Unraveling the potential clinical utility of circulating tumor DNA detection in colorectal cancer-evaluation in a nationwide Danish cohort.

BACKGROUND: Increasingly, circulating tumor DNA (ctDNA) is proposed as a tool for minimal residual disease (MRD) assessment. Digital PCR (dPCR) offers low analysis costs and turnaround times of less than a day, making it ripe for clinical implementation. Here, we used tumor-informed dPCR for ctDNA detection in a large colorectal cancer (CRC) cohort to evaluate the potential for post-operative risk assessment and serial monitoring, and how the metastatic site may impact ctDNA detection. Additionally, we assessed how altering the ctDNA-calling algorithm could customize performance for different clinical settings. PATIENTS AND METHODS: Stage II-III CRC patients (N = 851) treated with a curative intent were recruited. Based on whole-exome sequencing on matched tumor and germline DNA, a mutational target was selected for dPCR analysis. Plasma samples (8 ml) were collected within 60 days after operation and-for a patient subset (n = 246)-every 3-4 months for up to 36 months. Single-target dPCR was used for ctDNA detection. RESULTS: Both post-operative and serial ctDNA detection were prognostic of recurrence [hazard ratio (HR) = 11.3, 95% confidence interval (CI) 7.8-16.4, P < 0.001; HR = 30.7, 95% CI 20.2-46.7, P < 0.001], with a cumulative ctDNA detection rate of 87% at the end of sample collection in recurrence patients. The ctDNA growth rate was prognostic of survival (HR = 2.6, 95% CI 1.5-4.4, P = 0.001). In recurrence patients, post-operative ctDNA detection was challenging for lung metastases (4/21 detected) and peritoneal metastases (2/10 detected). By modifying the cut-off for calling a sample ctDNA positive, we were able to adjust the sensitivity and specificity of our test for different clinical contexts. CONCLUSIONS: The presented results from 851 stage II-III CRC patients demonstrate that our personalized dPCR approach effectively detects MRD after operation and shows promise for serial ctDNA detection for recurrence surveillance. The ability to adjust sensitivity and specificity shows exciting potential to customize the ctDNA caller for specific clinical settings.

Variations in the definition and perceived importance of positive resection margins in patients with colorectal cancer - an EYSAC international survey.

INTRODUCTION: Microscopically positive resection margins (R1) are associated with poorer outcomes in patients with colorectal cancer. However, different definitions of R1 margins exist. It is unclear to what extent the definitions used in everyday clinical practice differ within and between nations. This study sought to investigate variations in the definition of R1 margins in colorectal cancer and the importance of margin status in clinical decision-making. MATERIALS AND METHODS: A 14-point survey was developed by members of The European Society of Surgical Oncology (ESSO) Youngs Surgeons and Alumni Club (EYSAC) Research Academy targeting all members of the multidisciplinary team (MDT) treating patients with colorectal cancer. The survey was distributed on social media, in ESSO's monthly newsletter and via national societies. RESULTS: In total, 137 responses were received. Most respondents were from Europe (89.7%), with the majority from Denmark (56.9%). Less than 2/3 of respondents defined R1 margins as the presence of viable cancer cells ≤1 mm of the margin. Only 60% reported that subdivisions of R1 margins (primary tumour vs tumour deposit vs metastatic lymph node) are routinely available. More than 20% of respondents reported that pathology reports are not routinely reviewed at MDT meetings. Less than half of respondents considered margin status in decision-making for type and duration of adjuvant chemotherapy in Stage III colon cancer. CONCLUSION: The definitions and perceived clinical importance of microscopically positive margins in patients with colorectal cancer appear to vary. Adoption of an international dataset for pathology reporting may help to standardise current practices.

Differences in adjuvant chemotherapy and oncological outcomes according to margin status in patients with stage III colon cancer.

BACKGROUND: Microscopically positive margins to lymph node metastases (R1LNM) are associated with poorer oncological outcomes in patients with Stage 3 colon cancer. These poorer outcomes were seen despite a greater proportion of these patients receiving adjuvant chemotherapy when compared to those with microscopically negative (R0) margins. We sought to determine if differences in the type or duration of adjuvant chemotherapy could account for the differences in outcomes seen between patients with R0 and R1LNM margins. METHODS: A multicentre retrospective study including patients undergoing surgery for Stage 3 colon cancer between 2016-2019 at specialist centres. Patients were stratified according to margins status (R0 vs R1LNM). Type/duration of chemotherapy and oncological outcomes were compared between groups. RESULTS: 718 patients were included, of whom 100 had R1LNM margins (13.1%). Patients with R1LNM margins had significantly poorer 3-year distant metastases-free (R0 78.2% (95% CI 74.5-81.3) versus R1LNM 58.8% (95% CI 47.2-68.6), p < 0.001) and disease specific survival (R0 88.3% (95% CI 85.2-90.9) versus R1LNM 78.5% (95% CI 68.0-85.8), p < 0.001) when compared to those with R0 margins. No differences were noted in the proportion of patients who completed long-course chemotherapy or were treated with oxaliplatin-based combinations between the R1LNM and R0 groups. Differences in outcomes between R0 and R1LNM groups persisted even when only those patients who completed long-course chemotherapy were compared. DISCUSSION: Differences in adjuvant chemotherapy do not appear to account for the poorer oncological outcomes seen in patients with R1LNM margins after surgery for Stage 3 colon cancer. This suggests that adjuvant chemotherapy may be less effective in this patient group. Further studies to elucidate a potential biological basis for this difference are warranted.

[Practice guideline for patients with hyperuricemia/gout].

Hyperuricemia/gout is a common metabolic disease in China, which is a serious threat to people's health. In clinical practice, the standardization of prevention and diagnosis and the rate of treat-to-target need to be improved. There is still a lack of education for the patients about the understanding of clinical guidelines, the disease knowledge and the importance of cooperating with doctors to carry out diagnosis and treatment. From the most concerned issues of the patients, we established the hyperuricemia/gout patient practice guideline working group with multidisciplinary physicians and patients. Seventeen opinions, as the hyperuricemia/gout patient practice guidelines, are proposed in accordance with the relevant principles of the "WHO guidelines development manual" , and with the international normative process, aiming to improve the patients compliance, improve the level of health management of the disease.

X-ray diffraction analysis of spontaneously draining calcinosis in scleroderma patients.

OBJECTIVES: Calcium hydroxyapatite (HA) is reported to be the major constituent of soft tissue calcinosis in patients with scleroderma (systemic sclerosis, SSc). Mechanical stress and local tissue hypoxia are thought to be important in the pathogenesis of SSc calcinosis. We sought to analyse spontaneously draining material from calcinosis sites in SSc patients using X-ray diffraction (XRD). METHOD: With approval from our local Institutional Review Board (IRB), eligible SSc patients consented to submit their spontaneously draining calcinosis samples for XRD analysis. All patients met the American College of Rheumatology (ACR) criteria for definite SSc. XRD data were used to determine how much solid phase was present (e.g. HA vs. other calcium phosphate phases) and the percentage of crystalline components. Pertinent clinical data were collected. RESULTS: Draining calcinosis was submitted mostly from the hands of 10 female patients with advanced SSc, whose mean disease duration was 16 (range 9-29) years; six had diffuse cutaneous SSc and four had limited SSc. All 10 developed calcinosis later in their disease course; seven had extensive deposits affecting multiple sites. XRD confirmed that HA was the only crystalline material. However, HA was the minor component and most samples contained more than 50% organic material. Solid samples generally contained more HA and fluid samples contained HA in suspension. CONCLUSIONS: In this large series of SSc calcinosis analysis, XRD confirmed that HA was the only inorganic material that formed less than 50% of most draining samples. More research is needed to fully characterize and improve our understanding of calcinosis formation in SSc.

Does acute synovitis (pseudogout) occur in patients with chronic pyrophosphate arthropathy (pseudo-osteoarthritis)?

OBJECTIVES: Pyrophosphate arthropathy has been linked to diverse clinical subtypes. The two most common are: acute synovitis (pseudogout) and chronic pyrophosphate arthropathy ("pseudo-osteoarthritis"). We have conducted a study to examine whether these are overlapping syndromes. METHODS: We reviewed all synovial fluid (SF) analyses performed in our laboratory from January 1988 to May 1997 to determine if patterns of SF leukocyte counts and Alizarin red stains in patients with repeated samples suggest that some patients were prone to acute attacks and some to chronic pyrophosphate arthropathy and whether acute attacks superimposed on chronic symptoms were common. Joint x-rays were screened for osteoarthritis (OA) and chondrocalcinosis. RESULTS: We identified 67 patients who had Calcium pyrophosphate dehydrate (CPPD) in their SF and had more than one SF examined (185 SF). We divided the patients into 2 groups. Group A (n=25) had at least one SF leukocyte count > than 2000 per mm(3) and group B (n=42) had SF leukocyte counts always < than 2000 per mm(3). Chondrocalcinosis detected on x-ray was more common in group A versus group B, 48% versus 19% (p<0.05, Fisher's exact test). OA was mild (grades 0-1) in 39% of group A versus 12.5% of group B patients, but the difference between groups was not significant. CPPD crystals were not detected in 13.5% SFs previously having CPPD crystals. Alizarin red staining for suspected hydroxyapatite was more often 2+ to 3+ in group B (31.6%) compared to group A (15.5%; p<0.05, Fisher's exact test). CONCLUSION: Acute synovitis and chronic pyrophosphate arthropathy are often two distinctive syndromes with some patients never having inflammatory attacks. Acute synovitis is more common in patients with chondrocalcinosis while chronic pyrophosphate arthropathy is associated with increased alizarin red staining and a trend suggestive of increased severity of OA.

A modified Delphi exercise to determine the extent of consensus with OMERACT outcome domains for studies of acute and chronic gout.

OBJECTIVES: To reach consensus with recommendations made by an OMERACT Special Interest Group (SIG). METHODS: Rheumatologists and industry representatives interested in gout rated and clarified, in three iterations, the importance of domains proposed by the OMERACT SIG for use in acute and chronic gout intervention studies. Consensus was defined as a value of less than 1 of the UCLA/RAND disagreement index. RESULTS: There were 33 respondents (61% response rate); all agreed the initial items were necessary, except "total body urate pool". Additional domains were suggested and clarification sought for defining "joint inflammation" and "musculoskeletal function". Items that demonstrated no clear decision were re-rated in the final iteration. There were six highly rated items (rating 1-2) with four slightly lower rating items (rating 3) for acute gout; and 11 highly rated items with eight slightly lower ratings for chronic gout. CONCLUSIONS: Consensus is that the following domains be considered mandatory for acute gout studies: pain, joint swelling, joint tenderness, patient global, physician global, functional disability; and for chronic gout studies: serum urate, gout flares, tophus regression, health-related quality of life, functional disability, pain, patient global, physician global, work disability and joint inflammation. Several additional domains were considered discretionary.

Diagnosis of gout by ultrasound.

OBJECTIVES: To establish the usefulness of ultrasonography (US) for diagnosing gout and to determine whether there are sonographic features that are characteristic for gout but not for other arthropathies. METHODS: We retrospectively compared joint images of gout patients with matching images from patients with other rheumatic conditions. Images of 37 joints of 23 patients with monosodium urate (MSU) crystal-proven gout were reviewed. MSU crystals were identified in at least one joint in each patient. Our control group had 23 randomly selected patients with 33 examined joints with rheumatic conditions other than gout. RESULTS: Specific diagnostic features included a hyperechoic, irregular band over the superficial margin of the articular cartilage described as a double contour sign in 92% of gouty joints and in none of the controls (P < 0.001); hypoechoic to hyperechoic, inhomogeneous material surrounded by a small anechoic rim, representing tophaceous material, was seen in all gouty metatarsophalangeal (MTP) joints, in all metacarpophalangeal (MCP) joints and in none of the controls (P < 0.001); erosions adjacent to tophaceous material were seen in 65% of MTP joints and in 25% of MCP joints. One erosion was seen in a MTP joint in a control patient with psoriatic arthritis. CONCLUSIONS: US can detect deposition of MSU crystals on cartilaginous surfaces (P < 0.001) as well as tophaceous material and typical erosions. US may serve as a non-invasive means to diagnose gout.

Diagnosis of gout.

Acute gouty arthritis typically presents with rapid development of severe joint pain, swelling, and tenderness that reaches its maximum within just 6-12 h, especially with overlying erythema, most classically in the first metatarsophalangeal joint. Demonstrating the presence of monosodium urate (MSU) crystals in the joint fluid or tophus has been the gold standard for the diagnosis of gout. However, many physicians do not perform synovial fluid analysis. In the absence of demonstrating the presence of MSU crystals in aspirated joint fluid or tophus clinical, radiological and laboratory criteria are helpful. This paper presents an overview of the various classification criteria, clinical presentations, laboratory and radiological studies needed to make the diagnosis of gout.

