Emergent effects of global change on consumption depend on consumers and their resources in marine systems.

A better understanding of how environmental change will affect species interactions would significantly aid efforts to scale up predictions of near-future responses to global change from individuals to ecosystems. To address this need, we used meta-analysis to quantify the individual and combined effects of ocean acidification (OA) and warming on consumption rates of predators and herbivores in marine ecosystems. Although the primary studies demonstrated that these environmental variables can have direct effects on consumers, our analyses highlight high variability in consumption rates in response to OA and warming. This variability likely reflects differences in local adaptation among species, as well as important methodological differences. For example, our results suggest that exposure of consumers to OA reduces consumption rates on average, yet consumption rates actually increase when both consumers and their resource(s) are concurrently exposed to the same conditions. We hypothesize that this disparity is due to increased vulnerability of prey or resource(s) in conditions of OA that offset declines in consumption. This hypothesis is supported by an analysis demonstrating clear declines in prey survival in studies that exposed only prey to future OA conditions. Our results illustrate how simultaneous OA and warming produce complex outcomes when species interact. Researchers should further explore other potential sources of variation in response, as well as the prey-driven component of any changes in consumption and the potential for interactive effects of OA and warming.

Multi-Factor Coral Disease Risk: A new product for early warning and management.

Ecological forecasts are becoming increasingly valuable tools for conservation and management. However, there are few examples of near-real-time forecasting systems that account for the wide range of ecological complexities. We developed a new coral disease ecological forecasting system that explores a suite of ecological relationships and their uncertainty and investigates how forecast skill changes with shorter lead times. The Multi-Factor Coral Disease Risk product introduced here uses a combination of ecological and marine environmental conditions to predict the risk of white syndromes and growth anomalies across reefs in the central and western Pacific and along the east coast of Australia and is available through the US National Oceanic and Atmospheric Administration Coral Reef Watch program. This product produces weekly forecasts for a moving window of 6 months at a resolution of ~5 km based on quantile regression forests. The forecasts show superior skill at predicting disease risk on withheld survey data from 2012 to 2020 compared with predecessor forecast systems, with the biggest improvements shown for predicting disease risk at mid- to high-disease levels. Most of the prediction uncertainty arises from model uncertainty, so prediction accuracy and precision do not improve substantially with shorter lead times. This result arises because many predictor variables cannot be accurately forecasted, which is a common challenge across ecosystems. Weekly forecasts and scenarios can be explored through an online decision support tool and data explorer, co-developed with end-user groups to improve use and understanding of ecological forecasts. The models provide near-real-time disease risk assessments and allow users to refine predictions and assess intervention scenarios. This work advances the field of ecological forecasting with real-world complexities and, in doing so, better supports near-term decision making for coral reef ecosystem managers and stakeholders. Secondarily, we identify clear needs and provide recommendations to further enhance our ability to forecast coral disease risk.

Invasive predator tips the balance of symmetrical competition between native coral-reef fishes.

The importance of competition and predation in structuring ecological communities is typically examined separately such that interactions between these processes are seldom understood. By causing large reductions in native prey, invasive predators may modify native species interactions. I conducted a manipulative field experiment in The Bahamas to investigate the possibility that the invasive Pacific red lionfish (Pterois volitans) alters competition between planktivorous fairy and blackcap basslets (Gramma loreto and Gramma melacara, respectively). Competition between these coral-reef fishes is known to have symmetrical effects on the juveniles of both species, whereby the feeding positions under reef ledges and growth rates of these individuals are hindered. Following baseline censuses of local populations of competing basslets, I simultaneously manipulated the abundance of lionfish on entire reefs, and the abundance of basslets in local populations under isolated ledges within each reef, resulting in three treatments: unmanipulated control populations of both basslets, reduced abundance of fairy basslet, and reduced abundance of blackcap basslet. For eight weeks, I measured the change in biomass and feeding position of 2-5 cm size classes of each basslet species and calculated the growth rates of ~2 cm individuals using a standard mark-and-recapture method. Experimental populations were filmed at dusk using automated video cameras to quantify the behavior of lionfish overlapping with basslets. Video playback revealed lionfish hunted across all ledge positions, regardless of which basslet species were present, yet lionfish differentially reduced the biomass of only juvenile (2 cm) fairy basslet. Predation reduced the effects of interspecific competition on juvenile blackcap basslet as evidenced by corresponding shifts in feeding position toward coveted front edges of ledges and increases in growth rates that were comparable to the response of these fish in populations where competition was experimentally reduced. Thus, an invasive marine predator altered the outcome of interspecific competition via differential predation, which tipped the balance of competition between native prey species from symmetrical to asymmetrical effects on juveniles. This study reveals a newly demonstrated context in which predation can indirectly facilitate prey, further broadening our understanding of the interactive effects of predation and competition in the context of invasive species.

