Virtual oncology research-different models and lessons learned.

PURPOSE OF REVIEW: The COVID-19 pandemic posed several challenges to cancer research including halting of trials, reduced recruitment and protocol violations related to inflexible processes followed in clinical trials. Researchers adopted innovative measures to mitigate these problems and continue studies without compromising their quality. This review collates these adaptations that could well continue after the pandemic. RECENT FINDINGS: The COVID-19 pandemic forced researchers globally to adopt innovative measures to overcome the challenges of the pandemic. These included protocol amendments to adjust to the pandemic and travel restrictions, and increased use of digital technologies. 'Virtual' clinical trials were conducted increasingly with adaptations in ethics and regulatory approvals, patient recruitment and consenting, study interventions and delivery of study medications, trial assessments, and monitoring. Many of these adaptations are safe and feasible, without compromising study quality and data integrity. Although these may not be universally applicable in all types of research, they bring many benefits including more diverse patient participation, less burden on patients for study procedures and reduced resources to conduct trials. SUMMARY: The COVID-19 pandemic has affected cancer research adversely; however, learnings from the pandemic and adaptations from researchers are likely to improve the efficiency of clinical research beyond the pandemic.

Choroidal thickness in lupus nephritis.

OBJECTIVE: This study aimed to compare choroidal thickness between patients with systemic lupus erythematosus (SLE) and lupus nephritis (LN) in complete renal remission to that of patients with SLE without LN. METHODS: This was a retrospective case-control study of 23 SLE patients meeting either the American College of Rheumatology or Systemic Lupus International Collaborating Clinics classification criteria and followed at Washington University School of Medicine Rheumatology or Nephrology, and Ophthalmology outpatient clinics. The diagnosis of LN was based on renal pathology, and complete renal remission was defined as proteinuria <500 mg/daily and serum creatinine at baseline. Extra-renal flare status was determined using modified Fortin criteria. Choroidal thickness was measured using spectral-domain optical coherence tomography and read by blinded reviewers. RESULTS: In SLE patients without extra-renal flare, choroidal thickness of LN patients was 281 ± 78 µm compared to 288 ± 70 µm in non-LN SLE patients (p = 0.766) at the fovea. CONCLUSION: Choroidal thickness was not different in patients with LN in remission compared to non-LN SLE patients in remission. Additional studies are needed to examine choroidal thickness in patients with SLE with active LN.

Does a less intensive surveillance protocol affect the survival of patients after treatment of a sarcoma of the limb? updated results of the randomized TOSS study.

AIMS: A single-centre prospective randomized trial was conducted to investigate whether a less intensive follow-up protocol would not be inferior to a conventional follow-up protocol, in terms of overall survival, in patients who have undergone surgery for sarcoma of the limb. Initial short-term results were published in 2014. PATIENTS AND METHODS: The primary objective was to show non-inferiority of a chest radiograph (CXR) group compared with a CT scan group, and of a less frequent (six-monthly) group than a more frequent (three-monthly) group, in two-by-two comparison. The primary outcome was overall survival and the secondary outcome was a recurrence-free survival. Five-year survival was compared between the CXR and CT scan groups and between the three-monthly and six-monthly groups. Of 500 patients who were enrolled, 476 were available for follow-up. Survival analyses were performed on a per-protocol basis (n = 412). RESULTS: The updated results recorded 12 (2.4%) local recurrences, 182 (36.8%) metastases, and 56 (11.3%) combined (local + metastases) recurrence at a median follow-up of 81 months (60 to 118). Of 68 local recurrences, 60 (88%) were identified by the patients themselves. The six-monthly regime (overall survival (OS) 54%, recurrence-free survival (RFS) 46%) did not lead to a worse survival and was not inferior to the three-monthly regime (OS 55%, RFS 47%) in terms of detecting recurrence. Although CT scans (OS 53%, RFS 54%) detected pulmonary metastasis earlier, it did not lead to a better survival compared with CXR (OS 56%, RFS 59%). CONCLUSION: The overall survival of patients who are treated for a sarcoma of the limb is not inferior to those followed up with a less intensive regimen than a more intensive protocol, in terms of frequency of visits and mode of imaging. CXR at six-monthly intervals and patient education about examination of the site of the surgery will detect most recurrences without deleterious effects on the eventual outcome. Cite this article: Bone Joint J 2018;100-B:262-8.

An open-label randomized controlled clinical trial for comparison of continuous phenylephrine versus norepinephrine infusion in prevention of spinal hypotension during cesarean delivery.

