Praluzatamab Ravtansine, a CD166-Targeting Antibody-Drug Conjugate, in Patients with Advanced Solid Tumors: An Open-Label Phase I/II Trial.

PURPOSE: Praluzatamab ravtansine (CX-2009) is a conditionally activated Probody drug conjugate (PDC) comprising an anti-CD166 mAb conjugated to DM4, with a protease-cleavable linker and a peptide mask that limits target engagement in normal tissue and circulation. The tumor microenvironment is enriched for proteases capable of cleaving the linker, thereby releasing the mask, allowing for localized binding of CX-2009 to CD166. CX-2009 was evaluated in a phase I/II clinical trial for patients with advanced solid tumors. PATIENTS AND METHODS: Eligible patients had metastatic cancer receiving ≥2 prior treatments. CX-2009 was administered at escalating doses every 3 weeks (0.25-10 mg/kg) or every 2 weeks (4-6 mg/kg). Primary objective was to determine the safety profile and recommended phase II dose (RP2D). RESULTS: Of 99 patients enrolled, the most prevalent subtype was breast cancer (n = 45). Median number of prior therapies was 5 (range, 1-19). Dose-limiting toxicities were observed at 8 mg/kg every 3 weeks and 6 mg/kg every 2 weeks. On the basis of tolerability, the RP2D was 7 mg/kg every 3 weeks. Tumor regressions were observed at doses ≥4 mg/kg. In the hormone receptor-positive/HER2-nonamplified breast cancer subset (n = 22), 2 patients (9%) had confirmed partial responses, and 10 patients (45%) had stable disease. Imaging with zirconium-labeled CX-2009 confirmed uptake in tumor lesions and shielding of major organs. Activated, unmasked CX-2009 was measurable in 18 of 22 posttreatment biopsies. CONCLUSIONS: CD166 is a novel, ubiquitously expressed target. CX-2009 is the first conditionally activated antibody-drug conjugate to CD166 to demonstrate both translational and clinical activity in a variety of tumor types.

Expanding the Utility of High-Sensitivity Dried Blood Spot Immunoassay Testing with Single Molecule Counting.

BACKGROUND: Dried blood spot (DBS) testing has been used for years in newborn screening and for other applications when obtaining blood by venipuncture is impractical or expensive. However, several technical challenges have restricted the use of DBS testing to qualitative assays or to analytes that are present in relatively high concentrations. The application of high-sensitivity detection using single molecule counting (SMC™) technology can potentially overcome the limitations of DBS as specimen source. METHODS: A method was developed for reproducibly collecting, storing, and subsequently reconstituting DBS samples to be used with assays based on the SMC technology. Before extraction, DBS samples were scanned, and the blood spot area was calculated to normalize for sample volume and spot variability. DBS sample extraction was done using an efficient high-salt extraction buffer. DBS samples were tested using SMC-based cardiac troponin I (cTnI), prostate-specific antigen (PSA), and C-reactive protein (CRP) assays. RESULTS: The SMC-DBS assays showed reproducible sensitivity, precision, and the stability required for quantifying low-abundance biomarkers. These assays were not significantly impacted by normal variations in hematocrit or sample collection technique. Correlation coefficients obtained from method comparisons between SMC-DBS and laboratory-developed tests or Food and Drug Administration-cleared tests using traditional sample types were 1.08, 1.04, and 0.99 for cTnI, PSA, and high-sensitivity CRP, respectively. CONCLUSIONS: Combining DBS finger-stick blood collection with next-generation immunoassay technology will aid the expansion of DBS testing to protein biomarkers that are in low abundance or to low-volume samples, and will enable the development and adoption of DBS testing to far-reaching applications.

Physician Beware: Severe Cyanide Toxicity from Amygdalin Tablets Ingestion.