Circulating cytokines and monocyte subpopulations as biomarkers of outcome and biological activity in sunitinib-treated patients with advanced neuroendocrine tumours.

BACKGROUND: Sunitinib is approved worldwide for treatment of advanced pancreatic neuroendocrine tumours (pNET), but no validated markers exist to predict response. This analysis explored biomarkers associated with sunitinib activity and clinical benefit in patients with pNET and carcinoid tumours in a phase II study. METHODS: Plasma was assessed for vascular endothelial growth factor (VEGF)-A, soluble VEGF receptor (sVEGFR)-2, sVEGFR-3, interleukin (IL)-8 (n=105), and stromal cell-derived factor (SDF)-1α (n=28). Pre-treatment levels were compared between tumour types and correlated with response, progression-free (PFS), and overall survival (OS). Changes in circulating myelomonocytic and endothelial cells were also analysed. RESULTS: Stromal cell-derived factor-1α and sVEGFR-2 levels were higher in pNET than in carcinoid (P=0.003 and 0.041, respectively). High (above-median) baseline SDF-1α was associated with worse PFS, OS, and response in pNET, and high sVEGFR-2 with longer OS (P⩽0.05). For carcinoid, high IL-8, sVEGFR-3, and SDF-1α were associated with shorter PFS and OS, and high IL-8 and SDF-1α with worse response (P⩽0.05). Among circulating cell types, monocytes showed the largest on-treatment decrease, particularly CD14+ monocytes co-expressing VEGFR-1 or CXCR4. CONCLUSIONS: Interleukin-8, sVEGFR-3, and SDF-1α were identified as predictors of sunitinib clinical outcome. Putative pro-tumorigenic CXCR4+ and VEGFR-1+ monocytes represent novel candidate markers and biologically relevant targets explaining the activity of sunitinib.

Sunitinib in combination with gemcitabine for advanced solid tumours: a phase I dose-finding study.

BACKGROUND: This phase I, dose-finding study determined the maximum tolerated dose (MTD), safety, and pharmacokinetics of sunitinib plus gemcitabine in patients with advanced solid tumours. METHODS: Two schedules with sunitinib (25-50 mg per day) and IV gemcitabine (750-1250 mg m(-2)) in escalating doses were studied. First, patients received sunitinib on a 4-weeks-on-2-weeks-off schedule (Schedule 4/2) plus gemcitabine on days 1, 8, 22, and 29. Second, patients received sunitinib on a 2-weeks-on-1-week-off schedule (Schedule 2/1) plus gemcitabine on days 1 and 8. The primary endpoint was determination of MTD and tolerability. RESULTS: Forty-four patients received the combination (Schedule 4/2, n=8; Schedule 2/1, n=36). With no dose-limiting toxicities (DLTs) at maximum dose levels on Schedule 2/1, MTD was not reached. Grade 4 treatment-related AEs and laboratory abnormalities included cerebrovascular accident, hypertension, and pulmonary embolism (n=1 each), and neutropenia (n=3), thrombocytopenia and increased uric acid (both n=2), and lymphopenia (n=1). There were no clinically significant drug-drug interactions. Antitumor activity occurred across dose levels and tumour types. In poor-risk and/or high-grade renal cell carcinoma patients (n=12), 5 had partial responses and 7 stable disease ≥ 6 weeks. CONCLUSION: Sunitinib plus gemcitabine on Schedule 2/1 with growth factor support was well tolerated and safely administered at maximum doses of each drug, without significant drug-drug interactions.

A randomized, double-blind, phase II study of erlotinib with or without sunitinib for the second-line treatment of metastatic non-small-cell lung cancer (NSCLC).

