Scale (MCH-FS) was filled out by the primary caregiver during patient follow-up visits in the multidisciplinary EA clinic. Demographic information, EA subtype, associated anomalies and outcomes were recorded. Results were compared between groups and to a normative sample. Thirty caregivers have completed the MCH-FS; 26 patients had type C atresia (86.7%). In comparison to controls, 17.5% of EA cases are one standard deviation above the mean feeding difficulty score, while 6.7% (n = 2) cases are greater than two standard deviations above normative values. Typical EA patients (type C who were not born <30 weeks) had mean MCH-FS scores in the subclinical range, whereas one extremely premature child and the patients with non-type C EA (n = 4) all had scores in the severe range. Feeding difficulties of patients with typical EA appear mild. Likely explanations include the use of early protocolized care and intensive multidisciplinary care in follow up. Nonetheless, patients with complicated EA (non-type C) and their caregivers tend to experience significant feeding difficulties. Early targeted care may be required for this patient subset, and additional cases will be investigated to confirm these preliminary findings and explore further risk factors of feeding problem in this cohort.

Evaluation of aortopexy in the management of severe tracheomalacia after esophageal atresia repair.

Severe tracheomalacia (TM) is a difficult problem in esophageal atresia (EA) patients. We reviewed our experience with aortopexy and other interventions for severe TM in this population. With review ethics board approval, a retrospective review of TM in postoperative EA patients was conducted (1989-2010). Demographics, perinatal, and surgical information regarding EA repair was collected. TM infants were analyzed for symptomatology, clinical severity, investigations, interventions, and outcomes. Data are presented as proportions or median(range). One hundred and thirty-two EA patients were reviewed. Most had type C atresia (87.3%), and 18 patients (13.6%) died. Twenty-five patients (18.9%) had TM of whom five (20%) died. Median symptom onset was 18 days (0-729) after EA repair, with stridor (64%) or retractions/distress (44%) being most frequent. Four and two patients had airway obstruction or cardiorespiratory arrest, respectively. Median time from symptom onset to investigations was 11 days; these were most commonly rigid bronchoscopy (56%) and fluoroscopy (36%). Ten patients (40%) had severe TM on bronchoscopy. Six underwent aortopexy, one fundoplication, and three were treated medically. Length of hospital stay (LOS) post-aortopexy was 13 days (5-60), and ventilation time was 2 days (0-9). LOS was 60.5 (1-69) days postdiagnosis in non-aortopexy patients. Readmission rates for respiratory issues were significantly less in the aortopexy (median 0 vs. 5; P = 0.048) group over 2-year follow up after discharge. Complications of aortopexy included transfusion (1) and temporary diaphragmatic paresis (1), and one mortality secondary to severe congenital cardiac anomalies. Our experience suggests that aortopexy is safe and effective for the treatment of severe TM. It is associated with reduced LOS compared with other treatment strategies and few complications or long-term sequelae.

Human T-cell lymphotropic virus type 1 exposures following blood-borne virus incidents in central Australia, 2002-2012.

We retrospectively audited hospital occupational exposure events over a 10-year period, in a human T-cell lymphotropic virus type 1 (HTLV-1)-endemic area of Central Australia, and report on 53 individuals exposed to HTLV-1 with no transmissions documented (95% confidence interval, 0%-1.5%). This has important implications for the management of exposures including the role of postexposure prophylaxis.

First Report of Geosmithia morbida in North Carolina: The Pathogen Involved in Thousand Cankers Disease of Black Walnut.