Despite the risk of cyanide toxicity and lack of efficacy, amygdalin is still used as alternative cancer treatment. Due to the highly lethal nature of cyanide toxicity, many patients die before getting medical care. Herein, we describe the case of a 73-year-old female with metastatic pancreatic cancer who developed cyanide toxicity from taking amygdalin. Detailed history and physical examination prompted rapid clinical recognition and treatment with hydroxocobalamin, leading to resolution of her cyanide toxicity. Rapid clinical diagnosis and treatment of cyanide toxicity can rapidly improve patients' clinical outcome and survival. Inquiries for any forms of ingestion should be attempted in patients with clinical signs and symptoms suggestive of poisoning.

Bioactive Peptide Natural Products as Lead Structures for Medicinal Use.

The need for new drugs for the treatment of various diseases is enormous. From the previous century until the present, numerous peptide and peptide-derived natural products have been isolated from bacteria and fungi. Hence, microorganisms play a pivotal role as sources for novel drugs with an emphasis on anti-infective agents. Various disciplines from biology, chemistry, and medicine are involved in early stages of the search for peptide natural products including taxonomy, microbiology, bioanalytics, bioinformatics, and medicinal chemistry. Under biochemical aspects, small peptide drugs are basically either ribosomally synthesized and post-translationally modified (RiPPs) or synthesized by multimodular nonribosomal peptide synthetases (NRPSs). Within the context of current developments on bioactive peptide natural products, this Account predominantly highlights recent discoveries, approaches, and research from our laboratory on RiPPs and NRPSs from bacteria and fungi. In our search for peptides showing bioactivities of interest, different approaches were applied: classical screening, in silico prediction, in vitro reconstitution, site-directed mutagenesis, chemoenzymatics, heterologous expression, and total synthesis including structure-activity relationship (SAR) studies in the research on the labyrinthopeptins, albicidin, and the cyclodepsipeptides (CDPs). The ribosomally synthesized labyrinthopeptins, class III lanthipeptides, which have been discovered in a classical screening campaign, display highly attractive antiallodynic (against neuropathic pain caused by dysfunction of the nervous system) and antiviral activities. Therefore, the biosynthetic assembly was investigated by extensive enzymatic studies of the modifying enzymes, and site-directed mutagenesis was performed for the generation of analogs. By genome mining, other class III lanthipeptides have been uncovered, while synthetic access proved to be an unmet challenge for the labyrinthopeptins. In contrast, for the gyrase inhibitor albicidin, the establishment of a chemical synthesis followed by medicinal chemistry studies was the only viable option to gain access to derivatives. Albicidin, which has been discovered investigating plant host-pathogen interactions, has a strong activity against Gram-negative bacteria, for example, Escherichia coli and Pseudomonas aeruginosa, and a future synthetic derivative may become a lead structure for development of an anti-Gram-negative drug. The compound class of the cyclodepsipeptides contributes already two marketed drugs, enniatin (fusafungine) and emodepside. Cyclodepsipeptides show general antibacterial and antifungal effects, whereas specific insecticidal and anthelmintic activities provide lead structures for drug development. Hence, exploiting the chances of reprogramming NRPSs, the generation of chimeric or otherwise designed synthetases could render a new untapped structural space and thus novel bioactivities. While current developments in the fields of genomics, bioinformatics, and molecular biology facilitate the search for new natural products and the design of new peptide structures, the next decade will show which compounds have been carried on further applications and whether current developments have led to an increase in drug candidates.

Burden of Hospital Acquired Infections and Antimicrobial Use in Vietnamese Adult Intensive Care Units.