BACKGROUND: Combined inhibition of vascular, platelet-derived, and epidermal growth factor receptor (EGFR) pathways may overcome refractoriness to single agents in platinum-pretreated non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: This randomized, double-blind, multicenter, phase II trial evaluated sunitinib 37.5 mg/day plus erlotinib 150 mg/day versus placebo plus erlotinib continuously in 4-week cycles. Eligible patients had histologically confirmed stage IIIB or IV NSCLC previously treated with one or two chemotherapy regimens, including one platinum-based regimen. The primary end point was progression-free survival (PFS) by an independent central review. RESULTS: One hundred and thirty-two patients were randomly assigned, and the median duration of follow-up was 17.7 months. The median PFS was 2.8 versus 2.0 months for the combination versus erlotinib alone (HR 0.898, P = 0.321). The median overall survival (OS) was 8.2 versus 7.6 months (HR 1.066, P = 0.617). Objective response rates (ORRs) were 4.6% and 3.0%, respectively. Sunitinib plus erlotinib was fairly well tolerated although most treatment-related adverse events (AEs) were more frequent than with erlotinib alone: diarrhea (55% versus 33%), rash (41% versus 30%), fatigue (31% versus 25%), decreased appetite (30% versus 13%), nausea (28% versus 14%), and thrombocytopenia (13% versus 0%). CONCLUSIONS: The addition of sunitinib to erlotinib did not significantly improve PFS in patients with advanced, platinum-pretreated NSCLC.

Local human impacts disrupt depth-dependent zonation of tropical reef fish communities.

The influence of depth and associated gradients in light, nutrients and plankton on the ecological organization of tropical reef communities was first described over six decades ago but remains untested across broad geographies. During this time humans have become the dominant driver of planetary change, requiring that we revisit historic ecological paradigms to ensure they capture the dynamics of contemporary ecological systems. Analysing >5,500 in-water reef fish surveys between 0 and 30 m depth on reef slopes of 35 islands across the Pacific, we assess whether a depth gradient consistently predicts variation in reef fish biomass. We reveal predictable ecological organization at unpopulated locations, with increased biomass of planktivores and piscivores and decreased primary consumer biomass with increasing depth. Bathymetric steepness also had a striking influence on biomass patterns, primarily for planktivores, emphasizing potential links between local hydrodynamics and the upslope propagation of pelagic subsidies to the shallows. However, signals of resource-driven change in fish biomass with depth were altered or lost for populated islands, probably due to depleted fish biomass baselines. While principles of depth zonation broadly held, our findings expose limitations of the paradigm for predicting ecological dynamics where human impacts confound connections between ecological communities and their surrounding environment.

Movement and retention of derelict fishing nets in Northwestern Hawaiian Island reefs.

Derelict fishing nets pose hazards to marine systems as they travel through the ocean or become ensnared on coral reefs. Understanding of the movement of nets within shallow atolls can help to optimize operations to protect these shallow reefs. In 2018, six derelict fishing nets at Manawai (Pearl and Hermes Reef) in the Northwestern Hawaiian Islands were tagged with satellite-transmitting buoys and tracked for three years. This study reveals that nets that enter the atoll from the northeast travel southwest towards the center of the atoll, and nets in the center can remain ensnared on the same reef for at least three years. This study shows that satellite buoys are a successful approach to tracking derelict net movement, and can inform future debris removal missions.

Coral taxonomy and local stressors drive bleaching prevalence across the Hawaiian Archipelago in 2019.