In the past decade, black walnut (Juglans nigra) trees throughout western North America have suffered from widespread branch dieback and canopy loss, causing substantial tree mortality (2,3). The fungus, Geosmithia morbida, vectored by the walnut twig beetle (WTB), Pityophthorus juglandis, has been associated with this devastating disease known as Thousand Cankers Disease (TCD) (2,3). In August of 2012, branch samples from TCD symptomatic black walnut trees (5 to 10 cm in diameter and 15 to 30 cm long) were collected on the North Carolina side of the Great Smoky Mountain National Park (GRSM) in Cataloochee Cove (35°37.023' N, 83°07.351' W) and near the Big Creek Campground (35°45.290' N, 83°06.473' W), in Haywood County. Five symptomatic trees near the Big Creek Campground and three from Cataloochee Cove displayed typical TCD signs including progressive crown thinning, branch flagging, and branch dieback; however, insect holes were not observed. Samples were double bagged in Ziploc plastic bags, sealed in a 19-liter plastic bucket, and transported to the University of Tennessee. Outer bark was removed from the samples and small, elliptical, necrotic cankers were observed. Wood chips (3 to 4 mm2) from cankers were excised and placed on 1/10 strength potato dextrose agar amended with 30 mg/liter streptomycin sulfate and 30 mg/liter chlortetracycline HCL and incubated on a 12-h dark/light cycle at 22°C for 5 to 7 days. Fungal isolates were tentatively identified as G. morbida by using culture morphology, and characteristics of conidiophores and conidia (2). The isolated fungus from the Cataloochee Cove location was grown in 1/10 strength potato dextrose broth at room temperature for 2 weeks. Isolates from Big Creek Campground were contaminated and were not analyzed further. Fungal colonies were tan to light yellow. Conidia were tan, subcylindrical, and catenulate. Conidiophores were multibranched, verticillate, and verrucose. To verify the morphological data, DNA was extracted from fungal mycelia using DNeasy Plant Mini Kit (Qiagen, Valencia, CA) according to the manufacturer's published protocol. Isolates from Cataloochee Cove were characterized using ITS1 and ITS4 universal primers (4). The putative G. morbida isolate (GenBank Accession No. KC461929) had ITS sequences that were 100% identical to the G. morbida type isolate CBS124663 (FN434082.1) (2). Additionally, fungal DNA from Cataloochee Cove was amplified using G. morbida-specific microsatellite loci (GS04, GS27, and GS36) (1). PCR products were analyzed with the QIAxcel Capillary Electrophoresis System (Qiagen) and were similar to those previously published (2). To date, all confirmed cases of TCD in the native range of black walnut have been in urban areas, along rural roadsides and/or fence rows. The report in North Carolina is the first finding of G. morbida, the causal agent of TCD, in a forest setting. References: (1) D. Hadziabdic et al. Conserv. Genet. Resources 4:287, 2012. (2) M. Kolarik et al. Mycologia 103:325, 2011. (3) N. Tisserat et al. Plant Health Progr. doi:10.1094/PHP-2011-0630-01-BR, 2011. (4) T. J. White et al. Page 315 in: PCR Protocols: A Guide to Methods and Applications. M. A. Innis et al., eds. Academic Press, San Diego, CA, 1990.

Refractory strictures post-esophageal atresia repair: what are the alternatives?

Esophageal strictures remain the most frequent complication after esophageal atresia (EA) repair despite refinements in operative techniques. With an incidence of anastomotic stricture between 8% and 49%, EA is the most frequent cause of benign esophageal stricture in children. The mainstay of treatment for esophageal stricture is dilatation with a 58-96% success rate. In order to relieve dysphagia, between 1 and 15 dilatations will be required in each EA patient with an esophageal stricture. However dilatations may lead to complications including perforation (0.1-0.4% of all esophageal benign strictures) and sociopsychological morbidity. Fifty percent of EA strictures will improve in 6 months. However, 30% will persist and require repeat dilatations. The present article explores the variety of non-surgical alternative treatments for anastomotic strictures after EA repair, focusing on triamcinolone acetonide, mitomycin C and esophageal stents. We propose an algorithm for a more standardized therapeutic approach, with the hope that an international panel of experts could meet and establish a consensus.

