Same-day <Superscript>90</Superscript>Y radioembolization: implementing a new treatment paradigm

Purpose

To assess the feasibility of conducting pretreatment mesenteric angiography, coil embolization, ^99mTc macroaggregated albumin (^99mTc-MAA) scintigraphy, and ⁹⁰Y radioembolization treatment in a single, same-day, combined outpatient encounter.

Methods

This was a retrospective study of 78 patients treated during the period 2008 – 2015 who were managed in a single outpatient encounter under the guidance of the Interventional Radiology Department and The Nuclear Medicine Department. Pretreatment planning was performed by reviewing baseline imaging and estimated perfused liver volume bearing the tumor. The region of interest was estimated using 3-D software; this value was used for dosimetry planning. Maximum lung shunting fractions of 10 % for hepatocellular carcinoma and 5 % for liver metastases were assumed. Subsequently, hepatic angiography and ^99mTc-MAA scintigraphy were performed followed by ⁹⁰Y treatment in one outpatient encounter. Total in-room procedure time was recorded.

Results

All patients underwent same-day angiography, ^99mTc-MAA scintigraphy and ⁹⁰Y radioembolization. Of the 78 patients, 16 received multiple segmental treatments to both lobes, 44 received treatment to the right lobe, and 18 received treatment to the left lobe. The median dose was 106 Gy. The median number of ⁹⁰Y vials needed was two (range one to six). The median in-room time was 160 min (75 – 250 min). The residential status of the patients was as follows, 18 % (14/78) were local residents, 55 % (43/78) traveled from outside the city limits, 18 % (14/78) were from out-of-state, and 9 % (7/78) were resident abroad. Of the 78 patients, 61 (77 %) had hepatocellular carcinoma, and 17 (22 %) had liver metastases. The median lung dose was 3.5 Gy.

Conclusion

This study demonstrated the feasibility of same-day ⁹⁰Y evaluation and treatment while maintaining the principles of safe and effective ⁹⁰Y infusion including tumoricidal dosimetry (lobar, segmentectomy), minimization of nontarget flow, and minimization of lung dose. This paradigm translates into expeditious cancer care and significant cost savings.

     

Relationship between sample size and the definition of equivalence in non-inferiority drug studies

Statistical testing of clinical trial data leads to acceptance of a hypothesis if a test of the opposite (null) hypothesis (H0) fails to reach a critical probability value. The usual aim is to demonstrate that a new treatment is superior to a comparator, whence H0 is that the two treatments are the same. By contrast, in studies designed to show that a new treatment is equivalent to an existing therapy, the same principle is satisfied by an amended null hypothesis, that the treatments differ by more than a defined amount. This reversal entails subtle but important logical and practical problems which affect particularly the calculation of sample size. The choice of the limits used to define equivalence is critical to the calculation of sample size in a manner not previously discussed, and in the interpretation of data in relation to the probability of Type I and Type II errors. Investigators, regulatory bodies and institutional ethics committees must ensure that the range of values chosen to indicate equivalence is clinically appropriate and be aware of the effect of this decision on possible errors in accepting or rejecting H0.     

Factors associated with receipt of residential rehabilitation by opiate users indicate that these clients are more amenable to drug treatment

Aims: Residential rehabilitation (RR) is relatively expensive and is received by a minority of drug users seeking treatment. It is perceived to be particularly effective, but those entering RR may be more amenable to treatment than those treated in other modalities. The objective of this study was to explore ways in which opiate users treated in a residential setting differ, at treatment entry, from those treated in a community setting. Methods: Opiate users (N?=?406) who received either RR or community substitute prescribing (CSP) were sampled from the UK Drug Treatment Outcomes Research Study (DTORS). A logistic regression analysis, controlling for Drug Action Team, was used to predict the occurrence of RR versus CSP for the treatment of opiate dependence. Measures included self-reported levels of drug use, offending, social measures and health. Findings: RR clients were different to CSP clients in a number of respects that may positively influence treatment outcome; most importantly, their reasons for seeking treatment were different and they were better motivated. Conclusions: Higher treatment motivation may be one factor that explains why RR is a more effective treatment for clients with complex drug-related problems.     

Chitosan/Silver Nanoparticle/Graphene Oxide Nanocomposites with Multi-Drug Release,Antimicrobial, and Photothermal Conversion Functions

In this work, we designed and fabricated a multifunctional nanocomposite system that consists of chitosan, raspberry-like silver nanoparticles, and graphene oxide. The room temperature atmospheric pressure microplasma (RT-APM) process provides a rapid, facile, and environmentally-friendly method for introducing silver nanoparticles into the composite system. Our composite can achieve a pH controlled single and/or dual drug release. Under pH 7.4 for methyl blue loaded on chitosan, the drug release profile features a burst release during the first 10 h, followed by a more stabilized release of 70–80% after 40–50 h. For fluorescein sodium loaded on graphene oxide, the drug release only reached 45% towards the end of 240 h. When the composite acted as a dual drug release system, the interaction of fluorescein sodium and methyl blue slowed down the methyl blue release rate. Under pH 4, both single and dual drug systems showed a much higher release rate. In addition, our composite system demonstrated strong antibacterial abilities against E. coli and S. aureus, as well as an excellent photothermal conversion effect under irradiation of near infrared lasers. The photothermal conversion efficiency can be controlled by the laser power. These unique functionalities of our nanocomposite point to its potential application in multiple areas, such as multimodal therapeutics in healthcare, water treatment, and anti-microbials, among others.     