The Hawaiian Archipelago experienced a moderate bleaching event in 2019-the third major bleaching event over a 6-year period to impact the islands. In response, the Hawai'i Coral Bleaching Collaborative (HCBC) conducted 2,177 coral bleaching surveys across the Hawaiian Archipelago. The HCBC was established to coordinate bleaching monitoring efforts across the state between academic institutions, non-governmental organizations, and governmental agencies to facilitate data sharing and provide management recommendations. In 2019, the goals of this unique partnership were to: 1) assess the spatial and temporal patterns of thermal stress; 2) examine taxa-level patterns in bleaching susceptibility; 3) quantify spatial variation in bleaching extent; 4) compare 2019 patterns to those of prior bleaching events; 5) identify predictors of bleaching in 2019; and 6) explore site-specific management strategies to mitigate future bleaching events. Both acute thermal stress and bleaching in 2019 were less severe overall compared to the last major marine heatwave events in 2014 and 2015. Bleaching observed was highly site- and taxon-specific, driven by the susceptibility of remaining coral assemblages whose structure was likely shaped by previous bleaching and subsequent mortality. A suite of environmental and anthropogenic predictors was significantly correlated with observed bleaching in 2019. Acute environmental stressors, such as temperature and surface light, were equally important as previous conditions (e.g. historical thermal stress and historical bleaching) in accounting for variation in bleaching during the 2019 event. We found little evidence for acclimation by reefs to thermal stress in the main Hawaiian Islands. Moreover, our findings illustrate how detrimental effects of local anthropogenic stressors, such as tourism and urban run-off, may be exacerbated under high thermal stress. In light of the forecasted increase in severity and frequency of bleaching events, future mitigation of both local and global stressors is a high priority for the future of corals in Hawai'i.

Phase II study of continuous daily sunitinib dosing in patients with previously treated advanced non-small cell lung cancer.

BACKGROUND: Sunitinib malate (SUTENT) has promising single-agent activity given on Schedule 4/2 (4 weeks on treatment followed by 2 weeks off treatment) in advanced non-small cell lung cancer (NSCLC). METHODS: We examined the activity of sunitinib on a continuous daily dosing (CDD) schedule in an open-label, multicentre phase II study in patients with previously treated, advanced NSCLC. Patients > or =18 years with stage IIIB/IV NSCLC after failure with platinum-based chemotherapy, received sunitinib 37.5 mg per day. The primary end point was objective response rate (ORR). Secondary end points included progression-free survival (PFS), overall survival (OS), 1-year survival rate, and safety. RESULTS: Of 47 patients receiving sunitinib, one patient achieved a confirmed partial response (ORR 2.1% (95% confidence interval (CI) 0.1, 11.3)) and 11 (23.4%) had stable disease (SD) > or =8 weeks. Five patients had SD>6 months. Median PFS was 11.9 weeks (95% CI 8.6, 14.1) and median OS was 37.1 weeks (95% CI 31.1, 69.7). The 1-year survival probability was 38.4% (95% CI 24.2, 52.5). Treatment was generally well tolerated. CONCLUSIONS: The safety profile and time-to-event analyses, albeit relatively low response rate of 2%, suggest single-agent sunitinib on a CDD schedule may be a potential therapeutic agent for patients with advanced, refractory NSCLC.

Inhibitory effect of apigenin, a plant flavonoid, on epidermal ornithine decarboxylase and skin tumor promotion in mice.

This investigation studied the effect of topical application of apigenin on skin tumorigenesis initiated by 7,12-dimethylbenz(a)anthracene (DMBA) and promoted by 12-O-tetradecanoylphorbol-13-acetate (TPA) in SENCAR mice. Apigenin was a potent inhibitor of epidermal ornithine decarboxylase induction by TPA in a dose-dependent manner from 1 to 20 mumol. Two tumorigenesis studies were conducted. In the first study, 20 mumol of apigenin was applied topically and no effect on body weight was observed. By week 33 after DMBA initiation, 48% of DMBA/TPA-treated mice developed carcinomas, while none occurred in DMBA/apigenin/TPA-treated groups. In the second study, doses of 5 and 20 mumol of apigenin were used. The papilloma incidence for 0, 5, and 20 mumol apigenin at 26 weeks after DMBA was 93.3, 58, and 39.3%, and papilloma numbers per mouse were 7.5, 2.5, and 1.8, respectively. Apigenin prolonged by 3 weeks the latency period of tumor appearance. In addition, apigenin significantly inhibited the incidence of carcinoma and the numbers of carcinomas. The incidence of carcinomas per tumor-bearing animal and the ratio of carcinomas/papillomas in two apigenin-treated groups decreased although there were no significant differences between the three groups. These data indicate that apigenin inhibited skin papillomas and showed the tendency to decrease conversion of papillomas to carcinomas.

Phase II study of vorozole (R83842), a new aromatase inhibitor, in postmenopausal women with advanced breast cancer in progression on tamoxifen.