The role of surgery in patients with advanced gynaecological cancers participating in phase I clinical trials.

OBJECTIVE: While gynaecological cancer patients who participate in Phase I clinical trials are not routinely considered for elective surgery because of a short life expectancy, this should not be overlooked in carefully selected responding patients. METHODS/RESULTS: We describe two cases of patients with different gynaecological cancers, who received treatment within separate phase I trials, and who then proceeded to surgical resection of their cancers, resulting in complete remission. CONCLUSION: Surgery, when feasible, should be taken into consideration as a potential management option, even when patients are receiving treatment within a phase I trial.

Results of the phase IIa RADICAL trial of the FGFR inhibitor AZD4547 in endocrine resistant breast cancer.

We conducted a phase IIa, multi-centre, open label, single arm study (RADICAL; NCT01791985) of AZD4547 (a potent and selective inhibitor of Fibroblast Growth Factor Receptor (FGFR)-1, 2 and 3 receptor tyrosine kinases) administered with anastrozole or letrozole in estrogen receptor positive metastatic breast cancer patients who had become resistant to aromatase inhibitors. After a safety run-in study to assess safety and tolerability, we recruited 52 patients. The primary endpoint was change in tumour size at 12 weeks, and secondary endpoints were to assess response at 6 weeks, 20 weeks and every 8 weeks thereafter and tolerability of the combined treatment. Two partial responses (PR) and 19 stable disease (SD) patients were observed at the 12-week time point. At 28 weeks, according to centrally reviewed Response Evaluation Criteria in Solid Tumours (RECIST) criteria, five PR and 8 SD patients were observed in 50 assessable cases. Overall, objective response rate (5 PR) was of 10%, meeting the pre-specified endpoint. Fourteen patients discontinued due to adverse events. Eleven patients had retinal pigment epithelial detachments which was asymptomatic and reversible in all but one patient. Exploratory ribonucleic acid sequencing (RNA-Seq) analysis was done on patients' samples: 6 differentially-expressed-genes could distinguish those who benefited from the addition of AZD4547.

Toxicity associated with capecitabine plus oxaliplatin in colorectal cancer before and after an institutional policy of capecitabine dose reduction.

BACKGROUND: Capecitabine plus oxaliplatin (CAPOX) is an established treatment option in colorectal cancer, but can be associated with severe toxicities. METHODS: Following reporting of severe diarrhoea and dehydration with capecitabine 2000 mg m(-2) per day plus oxaliplatin every 3 weeks (CAPOX 2000) in 2006, we instituted a policy change to reduce capecitabine dose to 1700 mg m(-2) per day (CAPOX 1700). We undertook a retrospective analysis comparing toxicities encountered before and after this dose change. RESULTS: Of the 400 patients treated, no significant differences were seen between the CAPOX 2000 and CAPOX 1700 in grades 3 and 4 diarrhoea (21% vs 19%; P=0.80), stomatitis (0% vs 1%; P=0.50) or grades 2-4 hand foot syndrome (16% vs 11%; P=0.18). Grades 3 and 4 neutropenia (9.5% vs 3.5%; P=0.03) and all grades hyperbilirubinaemia (60% vs 40%; P<0.0001) were significantly reduced with CAPOX 1700. Rates of hospitalisation due to toxicities were not different between two groups (13% vs 11%; P=0.53). CONCLUSIONS: No clinically or statistically significant differences in gastrointestinal toxicities or hospitalisation rate were seen after reducing our routine capecitabine dose from CAPOX 2000 to CAPOX 1700.

Geospatial epidemiology of Staphylococcus aureus in a tropical setting: an enabling digital surveillance platform.