ERbeta1 and the ERbeta2 splice variant (ERbetacx/beta2) are expressed in distinct cell populations in the adult human testis

Estrogens can regulate germ cell function. Estrogen action is mediated via high affinity ERs; two subtypes (ERalpha and ERbeta) have been identified. We have shown previously that ERbeta is expressed in nuclei of multiple human testicular cells. A variant isoform of human (h) ERbeta (hERbetacx/2), formed by alternative splicing, has been identified in testicular cDNA libraries by two laboratories. The present study examined the expression of wild-type (ERbeta1) and variant (ERbeta2) beta receptors in human testes by 1) RT-PCR with isoform specific primers, and 2) single and double immunohistochemistry using monoclonal antibodies raised against peptides unique to the C termini of hERbeta1 and hERbeta2. PCR products specific for ERbeta1 and ERbeta2 were amplified from cDNA pools prepared from human testes and granulosa cells. On Western blots, the anti-ERbeta1 monoclonal antibody bound to recombinant ERbeta1 and the anti-ERbeta2 monoclonal to recombinant hERbeta2. Neither bound to the other ERbeta isoform nor to recombinant ERalpha. ERbeta1 and ERbeta2 proteins were both detected in human testis. Immunoexpression of ERbeta1 was most intense in pachytene spermatocytes and round spermatids, whereas low levels of expression were detected in Sertoli cells, spermatogonia, preleptotene, leptotene, zygotene, and diplotene spermatocytes. Highest levels of expression of ERbeta2 protein were detected in Sertoli cells and spermatogonia with low/variable expression in preleptotene, pachytene, and diplotene spermatocytes. No immunostaining was detected in elongating spermatids. Most interstitial cells expressed more ERbeta2 than ERbeta1. It is speculated that the cells most susceptible to modulation by estrogenic ligands are round spermatids in which levels of expression of ERbeta1 are high. In contrast, expression of ERbeta2, an isoform that may act as a dominant negative inhibitor of ER action, in Sertoli cells and spermatogonia, could protect these cells from adverse effects of estrogens.     

Proofreading DNA: recognition of aberrant DNA termini by the Klenow fragment of DNA polymerase I.

Fluorescence depolarization decays were measured for 5-dimethylaminonaphthalene-1-sulfonyl (dansyl) probes attached internally to 17-mer.27-mer oligonucleotides bound to Klenow fragment of DNA polymerase I. The time-resolved motions of the dansyl probes were sensitive indicators of DNA-protein contacts, showing that the protein binds to DNA with two footprints, corresponding to primer termini at either the polymerase or 3'-5' exonuclease sites. We examined complexes of Klenow fragment with DNAs containing various base mismatches. Single mismatches at the primer terminus caused a 3- to 4-fold increase in the equilibrium partitioning of DNA into the exonuclease site; the largest effects were observed for purine-purine mismatches. Two or more consecutive G.G mismatches caused the DNA to bind exclusively at the exonuclease site, with a partitioning constant at least 250-fold greater than that of the corresponding matched DNA sequence. Internal single mismatches produced larger effects than the same mismatch at the primer terminus, with a delta delta G relative to the matched sequence of -1.1 to -1.3 kcal/mol for mismatches located 2, 3, or 4 bases from the primer terminus. Although part of the observed effects may be attributed to the increased melting capacity of the DNA, it appears that the polymerase site also promotes movement of DNA into the exonuclease site by rejecting aberrant primer termini. These effects suggest that the polymerase and exonuclease sites act together to recognize specific errors that distort the primer terminus, such as frameshifts, in addition to proofreading misincorporated bases.     

A genomic sequencing protocol that yields a positive display of 5-methylcytosine residues in individual DNA strands.

The modulation of DNA-protein interactions by methylation of protein-binding sites in DNA and the occurrence in genomic imprinting, X chromosome inactivation, and fragile X syndrome of different methylation patterns in DNA of different chromosomal origin have underlined the need to establish methylation patterns in individual strands of particular genomic sequences. We report a genomic sequencing method that provides positive identification of 5-methylcytosine residues and yields strand-specific sequences of individual molecules in genomic DNA. The method utilizes bisulfite-induced modification of genomic DNA, under conditions whereby cytosine is converted to uracil, but 5-methylcytosine remains nonreactive. The sequence under investigation is then amplified by PCR with two sets of strand-specific primers to yield a pair of fragments, one from each strand, in which all uracil and thymine residues have been amplified as thymine and only 5-methylcytosine residues have been amplified as cytosine. The PCR products can be sequenced directly to provide a strand-specific average sequence for the population of molecules or can be cloned and sequenced to provide methylation maps of single DNA molecules. We tested the method by defining the methylation status within single DNA strands of two closely spaced CpG dinucleotides in the promoter of the human kininogen gene. During the analysis, we encountered in sperm DNA an unusual methylation pattern, which suggests that the high methylation level of single-copy sequences in sperm may be locally modulated by binding of protein factors in germ-line cells.