BACKGROUND: During spinal anesthesia for cesarean delivery phenylephrine is the vasopressor of choice but can cause bradycardia. Norepinephrine has both ß- and α-adrenergic activity suitable for maintaining blood pressure with less bradycardia. We hypothesized that norepinephrine would be superior to phenylephrine, requiring fewer rescue bolus interventions to maintain blood pressure. METHODS: Eighty-five parturients having spinal anesthesia for elective cesarean delivery were randomized to Group P (phenylephrine 0.1µg/kg/min) or Group N (norepinephrine 0.05µg/kg/min) fixed-rate infusions. Rescue bolus interventions of phenylephrine 100µg for hypotension, or ephedrine 5mg for bradycardia with hypotension, were given as required to maintain systolic blood pressure. Maternal hemodynamic variables were measured non-invasively. RESULTS: There was no difference between groups in the proportion of patients who required rescue vasopressor boluses (Group P: 65.8% [n=25] vs. Group N: 48.8% [n=21], P=0.12). The proportion of patients who received ⩾1 bolus of phenylephrine was similar between groups (Group P: 52.6% [n=20] vs. Group N: 46.5% [n=20], P=0.58). However, more patients received ⩾1 bolus of ephedrine in the phenylephrine group (Group P: 23.7% [n=9] vs. Group N: 2.3% [n=1], P<0.01). The incidence of emesis was greater in the phenylephrine group (Group P: 26.3% vs. Group P: 16.3%, P<0.001). Hemodynamic parameters including heart rate, the incidence of bradycardia, blood pressure, cardiac output, cardiac index, stroke volume, and systemic vascular resistance and neonatal outcome were similar between groups (all P<0.05). CONCLUSION: Norepinephrine fixed-rate infusion has efficacy for preventing hypotension and can be considered as an alternative to phenylephrine.

Next-generation XPO1 inhibitor shows improved efficacy and in vivo tolerability in hematological malignancies.

The nuclear export receptor, Exportin 1 (XPO1), mediates transport of growth-regulatory proteins, including tumor suppressors, and is overactive in many cancers, including chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML) and aggressive lymphomas. Oral selective inhibitor of nuclear export (SINE) compounds that block XPO1 function were recently identified and hold promise as a new therapeutic paradigm in many neoplasms. One of these compounds, KPT-330 (selinexor), has made progress in Phase I/II clinical trials, but systemic toxicities limit its administration to twice-per-week and requiring supportive care. We designed a new generation SINE compound, KPT-8602, with a similar mechanism of XPO1 inhibition and potency but considerably improved tolerability. Efficacy of KPT-8602 was evaluated in preclinical animal models of hematological malignancies, including CLL and AML. KPT-8602 shows similar in vitro potency compared with KPT-330 but lower central nervous system penetration, which resulted in enhanced tolerability, even when dosed daily, and improved survival in CLL and AML murine models compared with KPT-330. KPT-8602 is a promising compound for further development in hematological malignancies and other cancers in which upregulation of XPO1 is seen. The wider therapeutic window of KPT-8602 may also allow increased on-target efficacy leading to even more efficacious combinations with other targeted anticancer therapies.

Utilization of operating room time in a cancer hospital.

BACKGROUND: Appropriate usage of operating room (OR) time can improve efficiency of utilization of resources and help to decrease surgical waiting lists. AIMS: This study was conducted to evaluate the pattern of usage of OR time in a tertiary referral cancer hospital. SETTING AND DESIGN: This was a prospective audit carried out over 2 months in 11 major ORs in a cancer hospital. MATERIALS AND METHODS: OR anesthesiologists filled a standard form for all patients undergoing elective surgery and documented the following times: entry into OR, start of anesthesia, handover to surgeon, incision, start of reversal, end of anesthesia, and shifting out of patient. STATISTICAL ANALYSIS: Median time utilized for various OR processes was calculated. RESULTS: An average of two surgeries were performed per OR session (828 surgeries in 407 OR sessions). Anesthesia and surgery-related processes contributed to 17% and 79%, respectively, of total OR time, with turnover time between cases accounting for the remaining 4%. Fifteen percent (60 out of 407) OR sessions started more than 10 min later than the planned start time, and 17% (70 of 407) of OR sessions ended more than 2 h after the scheduled finish time. An anesthesia procedure room was utilized in only 15% of cases where it could potentially have been used. CONCLUSION: This audit identified patterns of OR usage in a cancer hospital and helped to detect areas of inefficient utilization. Anesthesia-related processes contributed to 17% of the total OR time.

Decontamination of laryngoscope blades: is our practice adequate?