Delivery of information to clinicians on evolving antimicrobial susceptibility needs to be accurate for the local needs, up-to-date and readily available at point of care. In northern Australia, bacterial infection rates are high but resistance to first- and second-line antibiotics is poorly described and currently-available datasets exclude primary healthcare data. We aimed to develop an online geospatial and interactive platform for aggregating, analysing and disseminating data on regional bacterial pathogen susceptibility. We report the epidemiology of Staphylococcus aureus as an example of the power of digital platforms to tackle the growing spread of antimicrobial resistance in a high-burden, geographically-sparse region and beyond. We developed an online geospatial platform called HOTspots that visualises antimicrobial susceptibility patterns and temporal trends. Data on clinically-important bacteria and their antibiotic susceptibility profiles were sought from retrospectively identified clinical specimens submitted to three participating pathology providers (96 unique tertiary and primary healthcare centres, n = 1,006,238 tests) between January 2008 and December 2017. Here we present data on S. aureus only. Data were available on specimen type, date and location of collection. Regions from the Australian Bureau of Statistics were used to provide spatial localisation. The online platform provides an engaging visual representation of spatial heterogeneity, demonstrating striking geographical variation in S. aureus susceptibility across northern Australia. Methicillin resistance rates vary from 46% in the west to 26% in the east. Plots generated by the platform show temporal trends in proportions of S. aureus resistant to methicillin and other antimicrobials across the three jurisdictions of northern Australia. A quarter of all, and up to 35% of methicillin-resistant S. aureus (MRSA) blood isolates in parts of the northern Australia were resistant to inducible-clindamycin. Clindamycin resistance rates in MRSA are worryingly high in regions of northern Australia and are a local impediment to empirical use of this agent for community MRSA. Visualising routinely collected laboratory data with digital platforms, allows clinicians, public health physicians and guideline developers to monitor and respond to antimicrobial resistance in a timely manner. Deployment of this platform into clinical practice supports national and global efforts to innovate traditional disease surveillance systems with the use of digital technology and to provide practical solutions to reducing the threat of antimicrobial resistance.

Burkholderia pseudomallei multi-centre study to establish EUCAST MIC and zone diameter distributions and epidemiological cut-off values.

OBJECTIVES: Melioidosis, caused by Burkholderia pseudomallei, requires intensive antimicrobial treatment. However, standardized antimicrobial susceptibility testing (AST) methodology based on modern principles for determining breakpoints and ascertaining performance of methods are lacking for B. pseudomallei. This study aimed to establish MIC and zone diameter distributions on which to set epidemiological cut-off (ECOFF) values for B. pseudomallei using standard EUCAST methodology for non-fastidious organisms. METHODS: Non-consecutive, non-duplicate clinical B. pseudomallei isolates (9-70 per centre) were tested at eight study centres against eight antimicrobials by broth microdilution (BMD) and the EUCAST disc diffusion method. Isolates without and with suspected resistance mechanisms were deliberately selected. The EUCAST Development Laboratory ensured the quality of study materials, and provided guidance on performance of the tests and interpretation of results. Aggregated results were analysed according to EUCAST recommendations to determine ECOFFs. RESULTS: MIC and zone diameter distributions were generated using BMD and disc diffusion results obtained for 361 B. pseudomallei isolates. MIC and zone diameter ECOFFs (mg/L; mm) were determined for amoxicillin-clavulanic acid (8; 22), ceftazidime (8; 22), imipenem (2; 29), meropenem (2; 26), doxycycline (2; none), tetracycline (8; 23), chloramphenicol (8; 22) and trimethoprim-sulfamethoxazole (4; 28). CONCLUSIONS: We have validated the use of standard BMD and disc diffusion methodology for AST of B. pseudomallei. The MIC and zone diameter distributions generated in this study allowed us to establish MIC and zone diameter ECOFFs for the antimicrobials studied. These ECOFFs served as background data for EUCAST to set clinical MIC and zone diameter breakpoints for B. pseudomallei.

Diplodia pinea, the Cause of Diplodia Blight of Pines, Confirmed in Alabama, Louisiana, and Mississippi.

