Oncology clinical trial disruption during the COVID-19 pandemic: a COVID-19 and cancer outcomes study.

BACKGROUND: COVID-19 disproportionately impacted patients with cancer as a result of direct infection, and delays in diagnosis and therapy. Oncological clinical trials are resource-intensive endeavors that could be particularly susceptible to disruption by the pandemic, but few studies have evaluated the impact of the pandemic on clinical trial conduct. PATIENTS AND METHODS: This prospective, multicenter study assesses the impact of the pandemic on therapeutic clinical trials at two large academic centers in the Northeastern United States between December 2019 and June 2021. The primary objective was to assess the enrollment on, accrual to, and activation of oncology therapeutic clinical trials during the pandemic using an institution-wide cohort of (i) new patient accruals to oncological trials, (ii) a manually curated cohort of patients with cancer, and (ii) a dataset of new trial activations. RESULTS: The institution-wide cohort included 4756 new patients enrolled to clinical trials from December 2019 to June 2021. A major decrease in the numbers of new patient accruals (-46%) was seen early in the pandemic, followed by a progressive recovery and return to higher-than-normal levels (+2.6%). A similar pattern (from -23.6% to +30.4%) was observed among 467 newly activated trials from June 2019 to June 2021. A more pronounced decline in new accruals was seen among academically sponsored trials (versus industry sponsored trials) (P < 0.05). In the manually curated cohort, which included 2361 patients with cancer, non-white patients tended to be more likely taken off trial in the early pandemic period (adjusted odds ratio: 2.60; 95% confidence interval 1.00-6.63), and substantial pandemic-related deviations were recorded. CONCLUSIONS: Substantial disruptions in clinical trial activities were observed early during the pandemic, with a gradual recovery during ensuing time periods, both from an enrollment and an activation standpoint. The observed decline was more prominent among academically sponsored trials, and racial disparities were seen among people taken off trial.

Productive performance of beef cows subjected to different nutritional levels in the third trimester of gestation.

In general, calf production occurs in less intensive systems. The limitation of nutrients during the gestation phase of beef cows can have negative impacts on the consequent productivity of females. Therefore, this study aimed to evaluate the effects of nutritional levels in the third trimester of pregnancy on the productive performance of beef cows kept in a natural pasture (NP). Eighty-three Charolais × Nelore cows were used, ranging in age from 4 to 12 years, which were divided according to their nutritional levels during the third trimester of pregnancy: NP, cows supplemented with 100% of their energy and protein requirements (SP100) and cows supplemented with 150% of their energy and protein requirements (SP150). The experimental design was completely randomized with three treatments and a varied number of repetitions. The SP100 and SP150 cows presented better body condition at calving (2.92 and 2.99 vs 2.81 points) and at the start of the breeding season (2.90 and 2.95 vs 2.80 points) than did NP cows. The nutritional level of the cows in the third trimester of gestation did not influence the blood metabolite concentrations. The plasma levels of albumin and total proteins were 3.11 and 8.18 g/dl, respectively. Glucose and cholesterol showed values of 74.96 and 166.50 mg/dl. The lowest concentration of blood metabolites was observed in the first postpartum weeks. The SP100 and SP150 cows showed faster follicular growth and, consequently, a higher percentage of females with ovulatory follicles at 21 days postpartum than did NP cows (45.68, 41.11, and 11.00%, respectively). The SP150 cows had a higher pregnancy rate (40.74%), total calf production (295.88 kg/cow), and consequently, offspring sale value. An increased nutritional level in the third trimester of pregnancy improves the postpartum metabolic condition and productive efficiency of beef cows kept on NP.

Characterization of the nasal, sublingual, and oropharyngeal mucosa microbiota in cleft lip and palate individuals before and after surgical repair.

OBJECTIVE: To delineate inherent differences in the microbial milieu in cleft palate patients compared with cleft lip patients and to document changes in microbial flora before and after cleft lip and palate repair. DESIGN: A prospective study of preoperative and postoperative culture results from the nasal, sublingual, and oropharyngeal surfaces of patients undergoing primary cleft lip repair and palate closure. SETTING: Shriners Hospitals for Children, Galveston, Texas, and University of Texas Medical Branch, Galveston, Texas. PATIENTS: Seventy-nine patients were included in a 3-year period. Ten patients with isolated cleft lip underwent primary lip repair. Twenty-five patients with cleft lip and palate underwent primary lip repair, and 44 patients underwent palatoplasty. RESULTS: Cleft palate patients had a significantly higher rate of colonization by staphylococcal species, but not methicillin-resistant Staphylococcus aureus , when compared to cleft lip patients (p=.0298; chi-square test). Closure of the palatal cleft coincided with significant decline in the prevalence of Klebsiella and Enterobacter species (p<.05; McNemar test). The only major complication, palatal dehiscence, was believed to be directly related to infection with group A beta-hemolytic streptococci. CONCLUSIONS: Despite a high prevalence of potential pathogenic and enteric flora preoperatively in primary palate repair, postoperative wound infection is rare in the prospective study population. However, the presence of beta-hemolytic streptococci was associated with a higher risk of repair dehiscence; therefore, screening for Streptococci prior to surgery should be performed routinely.

Everolimus in patients with rheumatoid arthritis receiving concomitant methotrexate: a 3-month, double-blind, randomised, placebo-controlled, parallel-group, proof-of-concept study.

OBJECTIVES: Everolimus, a proliferation signal inhibitor with disease-modifying properties, may be useful in treating rheumatoid arthritis (RA). This proof-of-concept study assessed efficacy and safety of everolimus in combination with methotrexate (MTX) in patients with refractory RA. METHODS: A multi-centre, randomised, double-blind, placebo-controlled trial was performed in 121 patients with active RA receiving MTX. Patients were randomised to receive everolimus (6 mg/day) or placebo. The primary endpoint was the American College of Rheumatology criteria for a 20% improvement in measures of disease activity (ACR20) at 12 weeks. RESULTS: There was a rapid onset of action and at 12 weeks the ACR20 response rate was significantly higher in the everolimus group (36.1%) than in the placebo group (16.7%; p = 0.022). Improvements from baseline in tender and swollen joint counts, patient's assessment of pain, and patient's and physician's global assessment of disease activity were significantly greater after treatment with everolimus. The most common adverse events (AEs) in the everolimus group were gastrointestinal (52.5% vs 31.7% in the placebo group), skin (29.5% vs 8.3%), and nervous system disorders (21.3% vs 10.0%); AEs leading to treatment discontinuation were reported for 16.4% and 10.0% of patients, respectively. Changes in haematological parameters, liver function tests, and lipid levels occurred more frequently with everolimus compared to placebo, but were mild and reversible. CONCLUSIONS: The study indicates that everolimus plus MTX provides clinical benefit with an acceptable safety and tolerability profile. It may offer a new treatment option in RA patients with inadequate response to MTX.

Clinical and serologic characteristics of patients with overlap syndrome: is mixed connective tissue disease a distinct clinical entity?

We discuss the clinical and serologic features of 27 patients with overlap syndrome followed prospectively by our group. The findings are similar to those of other reports, but we have drawn attention to the presence of peritendinous nodules in these patients and mentioned some peculiar neurologic manifestations. Rheumatoid arthritis was the most common diagnosis in our patients. The presence of high-titer antibodies against the nuclear ribonucleoprotein fraction of extractable nuclear antigen (nRNP) did not allow the identification of a particular subgroup. However, patients with this antibody tended to fulfill more criteria of more diseases than those without it. The findings lead us to conclude that antibodies to nRNP do not identify a particular subgroup within the overlap syndromes and that mixed connective tissue disease does not appear to be a distinct entity.

Idiopathic familial chondrocalcinosis due to apatite crystal deposition.

Idiopathic familial chondrocalcinosis was found in five members of a family. The clinical features of the disease were morning stiffness, pain and limitation of motion of the dorsolumbar spine in four of the five members, associated with arthritis of the small joints of the hands in three, shoulder periarthritis in two and costal cartilage pain in one. Radiologically, four of the five patients had multiple intervertebral disk calcifications, mainly located at the nucleus pulposus area. Three of them also had periarticular calcific deposits, associated with costal cartilage calcifications and degenerative changes in the small joints of the hands in two. None of these cases showed cartilage calcification in the knees, public symphysis or triangular ligament of carpus. In the propositus, optical microscopy of a specimen of the second proximal interphalangeal joint obtained by open biopsy showed the presence of multiple calcified areas in the intercellular matrix and chondroid metaplasia with calcification of the matrix in the synovial membrane and capsule. X-ray diffraction studies, energy dispersive analysis, and infrared spectrophotometry of a costal cartilage sample obtained by open biopsy demonstrated the presence of carbonate calcium hydroxyapatite. In this study, no relation was found between HLA antigens, loci A, B and C, and this syndrome due to calcium hydroxyapatite crystal deposition.

Protrusio acetabuli in seronegative spondyloarthropathy.

Protrusio acetabuli (PA) is a complication of many disorders involving the hip joint. Its frequency and clinical features in seronegative sponyloarthropathy (SNSA) are unknown. The prevalence and characteristics of PA were studied in 50 adults and 25 children with SNSA (40 ankylosing spondylitis, 24 psoriatic arthropathy, and 11 Reiter's syndrome). PA was considered present when the acetabular line medially exceeded the ilioischial line by 3 mm or more in men, 6 mm or more in women, more than 1 mm in boys, and more than 3 mm in girls. PA prevalence was 25% in the total group (19 of 75 patients), 22% in adults, and 32% in children. There were no significant differences in seronegative disease type; PA was present with similar frequency between genders and did not correlate with disease duration, clinical severity of hip involvement, or previous medication. Radiological damage was similar in adults and children and did not differ in those with and without PA. Similarly, functional capacity did not differ between groups. It is concluded that PA is a frequent complication in SNSA; however, its presence does not seem to modify the functional prognosis of these patients.

Radiologic review: the cervical spine in juvenile rheumatoid arthritis.

In our patients, zygapophyseal joint fusion was the most frequent and characteristic roentgenographic finding of cervical spine involvement in JRA. It was not associated with any subset of patients. Atlanto-dens interval greater than 4.5 mm was present in 20% of patients, but was not related to the development of neurologic manifestations. Mild enthesopathic-like changes around the upper cervical area were observed in some children. In patients with severe long standing disease and extensive zygapophyseal joint fusion, longitudinal ligament calcification was observed. Growth disturbances of the cervical spine were more frequently observed in patients with zygapophyseal joint fusion and earlier onset of disease.

Prospective study of the early course of rheumatoid arthritis in young adults: comparison of patients with and without rheumatoid factor positivity at entry and identification of variables correlating with outcome.

The early course of newly diagnosed RA among young adult patients (16-44 yr) is described from results of an ongoing study with a mean follow-up of 3.4 yr. Study diagnosis was based on the judgement of experienced rheumatologists, and data on several hundred variables were obtained on entry and annually for the purpose of defining patterns of onset and course of disease. Race and sex factors, as well as certain entry manifestations, e.g., RF, were found to correlate with onset and course patterns. Females, and especially white females, had significantly greater numbers of swollen upper extremity joints than males at entry and at last observation, with increased likelihood of developing bone erosions. At entry, RF positive patients differed only on few articular manifestations from RF negative patients, but had a higher frequency of positive ANA at entry and more subcutaneous nodules and bone erosions during follow-up. Seropositive white females at entry had significantly more swollen upper joints than their seronegative counterparts, but with no difference found at last follow-up. White females of each serogroup had more joint involvement at last examination than patients of other race-sex groups. Males had more acute onset, especially under age 30, with significantly greater improvement in arthritis and in ESR than did females. The majority (55%) of patients entered as seropositive, converted to seronegative during follow-up, and no correlation of either joint swelling or erosions was noted with this phenomenon. At last visit, RF positively did not correlate with bone erosions, but patients developing bone erosions had higher frequency of ANA and higher mean serum complement levels at last examination. The following entry factors were found to correlate significantly with a better outcome: maleness, acute onset under age 30, less swollen upper joints, and negative RF. Type of drug therapy tended to reflect severity of arthritis, rather than vice versa, and functional capacity improved significantly from entry to last evaluation in both males and females, even though the latter had stable or progressive arthritis. Further study is necessary over long intervals and in wider age range to more adequately interpret the biologic implications of findings of this ongoing study. A better understanding of the pathogenesis of RA may be derived from critical studies of the contribution of host factors, e.g., sex, and other variables predisposing to the development of RF positivity (and ANA), subcutaneous nodules, and bone erosions, particularly in systematic ongoing studies of patients with early diagnosed disease.

Spinal artery steal syndrome in Paget's disease of bone.

We report a case of vertebral Paget's disease with paraplegia and no evidence of spinal cord compression, in which the neurological condition improved dramatically after treatment with calcitonin. Spinal cord vascular steal syndrome is suggested as another mechanism responsible for this neurologic complication.

Juvenile onset Reiter's syndrome. A retrospective study of 26 patients.

Clinical, laboratory and radiological findings were evaluated in 26 children with Reiter's syndrome, all of whom met the 1982 diagnostic criteria of A. Calin. Twenty-two of the patients (85%) were male and 4 were female (15%); the mean age at onset was 10.5 years (range 4-15.5 yrs). Mean follow-up time was 28.6 months. Diarrhea prior to onset was observed in 18 cases (69%), but there was no report of venereal disease. The full classic triad was initially observed in only 9 patients (35%), urethritis alone in 6 (23%) and conjunctivitis alone in 4 (15%). Arthritis was present in all patients, with the lower limb joints involved in 25 cases (96%); the pattern was pauciarticular in 18 (69%), polyarticular in 7 (27%) and monoarticular in one (4%). There was complete remission in 15 out of the 26 patients (58%), while a sustained and fluctuating course was seen in 7 (27%) and 3 (11.5%) patients, respectively; a single patient showed a remitting course. Balanitis was present in 11 out of the 22 male (50%) cases. Twelve out of 18 patients tested (67%) proved to be HLA B27 positive and there was radiological evidence of sacroiliitis in 5 out of 24 patients (21%). Reiter's syndrome should be included in the differential diagnosis of the arthritic child. As a rule, the course of joint involvement is remittent and sequelae affecting functional capacity are indeed exceptional.

Lymphadenopathy secondary to silicone hand joint prostheses.

The occurrence of lymphadenopathies was investigated in 23 patients with diverse rheumatic conditions who had silastic prosthesis in joints of the hands, to determine whether these adenopathies were due to the presence of silicone particles. Five cases had clinically detectable lymph node enlargement and tissue samples were studied by light and scanning electron microscopy (SEM) and energy dispersive X-ray analysis (EDXA). In 3 out of the 5 cases foreign body granulomas were observed by light microscopy, SEM showing a highly irregular distribution of foreign body material with a peak for silicone by EDXA. Foreign body particle distribution closely correlated with silicone concentration. No granulomas were found in the two remaining patients with adenopathies who presented a non-specific reactive lymphadenitis. Our findings show that silicone lymphadenopathy is a more frequent complication (13%) of silastic arthroplasty than is usually recognized and therefore should be considered in the differential diagnosis of patients with lymph node enlargement who have previously received a silicone arthroplasty.

Adult Still's disease and inflammatory myositis.

Although myalgias occur often in adult onset Still's disease (AOSD), inflammatory myositis is rare. We describe a 41-year-old female with AOSD, who had clinical, enzymatic, electromyographic and pathological evidence of myositis, fulfilling the diagnostic criteria for polymyositis. To our knowledge, this exceptional association has only once been reported before.

Ectopic ossification following total hip replacement in juvenile chronic arthritis.

Of twenty-one patients with juvenile chronic arthritis (seventeen with juvenile rheumatoid arthritis and four with juvenile ankylosing spondylitis) who had total hip replacement before the age of thirty years, thirteen patients (62 per cent) showed different degrees of ectopic ossification: nine (53 per cent) of the seventeen with juvenile rheumatoid arthritis and all four of those with juvenile ankylosing spondylitis. Human leukocyte antigen B5 was found with an increased frequency in the patients with ectopic ossification. Functional capacity was not impaired regardless of the severity of the ectopic ossification. As in patients with adult-onset disease, ectopic ossification after total hip replacement occurred with a higher frequency in the patients with juvenile-onset ankylosing spondylitis than in those with juvenile-onset rheumatoid arthritis.