BACKGROUND: The laryngoscope has been identified as a potential source of cross-infection, because of blood and bacterial contamination. In India, there are no guidelines for cleaning and disinfection of anesthesia-related equipment. Practices for decontamination of laryngoscopes vary widely and in most healthcare institutes, laryngoscope blades are re-used after cleaning with tap-water. MATERIALS AND METHODS: We prospectively compared two techniques for decontamination of laryngoscope blades - a) washing with tap-water and b) washing with tap-water followed by disinfection by immersing in 5% v/v (volume/volume, 1:20 dilution) aldehyde-free biguanide agent for 10 min. We calculated the cost-effectiveness of using 5% v/v aldehyde-free biguanide agent for disinfection of laryngoscopes. We also conducted a survey to assess the decontamination practices in other Indian hospitals. RESULTS: Overall bacterial growth was 58% (29 out of 50 blades) after tap-water cleaning (of which 60% were pathogenic organisms) versus 3.4% (one out of 29 blades) after tap-water cleaning followed by immersion in disinfectant (all of which were commensals). The cost of disinfection with biguanide was Indian Rupees 1.13 (20 US cents) per laryngoscope. Most hospitals in India do not have guidelines regarding laryngoscope decontamination between uses, and cleaning with tap water is a commonly used method. CONCLUSION: Cleaning of laryngoscope blades with tap-water is a commonly used but inadequate method for decontamination. Washing with tap-water followed by disinfection with 5% v/v aldehyde-free biguanide for at least 10 min is an effective and inexpensive alternative. National guidelines for the decontamination of anesthesia equipment are necessary.

Alternative splicing of the Menkes copper Atpase (Atp7a) transcript in the rat intestinal epithelium.

The intestinal Menkes copper Atpase (Atp7a) gene is strongly induced by iron deficiency in the rat intestine. We sought to develop an in vitro model to understand the mechanism of this induction by performing molecular studies in native rat intestine and in intestinal epithelial (IEC-6) cells. IEC-6 cells express Atp7a, and induction was noted with iron deprivation. 5' Rapid amplification of cDNA ends and PCR experiments revealed three splice variants in rat intestine and IEC-6 cells; all variants were strongly induced during iron deprivation (five- to sevenfold). The splice variants presumably encode proteins that would either contain the extreme NH(2) terminus of the protein (containing copper binding domain 1) or not. We thus hypothesized that more than one version of Atp7a protein exists. Antibodies against this NH(2)-terminal region of the protein were developed (named N-term) and used along with previously reported antibodies (against more COOH-terminal regions, termed 54-10) to perform immunoblotting and immunolocalization studies. Results with the 54-10 antiserum revealed an Atp7a protein variant of approximately 190 kDa that localized to the trans-Golgi network of IEC-6 cells and trafficked to the plasma membrane with copper loading. Using the N-term antiserum, however, we noted protein of approximately 97 and 64 kDa. The 97-kDa protein was cytosolic and nuclear, whereas the 64-kDa protein was nuclear specific. Immunolocalization analyses with the N-term antiserum showed strong staining of nuclei in IEC-6 and Caco-2 cells and in rat intestine. We conclude that novel Atp7a protein variants may exist in rat and human intestinal epithelial cells, with different intracellular locations and potentially distinct physiological functions.

Genetics of bone loss in rheumatoid arthritis--role of vitamin D receptor polymorphisms.

RA is a systemic inflammatory arthritis that leads to local and systemic bone loss. Osteoporosis or the systemic bone loss associated with RA increases the risk for fragility fractures, which can affect quality of life dramatically in RA patients. Although traditional and RA-related risk factors have been defined and studied for osteoporosis associated with RA, genetic factors such as polymorphic variants in the traditional candidate genes for osteoporosis, such as the vitamin D receptor (VDR), type 1 collagen A1 (COLIA1) and oestrogen receptor-alpha (ESR1), have not been well elucidated in RA patients. This review summarizes the currently available literature on the association of VDR polymorphisms with local and systemic bone loss in RA. It also discusses potential targets for genetic research in this area, such as polymorphisms in genes, such as IL-6 (IL6) and TNF receptor type 2 (TNFRSF1B), which control the inflammatory response in RA and may influence bone loss in RA. Defining such genetic factors, in addition to traditional and RA-related risk factors for osteoporosis in RA, may facilitate early identification of patients at high risk for fractures who can then be targeted for treatment.

Induction of arachidonate 12-lipoxygenase (Alox15) in intestine of iron-deficient rats correlates with the production of biologically active lipid mediators.

To identify novel genes associated with iron metabolism, we performed gene chip studies in two models of iron deficiency: iron-deprived rats and rats deficient in the principal intestinal iron transporter, divalent metal transporter 1 (i.e., Belgrade rats). Affymetrix rat genome gene chips were utilized (RAE230) with cRNA samples derived from duodenum and jejunum of experimental and control animals. Computational analysis and statistical data reduction identified 29 candidate genes, which were induced in both models of iron deficiency. Gene ontology analysis showed enrichment for genes related to lipid homeostasis, and one gene related to this physiological process, a leukocyte type, arachidonate 12-lipoxygenase (Alox15), was selected for further examination. TaqMan real-time PCR studies demonstrated strong induction of Alox15 throughout the small and large intestine, and in the liver of iron-deficient rats. Polyclonal antibodies were developed and utilized to demonstrate that proteins levels are significantly increased in the intestinal epithelium of iron-deprived rats. HPLC analysis revealed altered intestinal lipid metabolism indicative of Alox15 activity, which resulted in the production of biologically active lipid molecules (12-HETE, 13-HODE, and 13-HOTE). The overall effect is a perturbation of intestinal lipid homeostasis, which results in the production of lipids essentially absent in the intestine of control rats. We have thus provided mechanistic insight into the alteration in lipid metabolism that occurs during iron deficiency, in that induction of Alox15 mRNA expression may be the primary event. The resulting lipid mediators may be related to documented alterations in villus structure and cell proliferation rates in iron deficiency, or to structural alterations in membrane lipid composition.

Possible link between glycated hemoglobin and lipid peroxidation in hyperthyroidism.

BACKGROUND: Glycated hemoglobin (HbA1C) levels are enhanced by elevated glucose concentrations. Glycation of hemoglobin is also modulated by lipid peroxides, ascorbic acid and reduced glutathione (GSH). We determined the strength of the relationships among these variables in a group of hyperthyroid patients. METHODS: Twenty-two untreated hyperthyroid patients and 17 healthy controls were recruited for the study. Whole blood GSH, HbA1C, plasma lipid peroxides, ascorbic acid and fasting glucose were analyzed in both the groups. Direct and partial correlation analysis was performed to explore the possible relationships between these variables. RESULTS: In hyperthyroid patients, HbA1C and lipid peroxides levels were found to be significantly increased than the controls. Ascorbic acid and GSH were decreased significantly in the test group when compared with the healthy control group. With partial correlation analysis, fasting glucose and lipid peroxides were found to have a significant positive correlation with HbA1C. Ascorbic acid and GSH showed no significant association with HbA1C levels. CONCLUSION: These data suggest that HbA1C levels are closely associated with fasting glucose and lipid peroxides in hyperthyroid patients. Therefore, serum lipid peroxides level should be kept in mind while interpreting HbA1C as a long-term glycemic index in hyperthyroid cases.

Will pharmacogenetics allow better prediction of methotrexate toxicity and efficacy in patients with rheumatoid arthritis?

Methotrexate (MTX) remains the most commonly used disease modifying antirheumatic drug in rheumatoid arthritis (RA) because of its cost and experience in its use, despite the availability of new treatments such as leflunomide and the biological agents. However, a significant number of patients with RA either do not benefit from the drug or are unable to tolerate it. Pharmacogenetic approaches may help optimise treatment with MTX, and also other agents, in RA.

Creatine kinase as an indicator of sperm quality and maturity in men with oligospermia.

OBJECTIVES: To determine the differences among the creatine kinase (CK) levels in the spermatozoa of subfertile men with mild, moderate, or severe oligospermia and to examine the differences in CK activity between infertile patients with various clinical diagnoses and a group of normal healthy donors (control). CK is a marker of sperm maturity that correlates with the sperm fertilizing capacity. Elevated levels are associated with an increased rate of functional abnormalities and increased cytoplasmic retention. METHODS: We compared the CK levels in 51 oligospermic men who could not initiate a pregnancy. Patients were categorized according to their degree of oligospermia as defined by the total sperm count: mild (greater than 10 to 40 x 10(6); n = 30), moderate (5 to 10 x 10(6); n = 11), and severe (less than 5 x 10(6); n = 10). These patients were further classified according to their diagnosis (ie, varicocele, n = 24; unexplained infertility, n = 17; vasectomy reversal, n = 9; and unknown diagnosis, n = 1). A separate group consisting of 25 healthy donors was included as a control group. A computer-assisted semen analyzer assessed the sperm characteristics, and the CK levels were measured using a CK test kit after the enzyme was extracted with Triton-X. RESULTS: The CK levels were significantly higher in the sperm of the severely oligospermic group (8.8 +/- 6.5 IU/10(8) sperm) than in the moderate (0.50 +/- 0.19 IU/10(8) sperm) and mild (0.49 +/- 0.15 IU/10(8) sperm) groups (P <0.0001). The mean CK level in the severely oligospermic group was 18-fold higher than that in the moderate (P = 0.03) and mild (P <0.001) groups. The CK levels were significantly higher in all three infertile groups compared with the donor group (0.06 +/- 0.01 IU/10(8) sperm). Patients with varicocele had the highest CK level (3.42 +/- 2.56 IU/10(8) sperm) compared with patients in the vasectomy reversal group (1.73 +/- 0.98 IU/10(8) sperm) and the idiopathic infertility group (0.26 +/- 0.08 IU/10(8) sperm). CONCLUSIONS: Elevated CK levels are associated with severe oligospermia, irrespective of the clinical diagnosis. CK may be a sensitive indicator of sperm quality and maturity in the follow-up of patients treated for male factor infertility.