Emerging growth factor receptor antagonists for the treatment of renal cell carcinoma

Introduction: The landscape of systemic treatment for metastatic renal cell carcinoma (RCC) has dramatically changed with the introduction of targeted agents including vascular endothelial growth factor (VEGF) inhibitors. Recently, multiple new agents including growth factor receptor antagonists and a checkpoint inhibitor were approved for the treatment of refractory metastatic RCC based on encouraging benefit shown in clinical trials.

Areas covered: The background and biological rationale of existing treatment options including a brief discussion of clinical trials which led to their approval, is presented. This is followed by reviewing the limitations of these therapeutic options, medical need to develop new treatments and major goals of ongoing research. We then discuss two recently approved growth factor receptor antagonists i.e. cabozantinib and lenvatinib, and a recently approved checkpoint inhibitor, nivolumab, and issues pertaining to drug development, and future directions in treatment of metastatic RCC.

Expert opinion: Recently approved growth factor receptor antagonists have shown encouraging survival benefit but associated drug toxicity is a major issue. Nivolumab, a programmed death 1 (PD-1) checkpoint inhibitor, has similarly shown survival benefit and is well tolerated. With multiple options now available in this patient population, the right sequence of these agents remains to be determined.     

An enzymatic cow immunity-targeted approach to reducing milk somatic cell count: 3. A comparative field trial

The effectiveness of lysosubtilin and lysozyme, a combination thereof and a combination of these enzyme preparations (each alone and in combination) with vitamins as possible coimmunostimulants, which reduced the milk somatic cell count (SCC), were compared in a field trial. Seventy second to third lactation Lithuanian Black and White cows with a similar milk SCC ([750±200]×10³?cells?ml^?1) and of a similar weight (550±50?kg) were involved in the trial and were randomly allocated into seven groups (n=10). Lysosubtilin and/or lysozyme at doses of 0.02?g?kg?wt^?1 and 0.2?g?kg?wt^?1, respectively, and vitamins A, C and E (if any) at doses twice as high as required for nutritional adequacy were given, except for control group cows, once daily with feed for ten successive days. After four-, seven-, and ten-day periods of giving enzymes (with or without vitamins) a significant reduction of SCC (p<0.001) was observed in the milk of cows that received a combination of lysozyme with vitamins. On the tenth day a significant reduction of SCC (p<0.001) was also observed in the milk of cows that received lysozyme and lysosubtilin (each alone; without vitamins) or lysosubtilin in combination with vitamins. At the end of the trial (on the 15th day) SCC in milk of cows of all of the study groups was significantly lower (p<0.001) when compared with that of the control group.     

Melphalan-Based Reduced-Intensity Conditioning is Associated with Favorable Disease Control and Acceptable Toxicities in Patients Older Than 70 with Hematologic Malignancies Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

Allogeneic hematopoietic stem cell transplantation (alloHCT) is offered increasingly to elderly patients with hematologic malignancies. However, outcome data in those who are 70 years or older are limited, and no standard conditioning regimen has been established for this population. In this retrospective study we evaluated the outcome of 53 consecutive patients aged 70 years and older who underwent alloHCT with melphalan-based reduced-intensity conditioning (RIC) at City of Hope. Engraftment was prompt, with median time to neutrophil engraftment of 15 days. More than 95% of patients achieved complete donor chimerism within 6 weeks from HCT, consistent with the “semiablative” nature of this regimen. With a median follow-up of 31.1 months, the 2-year overall survival (OS), progression-free survival (PFS), and nonrelapse mortality (NRM) were 68.9%, 63.8%, and 17.0%, respectively. Cumulative incidence of relapse at 1 and 2 years was 17.0% and 19.3%, respectively. One hundred–day cumulative incidence of grades II to IV acute graft-versus-host disease was 37.7% (grades III to IV, 18.9%), and 2-year cumulative incidence of chronic graft-versus-host disease was 61.9% (extensive, 45.9%). The only significant predictor for poor OS was high/very high disease risk index. Transplant-related complications and morbidities observed here did not differ from the commonly expected in younger patients treated with RIC. In conclusion, alloHCT with a melphalan-based conditioning regimen is associated with acceptable toxicities and NRM, lower incidence of relapse, and favorable OS and PFS in patients aged 70 years or older.     

In vitro comparative study of white and dark polycaprolactone trifumarate in situ cross-linkable scaffolds seeded with rat bone marrow stromal cells

OBJECTIVE:

Dark poly(caprolactone) trifumarate is a successful candidate for use as a bone tissue engineering scaffold. Recently, a white polymeric scaffold was developed that shows a shorter synthesis time and is more convenient for tissue-staining work. This is an in vitro comparative study of both the white and dark scaffolds.