BACKGROUND: Vietnam is a lower middle-income country with no national surveillance system for hospital-acquired infections (HAIs). We assessed the prevalence of hospital-acquired infections and antimicrobial use in adult intensive care units (ICUs) across Vietnam. METHODS: Monthly repeated point prevalence surveys were systematically conducted to assess HAI prevalence and antimicrobial use in 15 adult ICUs across Vietnam. Adults admitted to participating ICUs before 08:00 a.m. on the survey day were included. RESULTS: Among 3287 patients enrolled, the HAI prevalence was 29.5% (965/3266 patients, 21 missing). Pneumonia accounted for 79.4% (804/1012) of HAIs Most HAIs (84.5% [855/1012]) were acquired in the survey hospital with 42.5% (363/855) acquired prior to ICU admission and 57.5% (492/855) developed during ICU admission. In multivariate analysis, the strongest risk factors for HAI acquired in ICU were: intubation (OR 2.76), urinary catheter (OR 2.12), no involvement of a family member in patient care (OR 1.94), and surgery after admission (OR 1.66). 726 bacterial isolates were cultured from 622/1012 HAIs, most frequently Acinetobacter baumannii (177/726 [24.4%]), Pseudomonas aeruginosa (100/726 [13.8%]), and Klebsiella pneumoniae (84/726 [11.6%]), with carbapenem resistance rates of 89.2%, 55.7%, and 14.9% respectively. Antimicrobials were prescribed for 84.8% (2787/3287) patients, with 73.7% of patients receiving two or more. The most common antimicrobial groups were third generation cephalosporins, fluoroquinolones, and carbapenems (20.1%, 19.4%, and 14.1% of total antimicrobials, respectively). CONCLUSION: A high prevalence of HAIs was observed, mainly caused by Gram-negative bacteria with high carbapenem resistance rates. This in combination with a high rate of antimicrobial use illustrates the urgent need to improve rational antimicrobial use and infection control efforts.

Novel approach for the treatment of corneal ectasia in a graft.

PURPOSE: The aim of this study was to report the use of novel masking agents during an anterior lamellar keratoplasty performed using a femtosecond laser in a patient with corneal ectasia that was consistent with recurrent keratoconus. METHODS: This is a case report. RESULTS: A 55-year-old man, with a 23-year status after penetrating keratoplasty for keratoconus, presented with a chief complaint of ocular discomfort in the right eye. On slit-lamp examination, the physician estimated 70% to 80% inferior thinning at the graft-host interface with inferior corneal neovascularization. Because of the high risk of developing corneal perforation and the patient's desire to minimize visual recovery time, anterior lamellar keratoplasty was chosen. To minimize the risk of perforation during femtosecond dissection of the anterior lamellar bed, gentian violet and cyanoacrylate glue were used in the area of thinning as masking agents. CONCLUSIONS: This represents the first documented use of gentian violet and cyanoacrylate glue as double masking agents to defocus the femtosecond laser raster pass during keratoplasty.

Long-term effect of phacoemulsification on intraocular pressure using phakic fellow eye as control.

PURPOSE: To investigate the long-term effect of phacoemulsification on intraocular pressure (IOP) in patients with ocular hypertension and open-angle glaucoma. SETTING: Three multispecialty ophthalmology practices and one glaucoma specialty group. DESIGN: Retrospective comparative case series. METHODS: Review of medical records of patients with open-angle glaucoma or ocular hypertension who had had unilateral phacoemulsification (without other prior or concurrent ophthalmic procedure) with the fellow eye remaining phakic at least 3 years postoperatively. RESULTS: Preoperatively, the IOP in the surgical and fellow eyes in the 29 patients was 15.66 mm Hg ± 3.33 (SD) and 15.64 ± 4.23 mm Hg (P=.98), respectively. Postoperatively, it was 13.56 ± 2.04 mm Hg and 14.92 ± 2.85 mm Hg, respectively, at 4.5 months (P=.06); 14.88 ± 3.20 mm Hg and 15.27 ± 3.19 mm Hg, respectively, at 1 year (P=.67); 14.16 ± 2.61 mm Hg and 14.95 ± 2.79 mm Hg, respectively, at 2 years (P=.37); and 14.68 ± 3.44 mm Hg and 14.68 ± 2.68 mm Hg at 3 years (P=1.00), respectively. There was no significant difference in the mean number of IOP-lowering medications used in the surgical eyes (1.96 ± 1.40) and fellow eyes (2.08 ± 1.44) postoperatively (P=.77). CONCLUSIONS: In a cohort of ocular hypertensive and glaucoma patients, uncomplicated phacoemulsification had no significant IOP-lowering effect compared with the phakic fellow eye for up to 3 years postoperatively. There was also no difference between the mean number of postoperative IOP-lowering medications used in the surgical and fellow eyes. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned.