Targeting angiogenesis for radioimmunotherapy with a <Superscript>177</Superscript>Lu-labeled antibody

Purpose

Increased angiogenesis is a marker of aggressiveness in many cancers. Targeted radionuclide therapy of these cancers with angiogenesis-targeting agents may curtail this increased blood vessel formation and slow the growth of tumors, both primary and metastatic. CD105, or endoglin, has a primary role in angiogenesis in a number of cancers, making this a widely applicable target for targeted radioimmunotherapy.

Methods

The anti-CD105 antibody, TRC105 (TRACON Pharmaceuticals), was conjugated with DTPA for radiolabeling with ¹⁷⁷Lu (t _1/2 6.65 days). Balb/c mice were implanted with 4T1 mammary carcinoma cells, and five study groups were used: ¹⁷⁷Lu only, TRC105 only, ¹⁷⁷Lu-DTPA-IgG (a nonspecific antibody), ¹⁷⁷Lu-DTPA-TRC105 low-dose, and ¹⁷⁷Lu-DTPA-TRC105 high-dose. Toxicity of the agent was monitored by body weight measurements and analysis of blood markers. Biodistribution studies of ¹⁷⁷Lu-DTPA-TRC105 were also performed at 1 and 7 days after injection. Ex vivo histology studies of various tissues were conducted at 1, 7, and 30 days after injection of high-dose ¹⁷⁷Lu-DTPA-TRC105.

Results

Biodistribution studies indicated steady uptake of ¹⁷⁷Lu-DTPA-TRC105 in 4T1 tumors between 1 and 7 days after injection (14.3 ± 2.3%ID/g and 11.6 ± 6.1%ID/g, respectively; n = 3) and gradual clearance from other organs. Significant inhibition of tumor growth was observed in the high-dose group, with a corresponding significant increase in survival (p < 0.001, all groups). In most study groups (all except the nonspecific IgG group), the body weights of the mice did not decrease by more than 10%, indicating the safety of the injected agents. Serum alanine transaminase levels remained nearly constant indicating no damage to the liver (a primary clearance organ of the agent), and this was confirmed by ex vivo histological analyses.

Conclusion

¹⁷⁷Lu-DTPA-TRC105, when administered at a sufficient dose, is able to curtail tumor growth and provide a significant survival benefit without off-target toxicity. Thus, this targeted agent could be used in combination with other treatment options to slow tumor growth allowing the other agents to be more effective.

     

Multidrug-resistant Candida auris: an epidemiological review

ABSTRACT

Introduction

Since the emergence of Candida auris infection in 2009, the disease has been reported from multiple countries within a decade. The infection is classified under urgent threat, as it is multi-drug resistant, causes high mortality, spreads easily in hospital setting and is difficult to identify. Whole-genome sequencing has provided insights into this organisms biology and epidemiology. A comprehensive review of those issues would help the clinicians and scientists facing C. auris infection.     

Preferential allelic deletion of RBSP3, LIMD1 and CDC25A in head and neck squamous cell carcinoma: Implication in cancer screening and early detection

Head and neck squamous cell carcinoma is one of the leading cancers in terms of incidence and mortality. However, no reliable marker till date accurately predicts its progression when altered in healthy tissues. The study aims to identify alleles of microsatellites adjacent to important cell cycle regulatory, tumor suppressor genes altered in early head and neck lesions, viz. RBSP3, LIMD1 and CDC25A, which undergo frequent deletion and can be used for population screening and early detection. DNA for tumors and normal tissues was isolated from 143 patients in different stages of head and neck squamous cell carcinoma. The size of microsatellite present in normal tissues and their deletion in the corresponding tumor was identified, along with the correlation of expression in normal epithelium with respect to allele size. The results revealed a range of alleles (CA₉ to CA₃₂) for the different microsatellites of the genes in normal tissues. The larger alleles were significantly deleted with differential deletion of alleles observed in tumors, except for LIMD1, in which the smaller allele was significantly deleted. In normal tissues, some alleles represented as stable alleles with high prevalence, while in tumours, specific sizes showed greater propensity for deletion. However, similar expression of the proteins in normal epithelium adjacent to tumors was observed despite variations in allele size, possibly due to the location of the microsatellites. Thus, those alleles when present in normal tissues and undergoing persistent deletion in tumours could be used as markers for screening and early identification of populations at risk of developing head and neck lesions.     

Reasons for delayed presentation in oral and oropharyngeal cancer: the patients perspective

Patients with oral and oropharyngeal cancer (OOC) often delay presenting to their doctor or dentist. The aims of this study were to ask a consecutive cohort following treatment for OOC about their initial symptoms and the time spent before presentation to the healthcare profession. Also to discover their views on how to reduce delays in presentation. From a 2-year cohort treated within 2 years, 71 completed a short survey and 44 were subsequently interviewed by telephone. A non-healing ulcer or sore was the commonest symptom patients first related to having cancer. Around half interpreted their symptoms as something minor, staying much the same initially, and something that probably would get better by itself. Most would have sought advice earlier if they had been more aware of oral cancer. Although many patients talked about their symptoms to spouse, partner, family or friends, over one-third said they spoke to nobody about it. Our sample did not find that access to a doctor or a dentist was a barrier to seeking advice. This study highlights that from the patients perception they generally thought their symptoms were trivial, would get better by themselves and gave little thought as to whether it might be cancer. Patients commented they knew nothing more about the disease. In their views the best way to get patients to self refer earlier was through improved awareness of the disease, as many felt there was a gross lack of knowledge in this field of cancers compared to other cancers.     

Koebner's Phenomenon in Childhood Henoch‐Schönlein Purpura: A Report of Two Cases

Koebner's phenomenon occurs rarely in connection with Henoch‐Schönlein purpura (HSP). We report two children with HSP who developed Koebner's phenomenon on the second day after the onset of rash. The first was an 11‐year‐old girl with rheumatic heart disease who presented with abdominal pain for 1 month and subsequently developed rash and nephritis. The second patient was a 7‐year‐old girl who presented with rash and polyarthritis. To the best of our knowledge, Koebner's phenomenon in childhood HSP has not been reported.