METHODS:

Both white and dark poly(caprolactone) trifumarate macromers were characterized via Fourier transform infrared spectroscopy before being chemically cross-linked and molded into disc-shaped scaffolds. Biodegradability was assessed by percentage weight loss on days 7, 14, 28, 42 and 56 (n = 5) after immersion in 10% serum-supplemented medium or distilled water. Static cell seeding was employed in which isolated and characterized rat bone marrow stromal cells were seeded directly onto the scaffold surface. Seeded scaffolds were subjected to a series of biochemical assays and scanning electron microscopy at specified time intervals for up to 28 days of incubation.

RESULTS:

The degradation of the white scaffold was significantly lower compared with the dark scaffold but was within the acceptable time range for bone-healing processes. The deoxyribonucleic acid and collagen contents increased up to day 28 with no significant difference between the two scaffolds, but the glycosaminoglycan content was slightly higher in the white scaffold throughout 14 days of incubation. Scanning electron microscopy at day 1 revealed cellular growth and attachment.

CONCLUSIONS:

There was no cell growth advantage between the two forms, but the white scaffold had a slower biodegradability rate, suggesting that the newly synthesized poly(caprolactone) trifumarate is more suitable for use as a bone tissue engineering scaffold.     

Dose-dependent effect of histamine on liver function markers in immunized rabbits

ObjectiveThe present study was designed to delineate the hepatotoxicological roles of histamine dose-dependently in immunized rabbits.MethodsThe cohort comprised of three groups (II, III and IV), containing 18 rabbits each, and received subcutaneous histamine 50 μg/kg, 100 μg/kg and 200 μg/kg, respectively for 10 days (b.i.d., starting from 3 days prior to immunization until 7 days after immunization). Group I (control, n = 18) received subcutaneous sterile distilled water for 10 days. They were subsequently immunized at day 3 with intravenous injection of SRBC (1 × 10⁹ cells/ml). Blood samples were collected on pre-immunization (pre-I) day 0, as well as on days 7-, 14-, 21-, 28- and 58-post-immunization (post-I). Biochemical parameters aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) and bilirubin [total bilirubin (TB), direct bilirubin (DB) and indirect bilirubin (IB)] were determined.ResultsGroups II and IV revealed a significant decrease (on day 0-pre-I) and a significant increase (on days 7-, 14-, 21-, 28- and 58-post-I) in ALT and AST levels, when compared with the corresponding values of groups I and III while group II showed a significant increase in ALT and AST levels as compared to group IV. ALP levels in groups II, III and IV showed a significant enhancement when compared with group I. Moreover, results of TB, DB and IB demonstrated increased levels in group III when compared with groups I, II and IV. The results were found statistically significant (p < 0.05).ConclusionShort-term treatment of histamine produces dose-dependent differential patterns of hepatic dysfunctions suggestive mild liver degeneration warranting further long-term studies.     

Complex distal 10q rearrangement in a girl with mild intellectual disability: follow up of the patient and review of the literature of non-acrocentric satellited chromosomes

We report on an intellectually disabled girl with a de novo satellited chromosome 10 (10qs) and performed a review of the literature of the non-acrocentric satellited chromosomes (NASC). Satellites and stalks normally occur on the short arms of acrocentric chromosomes; however, the literature cites several reports of satellited non-acrocentric chromosomes, which presumably result from a translocation with an acrocentric chromosome. This is, to our knowledge, the third report of a 10qs chromosome. The phenotype observed in the proband prompted a search for a structural rearrangement of chromosome 10q. By microsatellite analysis we observed a 4 Mb deletion on the long arm of chromosome 10, approximately 145 kb from the telomere. FISH and array CGH analyses revealed a complex rearrangement involving in range from the centromere to the telomere: A 9.64 Mb 10q26.11-q26.2 duplication, a 1.3 Mb region with no copy number change, followed by a 5.62 Mb 10q26.2-q26.3 deletion and a translocation of satellite material. The homology between the repeat sequences at 10q subtelomere region and the sequences on the acrocentric short arms may explain the origin of the rearrangement and it is likely that the submicroscopic microdeletion and microduplication are responsible for the abnormal phenotype in our patient. The patient presented here, with a 15-year follow-up, manifests a distinct phenotype different from the 10q26 pure distal monosomy and trisomy syndromes.