Sacituzumab govitecan, a Trop-2-directed antibody-drug conjugate, for patients with epithelial cancer: final safety and efficacy results from the phase I/II IMMU-132-01 basket trial.

BACKGROUND: Sacituzumab govitecan (SG), a trophoblast cell surface antigen-2 (Trop-2)-directed antibody-drug conjugate, has demonstrated antitumor efficacy and acceptable tolerability in a phase I/II multicenter trial (NCT01631552) in patients with advanced epithelial cancers. This report summarizes the safety data from the overall safety population (OSP) and efficacy data, including additional disease cohorts not published previously. PATIENTS AND METHODS: Patients with refractory metastatic epithelial cancers received intravenous SG (8, 10, 12, or 18 mg/kg) on days 1 and 8 of 21-day cycles until disease progression or unacceptable toxicity. Endpoints for the OSP included safety and pharmacokinetic parameters with investigator-evaluated objective response rate (ORR per RECIST 1.1), duration of response, clinical benefit rate, progression-free survival, and overall survival evaluated for cohorts (n > 10 patients) of small-cell lung, colorectal, esophageal, endometrial, pancreatic ductal adenocarcinoma, and castrate-resistant prostate cancer. RESULTS: In the OSP (n = 495, median age 61 years, 68% female; UGT1A1∗28 homozygous, n = 46; 9.3%), 41 (8.3%) permanently discontinued treatment due to adverse events (AEs). Most common treatment-related AEs were nausea (62.6%), diarrhea (56.2%), fatigue (48.3%), alopecia (40.4%), and neutropenia (57.8%). Most common treatment-related serious AEs (n = 75; 15.2%) were febrile neutropenia (4.0%) and diarrhea (2.8%). Grade ≥3 neutropenia and febrile neutropenia occurred in 42.4% and 5.3% of patients, respectively. Neutropenia (all grades) was numerically more frequent in UGT1A1∗28 homozygotes (28/46; 60.9%) than heterozygotes (69/180; 38.3%) or UGT1A1∗1 wild type (59/177; 33.3%). There was one treatment-related death due to an AE of aspiration pneumonia. Partial responses were seen in endometrial cancer (4/18, 22.2% ORR) and small-cell lung cancer (11/62, 17.7% ORR), and one castrate-resistant prostate cancer patient had a complete response (n = 1/11; 9.1% ORR). CONCLUSIONS: SG demonstrated a toxicity profile consistent with previous published reports. Efficacy was seen in several cancer cohorts, which validates Trop-2 as a broad target in solid tumors.

Patient preferences of chemotherapy treatment options and tolerance of chemotherapy side effects in advanced stage lung cancer.

BACKGROUND: In the U.S., lung cancer accounts for 14% of cancer diagnoses and 28% of cancer deaths annually. Since no cure exists for advanced lung cancer, the main treatment goal is to prolong survival. Chemotherapy regimens produce side effects with different profiles. Coupling this with individual patient's preferred side effects could result in patient-centered choices leading to better treatment outcomes. There are apparently no previous studies of or tools for assessing and utilizing patient chemotherapy preferences in clinical settings. The long-term goal of the study was to facilitate patients' treatment choices for advanced-stage lung cancer. A primary aim was to determine how preferences for chemotherapy side effects relate to chemotherapy choices. METHODS: An observational, longitudinal, open cohort study of patients with advanced-stage non-small cell lung cancer (NSCLC) was conducted. Data sources included patient medical records and from one to three interviews per subject. Data were analyzed using Chi-square, Fisher's Exact and McNamara's test, and logistic regression. RESULTS: Patients identified the top three chemotherapy side effects that they would most like to avoid: shortness of breath, bleeding, and fatigue. These side effects were similar between first and last interviews, although the rank order changed after patients experienced chemotherapy. CONCLUSIONS: Patients ranked drug side effects that they would most like to avoid. Patient-centered clinical care and patient-centered outcomes research are feasible and may be enhanced by stakeholder commitment. The study results are limited to patients with advanced NSCLC. Most of the subjects were White, since patients were drawn from the U.S. Midwest, a predominantly White population.

Differential association of STK11 and TP53 with KRAS mutation-associated gene expression, proliferation and immune surveillance in lung adenocarcinoma.