Loblolly pine (Pinus taeda) is the major commercial pine species cultivated in the Gulf Coast Region of the southern United States. Symptoms of Diplodia shoot blight (including yellow and brown needles and resin-soaked, dead, small twigs), pycnidia with conidia typical of Diplodia pinea on blighted shoots, and damaged, immature seed cones were observed during the summer of 2007 in loblolly pine seed orchards near Ward, AL, Winn Parish, LA, and Moselle, MS. Similar conidia also were obtained from pycnidia on opened seed cones of longleaf pine (P. palustris) collected on the campus of Mississipi State University, Starkville. Pure cultures obtained from specimens collected at each location were confirmed as D. pinea using species-specific PCR primers (3) that allow differentiation of D. pinea from the similar pine shoot blight pathogen D. scrobiculata. Isolates from loblolly pines in Alabama (07-58), Louisiana (07-38), and Mississippi (06-45) were used individually to inoculate potted 6- to 7-month-old loblolly pine seedlings grown from seed in a greenhouse in each of two independent trials. Elongating terminal shoots of seedlings to be inoculated were wounded by removing a needle fascicle ∼2 cm below the shoot apex. A 4-mm-diameter plug cut from an actively growing colony on water agar (WA) was placed on the wound, mycelium side toward the stem. Noncolonized WA plugs were placed in the same manner on similarly wounded control seedlings and nonwounded control seedlings also were used. Parafilm was wrapped around the shoots to hold the agar plugs in place and was removed after 1 week. Each of the five isolate-treatment combinations was applied to seven (trial 1) or eight (trial 2) seedlings (35 and 40 seedlings per trial, respectively). One week after inoculation, small, brown lesions were visible at the point of inoculation on stems of most of the inoculated seedlings. At 25 days after inoculation, all inoculated seedlings exhibited needle browning and stem cankers ranging from 0.6 cm to 9.0 cm long (mean 2.5 cm) that girdled and killed distal portions of the shoots of ∼25% of the inoculated seedlings in each trial. Wounded control and nonwounded control seedlings did not develop symptoms. Stem segments including the point of inoculation (or comparable segments of wounded and nonwounded control seedlings) were excised, surface disinfested, and incubated on tannic acid agar with sterile red pine needles. D. pinea was cultured from all inoculated seedlings and also from one wounded control seedling. Although occurrence of D. pinea on Cedrus spp. is included in an index (1), to our knowledge this is the first confirmed report of D. pinea on pines in Alabama, Louisiana, and Mississippi. The degree of risk presented by D. pinea to loblolly pine, longleaf pine, and other pine species native to the southern United States when grown in their native ranges is unknown. Reports of Diplodia shoot blight of southern U.S. pines when grown as exotics in the southern hemisphere (4) and the potential for epidemics to develop suddenly under severe weather conditions (2,4) justify additional studies to evaluate the potential for damage to these hosts in their native ranges. References: (1) Anonymous. Page 333 in: Index of Plant Diseases in the United States. Agric. Handb. 165, U.S. Dep. Agric. Washington, DC, 1960. (2) T. H. Nicholls and M. E. Ostry. Plant Dis. 74:54, 1990. (3) D. R. Smith and G. R. Stanosz. Plant Dis. 90:307, 2006. (4) W. J. Swart and M. J. Wingfield. Plant Dis. 75:761, 1991.

First Report of Ophiosphaerella herpotricha Causing Spring Dead Spot of Bermudagrass in Mississippi.