Idiopathic osteoporosis during pregnancy.

Among the idiopathic forms of osteoporosis, the one developing during pregnancy is the least common and scarcely studied. Poorly understood, it seems to stem from transient failure of calcitropic hormones and decreased osteoblast activity. A 25-year-old patient presented with coxofemoral pain during the last three months of pregnancy, followed by multiple vertebral compression fractures at postpartum. Laboratory, radiological, densitometric and histological examinations led to a diagnosis of idiopathic osteoporosis in pregnancy, once other causes of osteopenia had been ruled out. Bone densitometries performed 12 and 24 months later showed an increase in mineral density, thus demonstrating the self-limited nature of this entity.

Neurological features in overlap syndrome.

We report the frequency of neurological findings in 33 patients with overlap syndrome and describe 2 patients presenting unusual neurological involvement. Five of the 33 patients (15%) had one or more neurological findings. Unilateral trigeminal sensory neuropathy was presents, in 4 patients, in 3 of whom this was the only neurological feature. In the other patient it was associated with other manifestations of central as well as peripheral nervous system involvement, with an overall clinical pattern highly suggestive of a demyelinating disorder. The fifth patient, after an aseptic meningitis-like illness, developed a slowly progressive paraparesis, likewise pointing to a demyelinating disease. Our findings suggest that neurological manifestations, mainly trigeminal neuropathy, are frequent features in overlap syndrome; occasionally, central nervous system involvement mimicking a demyelinating disease may also be observed.

Protrusio acetabuli in adult rheumatoid arthritis.

In a retrospective study of 100 patients with adult rheumatoid arthritis, 23/100 (23%) were found presenting protrusio acetabuli (PA). PA of the hips was present in 28/193 (14.5%). This complication was more frequent in females, with 19/23 cases (82%), and its presence and severity were associated with longer duration of disease. On analysing the probable relationship between PA and glucocorticoid intake, no statistically significant differences were found between patients who had received such drugs and those who had not. With the method employed and in a selected rheumatoid arthritis population, PA was found in high prevalence.

Protrusio acetabuli in juvenile rheumatoid arthritis.

Acetabular protrusion (PA) as measured by a line crossing method was studied in 73 patients with juvenile rheumatoid arthritis (JRA) and its frequency found to be 12% (9/73), presenting bilaterally in 5 cases and unilaterally in 4. All patients had some other forms of radiological damage and the presence of PA was predominantly observed in the JRA group with greater age at onset (8 vs 4.2 years; p < 0.001) and lower frequency of extraarticular manifestations (22% vs 72%; p < 0.01). There was no correlation with type of JRA onset, course of disease, sex, disease duration, seropositivity for rheumatoid factor, and prior steroid intake.

Rheumatoid nodulosis: a puzzling variant of rheumatoid arthritis.

Four patients with rheumatoid nodulosis are here described, together with a review of cases reported to date in the literature. This particular variant of rheumatoid arthritis (RA) is characterized by the presence of subcutaneous rheumatoid nodules, scanty or absent systemic manifestations and a clinically benign course. Joint involvement appears more commonly as palindromic rheumatism, although patients with arthralgia episodes alone and others with chronic polyarthritis have been described. Seldom reported up to now, a consideration of this entity may help to avoid diagnostic pitfalls and the use of aggressive therapy.

Joint involvement in polymyositis/dermatomyositis.

The frequency and features of joint involvement were evaluated in 29 patients with polymyositis/dermatomyositis (PM/DM); eight of them (27.5%) presented arthritis. Mean age was 30 years, and mean disease duration was 5.3 years. Oligoarthritis was observed in 5 cases, while 3 presented polyarthritis; in most cases arthritis was concurrent with the musculocutaneous picture. On comparing the 8 arthritis patients with the remaining 21, no significant clinical or serological differences were found. However, males predominated in the arthritis group, 75% vs 19% (p < 0.05). Arthritis responded favourably to underlying disease treatment and articular sequelae were not observed.