This Phase II study was designed to determine the efficacy and tolerability of vorozole (R83842), a new nonsteroidal aromatase inhibitor, in postmenopausal women with advanced breast cancer in progression being treated with tamoxifen, and to correlate these effects with the hormonal profile and plasma drug levels. Twenty-nine eligible women with estrogen receptor-positive or unknown disease were treated with 2.5 mg vorozole once daily p.o. until disease progression. All 29 are evaluable for toxicity and 27 for response as assessed by International Union Against Cancer (UICC) criteria. After a median follow-up of 8 months, 3 patients (11%) had partial remission of their disease for 14, 15, and 16 months and 14 patients had disease stabilization for 7-24 months (median, 12). Patients with a normal carcinoembryonic antigen level (

Evaluating Temporal Consistency in Marine Biodiversity Hotspots.

With the ongoing crisis of biodiversity loss and limited resources for conservation, the concept of biodiversity hotspots has been useful in determining conservation priority areas. However, there has been limited research into how temporal variability in biodiversity may influence conservation area prioritization. To address this information gap, we present an approach to evaluate the temporal consistency of biodiversity hotspots in large marine ecosystems. Using a large scale, public monitoring dataset collected over an eight year period off the US Pacific Coast, we developed a methodological approach for avoiding biases associated with hotspot delineation. We aggregated benthic fish species data from research trawls and calculated mean hotspot thresholds for fish species richness and Shannon's diversity indices over the eight year dataset. We used a spatial frequency distribution method to assign hotspot designations to the grid cells annually. We found no areas containing consistently high biodiversity through the entire study period based on the mean thresholds, and no grid cell was designated as a hotspot for greater than 50% of the time-series. To test if our approach was sensitive to sampling effort and the geographic extent of the survey, we followed a similar routine for the northern region of the survey area. Our finding of low consistency in benthic fish biodiversity hotspots over time was upheld, regardless of biodiversity metric used, whether thresholds were calculated per year or across all years, or the spatial extent for which we calculated thresholds and identified hotspots. Our results suggest that static measures of benthic fish biodiversity off the US West Coast are insufficient for identification of hotspots and that long-term data are required to appropriately identify patterns of high temporal variability in biodiversity for these highly mobile taxa. Given that ecological communities are responding to a changing climate and other environmental perturbations, our work highlights the need for scientists and conservation managers to consider both spatial and temporal dynamics when designating biodiversity hotspots.

Patterns and Variation in Benthic Biodiversity in a Large Marine Ecosystem.

While there is a persistent inverse relationship between latitude and species diversity across many taxa and ecosystems, deviations from this norm offer an opportunity to understand the conditions that contribute to large-scale diversity patterns. Marine systems, in particular, provide such an opportunity, as marine diversity does not always follow a strict latitudinal gradient, perhaps because several hypothesized drivers of the latitudinal diversity gradient are uncorrelated in marine systems. We used a large scale public monitoring dataset collected over an eight year period to examine benthic marine faunal biodiversity patterns for the continental shelf (55-183 m depth) and slope habitats (184-1280 m depth) off the US West Coast (47°20'N-32°40'N). We specifically asked whether marine biodiversity followed a strict latitudinal gradient, and if these latitudinal patterns varied across depth, in different benthic substrates, and over ecological time scales. Further, we subdivided our study area into three smaller regions to test whether coast-wide patterns of biodiversity held at regional scales, where local oceanographic processes tend to influence community structure and function. Overall, we found complex patterns of biodiversity on both the coast-wide and regional scales that differed by taxonomic group. Importantly, marine biodiversity was not always highest at low latitudes. We found that latitude, depth, substrate, and year were all important descriptors of fish and invertebrate diversity. Invertebrate richness and taxonomic diversity were highest at high latitudes and in deeper waters. Fish richness also increased with latitude, but exhibited a hump-shaped relationship with depth, increasing with depth up to the continental shelf break, ~200 m depth, and then decreasing in deeper waters. We found relationships between fish taxonomic and functional diversity and latitude, depth, substrate, and time at the regional scale, but not at the coast-wide scale, suggesting that coast-wide patterns can obscure important correlates at smaller scales. Our study provides insight into complex diversity patterns of the deep water soft substrate benthic ecosystems off the US West Coast.

Combined results of two phase II studies of Taxol (paclitaxel) in patients with relapsed or refractory lymphomas.

This study was performed to determine the clinical activity and safety of paclitaxel in the treatment of patients with refractory or relapsing aggressive Non-Hodgkin's lymphoma (NHL). Between May 3, 1994 and February 16, 1996, 39 patients with refractory or relapsing NHL consented to be enrolled in two, multicenter, open-labelled studies to evaluate the efficacy, safety, time to progression and overall survival of paclitaxel given at a dose of 175 mg/m2 by a 3-hour IV infusion every three weeks without G-CSF use. Data from the two studies is combined. One patient, although registered, did not receive treatment. Of the remaining 38 patients, 17 men and 21 women aged 26-82 years (median 60) were given 104 courses of paclitaxel [median 2 (range 1-6)]. Seventeen patients had stage IV, 7 stage III, 8 stage II, 5 stage 1 and 1 unknown stage of disease. Histologic grades included 1 low, 33 intermediate, and 4 high. Three patients had bone marrow involvement. Median time from diagnosis to study entry was 19 months (1-160). The median number of previous chemotherapy regimens was 2 (range 1-6). Three of the 35 (8.6%) patients evaluable for response had partial remission (PR) of their disease for 1-7 months (median 2) and 11/35 (31.4%) stable disease (SD) for 1 to 19 months (median 3). All three responders and 3 of the 11 SD patients had received paclitaxel after relapsing from a CR. At analysis, nine of the 38 patients were alive. Median duration of follow up at analysis was 6 months (3 days-29 months). The estimated survival rates for all patients at 1 and 2 years are 34% and 27%, respectively (Kaplan-Meier) from the start of paclitaxel treatment. The median survival time was 5.4 months (3 days to 28+ months). Febrile neutropenia occurred in two patients. Seven (18%) patients developed a neutrophil nadir of < 0.5 x 10(9)/L and 2 (5%) patients developed a platelet nadir of < 50 x 10(9)/L. Six patients received blood transfusions. Non-hematologic toxicity was generally mild to moderate with all patients experiencing some toxicity. Twenty-seven patients experienced grade III toxicity including: alopecia (n = 19), pain (n = 9), fatigue (n = 5), nausea/vomiting (n = 3), diarrhoea (n = 2), pulmonary/shortness of breath (n = 2), anorexia (n = 1) and fluctuating levels of consciousness and somnolence (n = 1). Two patients experienced grade IV toxicity (infection, peripheral neuropathy, pain). No patient discontinued paclitaxel for a severe hypersensitivity reaction. In summary, administered as a 3-hour infusion, paclitaxel 175 mg/m2 results in mild myelotoxicity but minimal antitumor activity in patients with refractory NHL.

Anastrozole: a new selective nonsteroidal aromatase inhibitor.

Aromatase (estrogen synthetase) is the enzyme complex responsible for the final step in estrogen synthesis--the conversion of androstenedione and testosterone to estrone and estradiol, respectively. Inhibitors of this enzyme have been shown to be clinically effective in the treatment of advanced breast cancer in postmenopausal women, in whom the major source of estrogen production derives from aromatization of adrenal androgens in peripheral tissues, such as muscle, liver, and fat. The most widely used aromatase inhibitor has been aminoglutethimide; however, it is nonselective and also inhibits adrenocorticosteroid synthesis, necessitating hydrocortisone supplementation. Aminoglutethimide is also associated with frequent and troublesome side effects. Formestane, the first selective aromatase inhibitor to be developed, has an improved safety profile and selectivity, but its use has been limited somewhat by its inconvenient administration via intramuscular injection. In this article, the preclinical and clinical data published to date on the new third-generation aromatase inhibitor anastrozole (Arimidex) are presented in the context of current endocrine therapies. Future applications of aromatase inhibitors, both as monotherapy and in combination with other endocrine therapies, are discussed. The use of aromatase inhibitors in advanced disease, the adjuvant setting, and as possible chemopreventive agents are examined.

[Clinical evaluation of brain scintigrams for basal midline lesions (author's transl)].

Brain scintigrams with 8-10 mci of pertechnetate were studied refering to surgical, histological and other neuroradiological findings in 91 cases with diagnosis or suspect of basal midline lesions. Anterior view of 45 cases was stored in high speed magnetic tape, displayed on CRT of our data processing system and studied of the ratio of average count for regions of interest, 2 cm x 2 cm in size, placed on the areas of lesion, the sagittal sinus and the normal brain hemispheres. In 18 pituitary adenomas, excluding acromegaly and other intrasellar lesions, 89% of cases with surgical indication for optic nerve symptoms were reported as abnormal scintigrams. In 20 craniopharyngiomas, 11 positive cases consisted mainly of solid, recurrent or thick cystic tumors. Five of 6 ectopic pinealomas and all 6 parasellar or medial sphenoidal ridge meningiomas showed positive uptake. Average counts of the regions of interest placed on tumor areas were 169.4% of normal hemispheric areas in 9 pituitary adenomas, 192.5% in 3 solid craniopharyngiomas, 192.3% in 6 meningiomas and 193.3% in ectopic pinealomas. The difference in the average ratio of the lesion count to the normal hemispheric count was statistically significant between cystic craniopharyngioma and adenoma, ectopic pinealoma, meningioma, glioma and solid craniopharyngioma, and between adenoma and acromegaly with p less than 0.005, and between solid craniopharyngioma and acromegaly, and between glioma and acromegaly with p less than 0.025. In the ratio of the lesion count to the sagittal sinus count, on the other hand, the difference of the average ratio was significant with p less than 0.005, only between cystic craniopharyngioma and ectopic pinealoma, and between cystic and solid craniopharyngioma. These facts suggested that the sagittal sinus count was unsuitable to be the standard count of an anterior scintigram to compare with basal midline count. The routine Polaroid scintigram with Tc99m pertechnetate proved their useful clinical diagnostic value for various basal midline lesions, the size of which indicated the surgical procedures. The digital analysis of anterior scintigrams supported the clinical value of the routine brain scintigram in the detection of these lesions. The ratio of the average count of the basal midline lesion to the normal brain area on the anterior scintigram presents more useful clinical information than the ratio of the lesion to the sagittal sinus count. Brain scintigram is found to be very helpful for the differential diagnosis between solid and cystic sellar tumors which is very important for the decision of surgical indications, and is not always possible by any other conventional neuroradiological procedures.

A phase I dose-escalation and pharmacokinetic study of sunitinib in combination with pemetrexed in patients with advanced solid malignancies, with an expanded cohort in non-small cell lung cancer.

PURPOSE: The primary objective of this phase I dose-escalation study was to identify the maximum tolerated dose (MTD) of sunitinib plus pemetrexed in patients with advanced cancer. METHODS: Using a 3 + 3 dose-escalation design, patients received oral sunitinib qd by continuous daily dosing (CDD schedule; 37.5 or 50 mg) or 2 weeks on/1 week off treatment schedule (Schedule 2/1; 50 mg). Pemetrexed (300-500 mg/m(2) IV) was administered q3w. At the proposed recommended phase 2 dose (RP2D), additional patients with non-small cell lung cancer (NSCLC) were enrolled. RESULTS: Thirty-five patients were enrolled on the CDD schedule and seven on Schedule 2/1. MTDs were sunitinib 37.5 mg/day (CDD/RP2D) or 50 mg/day (Schedule 2/1) with pemetrexed 500 mg/m(2). Dose-limiting toxicities included grade (G) 5 cerebral hemorrhage, G3 febrile neutropenia, and G3 anorexia. Common G3/4 drug-related non-hematologic adverse events (AEs) at the CDD MTD included fatigue, anorexia, and hand-foot syndrome. G3/4 hematologic AEs included lymphopenia, neutropenia, and thrombocytopenia. No significant drug-drug interactions were identified. Five (24%) NSCLC patients had partial responses. CONCLUSIONS: In patients with advanced solid malignancies, the MTD of sunitinib plus 500 mg/m(2) pemetrexed was 37.5 mg/day (CDD schedule) or 50 mg/day (Schedule 2/1). The CDD schedule MTD was tolerable and demonstrated promising clinical benefit in NSCLC.