Spring dead spot (SDS) is the most destructive disease of bermudagrass (Cynodon dactylon (L.) Pers.). Symptoms of SDS appear in the spring when bermudagrass transitions out of winter dormancy. These symptoms include depressed, straw-colored patches that range from several centimeters to a meter in diameter. Infected roots and rhizomes are black, brittle, and necrotic. The disease is caused by three species of fungi: Ophiosphaerella herpotricha (Fr:Fr) J. Walker; O. korrae (J. Walker & A.M. Smith) Shoemaker & C.E. Babcock; or O. narmari (J. Walker & A.M. Smith) Wetzel, Hubert & Tisserat. However, O. korrae is the most prevalent causal organism of SDS in the southeastern United States and was the only species reported in Mississippi (1). In April of 2006, root samples were collected from a bermudagrass putting green in Booneville, MS with a high level of SDS incidence and severity. Symptomatic roots were collected and surface disinfested in 0.6% NaOCl and plated on one-quarter-strength potato dextrose agar (PDA) amended with streptomycin sulfate and chloramphenicol. Hyphae growing from the roots were transferred to full-strength PDA after 5 to 7 days. Mycelium from five pure-culture colonies plus an O. herpotricha control was harvested after 4 weeks of growth and the genomic DNA was extracted. The genomic DNA of the Booneville isolates and the O. herpotricha control were amplified by PCR using species-specific primers OHITS1 and OHITS2 for O. herpotricha (2). Amplification of a 454-bp fragment of DNA confirmed one of the five unknown isolates as O. herpotricha. The other four isolates were not identified. 'Sahara' bermudagrass (4 weeks old in 3.8 × 20 cm Cone-tainers containing a sand and soil mixture) was inoculated with the Booneville-O. herpotricha isolate and the O. herpotricha control. One gram of oat seed infested with O. herpotricha isolates was inserted 2 cm below the crowns in the root zone of bermudagrass plugs. The inoculated bermudagrass plants were incubated for 4 weeks in the greenhouse. A control consisting of noninfested sterile oats was included. Following incubation, black, necrotic roots were observed on the plants inoculated with both O. herpotricha isolates. No symptoms were observed on roots of noninfested plants. Symptomatic roots were disinfested and plated on one-quarter-strength PDA. Koch's postulates were completed after O. herpotricha was reisolated from roots of plants inoculated with both O. herpotricha isolates and confirmed by PCR as mentioned above. The identification of O. herpotricha as a causal organism of SDS in Mississippi clarifies the involvement of multiple causal agents in this state and broadens the geographic distribution of this root-rot species. References: (1) F. B. Iriarte et al. Plant Dis. 88:1341, 2004. (2) N. A. Tisserat et al. Phytopathology 84:478, 1994.

An extended phase Ib study of epertinib, an orally active reversible dual EGFR/HER2 tyrosine kinase inhibitor, in patients with solid tumours.

BACKGROUND: Dose-escalation of epertinib (S-222611), a new potent oral EGFR/HER2 inhibitor, has established a recommended daily dose of 800 mg in patients with solid tumours. In this study, we have recruited a larger number of patients to assess further the safety, tolerability, pharmacokinetics (PKs) and antitumour activity. PATIENTS AND METHODS: Patients with solid tumours expressing EGFR or HER2 received a single dose of epertinib at 800 mg on Day 1 to assess PK over 7 days, followed by continuous once-daily dosing from Day 8. RESULTS: We treated 76 patients with breast (n = 27), upper gastrointestinal (GI; n = 30), head and neck (n = 12) or renal cancers (n = 7). Epertinib was well-tolerated with mostly grade I and II adverse events (AEs). The most frequent AE was diarrhoea, which was generally manageable with loperamide. The objective response rate (ORR) in patients with heavily pretreated breast and upper GI cancers was 16.0% (4 PRs) and 8.3% (1CR, 1PR), respectively. All six responding patients had HER2-positive tumours; the ORR for HER2-positive breast and upper GI cancer populations was 19.0% and 20.0%. Partial response in the brain disease of one breast cancer patient lasted 7.5 months. CONCLUSION: Once-daily dosing of epertinib at 800 mg was well-tolerated and demonstrated promising antitumour activity in patients with heavily pretreated HER2-positive breast and upper GI cancer, including those with brain metastases. EUDRACT NUMBER: 2009-017817-31.