While mutations in the KRAS oncogene are among the most prevalent in human cancer, there are few successful treatments to target these tumors. It is also likely that heterogeneity in KRAS-mutant tumor biology significantly contributes to the response to therapy. We hypothesized that the presence of commonly co-occurring mutations in STK11 and TP53 tumor suppressors may represent a significant source of heterogeneity in KRAS-mutant tumors. To address this, we utilized a large cohort of resected tumors from 442 lung adenocarcinoma patients with data including annotation of prevalent driver mutations (KRAS and EGFR) and tumor suppressor mutations (STK11 and TP53), microarray-based gene expression and clinical covariates, including overall survival (OS). Specifically, we determined impact of STK11 and TP53 mutations on a new KRAS mutation-associated gene expression signature as well as previously defined signatures of tumor cell proliferation and immune surveillance responses. Interestingly, STK11, but not TP53 mutations, were associated with highly elevated expression of KRAS mutation-associated genes. Mutations in TP53 and STK11 also impacted tumor biology regardless of KRAS status, with TP53 strongly associated with enhanced proliferation and STK11 with suppression of immune surveillance. These findings illustrate the remarkably distinct ways through which tumor suppressor mutations may contribute to heterogeneity in KRAS-mutant tumor biology. In addition, these studies point to novel associations between gene mutations and immune surveillance that could impact the response to immunotherapy.

A parallel-arm phase I trial of the humanised anti-IGF-1R antibody dalotuzumab in combination with the AKT inhibitor MK-2206, the mTOR inhibitor ridaforolimus, or the NOTCH inhibitor MK-0752, in patients with advanced solid tumours.

BACKGROUND: Two strategies to interrogate the insulin growth factor 1 receptor (IGF-1R) pathway were investigated: vertical inhibition with dalotuzumab and MK-2206 or ridaforolimus to potentiate PI3K pathway targeting and horizontal cross-talk inhibition with dalotuzumab and MK-0752 to exert effects against cellular proliferation, angiogenesis, and stem cell propagation. METHODS: A phase I, multi-cohort dose escalation study was conducted in patients with advanced solid tumours. Patients received dalotuzumab (10 mg kg(-1)) and escalating doses of MK-2206 (90-200 mg) or escalating doses of dalotuzumab (7.5-10 mg kg(-1)) and MK-0752 (1800 mg) weekly. Upon maximum tolerated dose determination, patients with low-RAS signature, high-IGF1 expression ovarian cancer were randomised to dalotuzumab/MK-2206 versus dalotuzumab/ridaforolimus, whereas patients with high IGF1/low IGF2 expression colorectal cancer received dalotuzumab/MK-0752. RESULTS: A total of 47 patients were enrolled: 29 in part A (18 in the dalotuzumab/MK-2206 arm and 11 in the dalotuzumab/MK-0752 arm) and 18 in part B (6 in each arm). Dose-limiting toxicities (DLTs) for dalotuzumab/MK-2206 included grade 4 neutropenia and grade 3 serum sickness-like reaction, maculopapular rash, and gastrointestinal inflammation. For dalotuzumab/MK-0752, DLTs included grade 3 dehydration, rash, and diarrhoea. Seven patients remained on study for >4 cycles. CONCLUSIONS: Dalotuzumab/MK-2206 and dalotuzumab/MK-0752 combinations were tolerable. Further developments of prospectively validated predictive biomarkers to aid in patient selection for anti-IGF-1R therapies are needed.

Real time patient safety audits: improving safety every day.

BACKGROUND: Timely error detection including feedback to clinical staff is a prerequisite for focused improvement in patient safety. Real time auditing, the efficacy of which has been repeatedly demonstrated in industry, has not been used previously to evaluate patient safety. Methods successful at improving quality and safety in industry may provide avenues for improvement in patient safety. OBJECTIVE: Pilot study to determine the feasibility and utility of real time safety auditing during routine clinical work in an intensive care unit (ICU). METHODS: A 36 item patient safety checklist was developed via a modified Delphi technique. The checklist focused on errors associated with delays in care, equipment failure, diagnostic studies, information transfer and non-compliance with hospital policy. Safety audits were performed using the checklist during and after morning work rounds thrice weekly during the 5 week study period from January to March 2003. RESULTS: A total of 338 errors were detected; 27 (75%) of the 36 items on the checklist detected >or=1 error. Diverse error types were found including unlabeled medication at the bedside (n = 31), ID band missing or in an inappropriate location (n = 70), inappropriate pulse oximeter alarm setting (n = 22), and delay in communication/information transfer that led to a delay in appropriate care (n = 4). CONCLUSIONS: Real time safety audits performed during routine work can detect a broad range of errors. Significant safety problems were detected promptly, leading to rapid changes in policy and practice. Staff acceptance was facilitated by fostering a blame free "culture of patient safety" involving clinical personnel in detection of remediable gaps in performance, and limiting the burden of data collection.

Ripening-related occurrence of phosphoenolpyruvate carboxykinase in tomato fruit.

Phosphoenolpyruvate carboxykinase (PEPCK) is present in ripening tomato fruits. A cDNA encoding PEPCK was identified from a PCR-based screen of a cDNA library from ripe tomato fruit. The sequence of the tomato PEPCK cDNA and a cloned portion of the genomic DNA shows that the complete cDNA sequence contains an open reading frame encoding a peptide of 662 amino acid residues in length and predicts a polypeptide with a molecular mass of 73.5 kDa, which corresponds to that detected by western blotting. Only one PEPCK gene was identified in the tomato genome. PEPCK is shown to be present in the pericarp of ripening tomato fruits by activity measurements, western blotting and mRNA analysis. PEPCK abundance and activity both increased during fruit ripening, from an undetectable amount in immature green fruit to a high amount in ripening fruit. PEPCK mRNA, protein and activity were also detected in germinating seeds and, in lower amounts, in roots and stems of tomato. The possible role of PEPCK in the pericarp of tomato fruit during ripening is discussed.

Medical physics: some recollections in diagnostic X-ray imaging and therapeutic radiology.

Medical physics has changed dramatically since 1895. There was a period of slow evolutionary change during the first 70 years after Roentgen's discovery of x rays. With the advent of the computer, however, both diagnostic and therapeutic radiology have undergone rapid growth and changes. Technologic advances such as computed tomography and magnetic resonance imaging in diagnostic imaging and three-dimensional treatment planning systems, stereotactic radiosurgery, and intensity modulated radiation therapy in radiation oncology have resulted in substantial changes in medical physics. These advances have improved diagnostic imaging and radiation therapy while expanding the need for better educated and experienced medical physics staff.

Ca2+signalling in stomatal guard cells.

Ca(2+) is a ubiquitous second messenger in the signal transduction pathway(s) by which stomatal guard cells respond to external stimuli. Increases in guard-cell cytosolic free Ca(2+) concentration ([Ca(2+)](cyt)) have been observed in response to stimuli that cause both stomatal opening and closure. In addition, several important components of Ca(2+)-based signalling pathways have been identified in guard cells, including the cADP-ribose and phospholipase C/Ins(1, 4,5)P(3)-mediated Ca(2+)-mobilizing pathways. The central role of stimulus-induced increases in [Ca(2+)](cyt) in guard-cell signal transduction has been clearly demonstrated in experiments examining the effects of modulating increases in [Ca(2+)](cyt) on alterations in guard-cell turgor or the activity of ion channels that act as effectors in the guard-cell turgor response. In addition, the paradox that Ca(2+) is involved in the transduction of signals that result in opposite end responses (stomatal opening and closure) might be accounted for by the generation of stimulus-specific Ca(2+) signatures, such that increases in [Ca(2+)](cyt) exhibit unique spatial and temporal characteristics.

Expression of a proteasome alpha-type subunit gene during tobacco development and senescence.

Proteasomes degrade specific proteins that have been targeted for proteolysis by ubiquitination. In animals and yeast nuclear-localised proteasomes play a role in regulating the cell cycle, and other developmental processes, via control of the levels of regulatory nuclear proteins such as cyclins and transcription factors. A cDNA, NtPSA1, isolated from tobacco styles was found to have high similarity to human and yeast genes, PRCI_human and PRCI_yeast with 63.4% and 51.6% overall identity respectively. These genes are believed to encode non-catalytic alpha-type subunits of 26S proteasomes and like NtPSA1 have putative nuclear localisation signals. NtPSA1 RNA was found to accumulate to varying levels in different parts of the plant and at different developmental stages. In particular, the level of NtPSA1 RNA was high in young dividing and expanding tissues, and declined during the senescence of both leaves and flowers. These results suggest that a role of proteasomes in plant nuclei may be to regulate developmental events by controlling the levels of regulatory proteins in proliferating and developing tissues, rather than to degrade and recycle proteins during senescence.

Variation among neonatal intensive care units in narcotic administration.

OBJECTIVES: To compare rates of narcotic administration for medically treated neonates in different neonatal intensive care units (NICUs) and to compare treated and untreated neonates to assess whether narcotics provided advantages or disadvantages for short-term outcomes, such as cardiovascular stability (ie, blood pressure and heart rate), hyperbilirubinemia, duration of respiratory support, growth, and the incidence of intraventricular hemorrhage. STUDY DESIGN: The medical charts of neonates weighing less than 1500 g, admitted to 6 NICUs (A-F), were abstracted. Neonates who had a chest tube or who had undergone surgery were excluded from the study, leaving the records of 1171 neonates. We modeled outcomes by linear or logistic regression, controlling for birth weight (<750, 750-999, and 1000-1499 g) and illness severity (low, 0-9; medium, 10-19; high, > or =20) using the Score for Neonatal Acute Physiology (SNAP), and adjusted for NICU. RESULTS: Narcotic use varied by birth weight (<750 g, 21%; 750-999 g, 13%; and 1000-1499 g, 8%), illness severity (low, 9%; medium, 19%; and high, 37%), day (1, 11%; 3, 6%; and 14, 2%), and NICU. We restricted analyses to the 1018 neonates who received mechanical ventilation on day 1. Logistic regression, adjusting for birth weight and SNAP, confirmed a 28.6-fold variation in narcotic administration (odds ratios, 4.1-28.6 vs NICU A). Several short-term outcomes also were associated with narcotic use, including more than 33 g of fluid retention on day 3 and a higher direct bilirubin level (6.8 micromol/L higher [0.4 mg/dL higher], P = .03). There were no differences in weight gain at 14 and 28 days or mechanical ventilatory support on days 14 and 28. Narcotic use was not associated with differences in worst blood pressure or heart rate or with increased length of hospital stay. CONCLUSIONS: Our study found a 28.6-fold variation among NICUs in narcotic administration in very low-birth-weight neonates. We were unable to detect any major advantages or disadvantages of narcotic use. We did not assess iatrogenic abstinence syndrome or long-term outcomes. These results indicate the need for randomized trials to rationalize these widely differing practices.

Determination of bisnafide, a novel bis-naphthalimide anticancer agent, in human plasma by high-performance liquid chromatography with UV detection.

A simple, specific, and sensitive high-performance liquid chromatographic (HPLC) assay utilizing ultraviolet (UV) detection for the determination of bisnafide in human plasma was developed, validated, and applied to plasma samples from patients undergoing cancer therapy. Plasma samples, containing an internal standard, XE842, were first deproteinized with 2.0 ml acetonitrile, and subsequently, 1.0 ml and pH 9 boric acid-potassium chloride-sodium hydroxide buffer (0.1 M) was added. To this mixture, 9.0 ml of ethyl ether was added then vortex mixed. Following centrifugation, the ether layer was back-extracted into 250 microliters of 0.1 M phosphoric acid, then removed by vacuum aspiration. A portion of the remaining acid layer was directly injected onto the HPLC. Bisnafide was quantified using a Shiseido Capcell Pak C8 HPLC column and ultraviolet detection (274 nm). The lower limit of quantification was 10 ng ml-1 using 1.0 ml plasma. The intraday precision (RSD) ranged from 2.7 to 8.6% over a concentration range of 10-1000 ng ml-1. The interday precision (RSD) ranged from 5.6 to 11.5%. Overall mean accuracy was +/- 5.2%. The drug was stable in frozen heparinized human plasma stored at -20 degrees C for at least 1 year and stable throughout at least two freeze-thaw cycles. This method was successfully utilized for quantifying plasma concentrations needed to study the clinical pharmacokinetics of bisnafide in patients undergoing cancer therapy.

Radiation shielding implications of computed tomography scatter exposure to the floor.

This article investigates whether CT scanners used primarily for either head or body work have scattered radiation levels that may impact shielding considerations. Several 35 x 43 cm film cassettes were used to cover the floor area around a General Electric Hi-Speed Advantage CT unit. Regions of maximum exposure were identified (visually with sensitometric confirmation). An ion chamber was used to obtain radiation exposure levels for typical head and body protocols. Greater scattered radiation was found behind the gantry for head scanning (20 vs. 16 microGy for a body scan) while greater scatter was observed in front of the scanner for body scans (46 vs. 31 microGy for the head scan). The resulting annual doses to the floor from typical workloads (assuming 32 cases a day) can be as great as 0.63 Gy for head protocols or 1 Gy from body work. Care may be needed to assure adequate shielding for floor areas near CT scanners specializing in either head or body work. Also, while increased throughput with helical scanners is currently x-ray tube heat limited, shielding plans should allow for enhanced heat capacity (and greater throughput) in future generation scanners.

A phase I and pharmacologic study of DMP 840 administered by 24-hour infusion.

PURPOSE: DMP 840, a novel bisnaphthalimide, has demonstrated promising schedule dependent anti-tumor activity in vitro and in vivo against several tumor cell lines. A phase I study was conducted to evaluate the effect of a 24-hour infusion schedule repeated every three weeks, on the therapeutic efficacy of DMP 840. PATIENTS AND METHODS: Fourteen patients with refractory solid tumor malignancies were treated with DMP 840 at doses of 20, 40, 50 and 60 mg/m2. RESULTS: A combination of neutropenia, thrombocytopenia and stomatitis were dose-limiting at doses of 50 and 60 mg/m2 in both minimally- and extensively-pretreated patients. In contrast, all courses at lower dose levels were well tolerated. Pharmacokinetic analysis demonstrated that DMP 840 had a prolonged terminal half life (median 39 hours; range 25-86) and that dose-limiting events were significantly related to several indices of systemic DMP 840 exposure (P < 0.01, Wilcoxon Rank Sum test). CONCLUSION: The recommended dose of DMP 840 for further disease oriented evaluations is 40 mg/m2 administered over 24 hours every three weeks. The infusion duration evaluated in this study did not result in a substantial increase in the tolerable dose compared to shorter, less cumbersome schedules.

Molecular and enzymatic characterization of three phosphoinositide-specific phospholipase C isoforms from potato.

Many cellular responses to stimulation of cell-surface receptors by extracellular signals are transmitted across the plasma membrane by hydrolysis of phosphatidylinositol-4,5-bisphosphate (PIP2), which is cleaved into diacylglycerol and inositol-1,4,5-trisphosphate by phosphoinositide-specific phospholipase C (PI-PLC). We present structural, biochemical, and RNA expression data for three distinct PI-PLC isoforms, StPLC1, StPLC2, and StPLC3, which were cloned from a guard cell-enriched tissue preparation of potato (Solanum tuberosum) leaves. All three enzymes contain the catalytic X and Y domains, as well as C2-like domains also present in all PI-PLCs. Analysis of the reaction products obtained from PIP2 hydrolysis unequivocally identified these enzymes as genuine PI-PLC isoforms. Recombinant StPLCs showed an optimal PIP2-hydrolyzing activity at 10 microM Ca2+ and were inhibited by Al3+ in equimolar amounts. In contrast to PI-PLC activity in plant plasma membranes, however, recombinant enzymes could not be activated by Mg2+. All three stplc genes are expressed in various tissues of potato, including leaves, flowers, tubers, and roots, and are affected by drought stress in a gene-specific manner.

Detection of small low-contrast objects in mammography: effect of viewbox masking and luminance.

OBJECTIVE: Viewing conditions can affect an observer's performance in object detection. Our objective was to determine the effect of viewbox masking and luminance on the detection of small low-contrast objects revealed by mammography. MATERIALS AND METHODS: Mammographic contrast-detail images having various film densities were viewed on masked and unmasked viewboxes. Similar images with fixed film contrast and density were viewed when luminance ranged from 250 to 8000 nits (1 nit = 1 cd/m2). RESULTS: Detection of small low-contrast objects was significantly easier using a masked viewbox with high luminance that using a regular unmasked viewbox. When a regular viewbox (approximately 3000 nits) was used masking had a more significant effect on films with high optical densities than on films with low optical densities. Brighter, masked viewboxes improved detection on films with higher optical densities. CONCLUSION: Better detection of small low-contrast objects results when mammographic images are masked and viewed on high-luminance viewboxes than when a regular unmasked viewbox is used.

Pollination-enhanced expression of a receptor-like protein kinase related gene in tobacco styles.

We have isolated a putative serine/threonine receptor kinase gene with an expression pattern indicating that it may play a role in the stylar response to pollination. Differential display PCR was used to select tobacco mRNAs with increased accumulation following pollination. NTS16, a cDNA identified by this method, is homologous to a ca. 2.4 kb mRNA primarily expressed in pistil tissues. Levels of this mRNA increase during floral development and are further increased by pollination reaching maximal accumulation 12-18 hours after pollination and then declining. mRNA levels can also be increased by the application of ethylene to unpollinated flowers. A polypeptide encoded by the NTS 16 open reading frame has sequence similarity to the catalytic domain of several receptor protein kinases from plants including the S-receptor kinases implicated in the rejection of self-pollen in Brassica species and the Pto gene product of tomato which confers resistance to a bacterial pathogen.