Colchicine for acute gout.

BACKGROUND: Gout is one of the most common rheumatic diseases worldwide. Colchicine is regarded as beneficial in the treatment of acute gout, but has a high frequency of gastrointestinal adverse events. OBJECTIVES: To evaluate the efficacy and safety of colchicine for relief of the signs and symptoms of acute gouty arthritis, compared to placebo and other treatment interventions. SEARCH STRATEGY: We searched the following electronic databases to March 2006: Cochrane Central Register of Controlled Trials (CENTRAL, Issue 1, 2006), MEDLINE (from 1966), EMBASE (from 1980), CINAHL (from 1982), AMED (from 1985), Web of Science (from 1945) and Current Controlled Trials. SELECTION CRITERIA: Published randomised controlled trials (RCTs) and controlled clinical trials evaluating symptom relief and adverse outcomes of colchicine therapy in acute gout were considered for this review. DATA COLLECTION AND ANALYSIS: Two reviewers independently screened search results for inclusion, collected the data in a standardized form and assessed the methodological quality of the trial using validated criteria. Results for continuous outcome measures were expressed as weighted mean differences. Dichotomous outcome measures were pooled using relative risk. The number needed to treat was calculated for significant outcomes. MAIN RESULTS: One RCT (N=43) comparing colchicine to placebo for the treatment of acute gout was included in this review. The results favour the use of colchicine over placebo with an absolute reduction of 34% for pain and a 30% reduction in clinical symptoms such as tenderness on palpation, swelling, redness, and pain. The number needed to treat (NNT) with colchicine versus placebo to reduce pain was 3 and the NNT to reduce clinical symptoms was 2. All participants treated with colchicine experienced gastrointestinal side effects (diarrhea and/or vomiting) and the number needed to harm (NNH) with colchicine versus placebo was 1. No studies comparing colchicine to NSAIDs or other treatments such as corticosteroids or ACTH were identified. AUTHORS' CONCLUSIONS: Colchicine is an effective treatment for the reduction of pain and clinical symptoms in patients experiencing acute attacks of gout, although in the regimen studied its low benefit to toxicity ratio limits its usefulness. It should be used as a second line therapy when NSAIDs or corticosteroids are contraindicated or ineffective. More evidence is needed to compare the efficacy of colchicine to that of NSAIDs or corticosteroids, the current first line therapy for acute gout.

Nail involvement in pemphigus vulgaris.

BACKGROUND: Involvement of the nail unit in pemphigus vulgaris (PV) is thought to be rare. OBJECTIVES: To determine the frequency of nail changes among patients with PV. METHODS: Nail changes were recorded in patients with PV and were analysed retrospectively. Biopsies were taken from the nail bed and nail matrix for histological and immunofluorescence observations. Microscopic (potassium hydroxide) examination and fungal culture were performed. RESULTS: Nail changes were present in 30 of 64 (47%) patients with PV. Sixteen patients had onychomycosis and 14 had nail changes due to PV. These included onychomadesis, discoloration, deformity, onychorrhexis, onycholysis, subungual haemorrhage, subungual hyperkeratosis and paronychia. Onychomycosis affected fingernails and toenails, but changes due to PV occurred only in fingernails, most commonly on the thumb and index finger. No connection was found between the patient's occupation and nail involvement, and there was no correlation with the severity or duration of PV. In a control group of 64 patients of similar sex and age, only two had non-specific fingernail changes. CONCLUSIONS: Nail changes in PV may be more frequent than previously thought.

Gout: can management be improved?

Ongoing reviews of Cochrane collaboration show that there is still very little reliable information based on randomized controlled trials on which to base treatment decisions in acute and chronic gout. Recent studies have stressed that avoidance of factors contributing to development of gouty attacks such as diuretic therapy, weight gain, and alcohol consumption may lead to a decrease in gouty arthritis. Attention to minidose aspirin and its effect on serum uric acid levels was addressed. A low carbohydrate, high protein and unsaturated fat diet was recommended for gouty patients since they all enhance insulin sensitivity and therefore may promote a reduction in serum uric acid levels. Treatment of gout in transplant recipients brings into focus some of the issues regarding management of gout, because gout is a common problem among transplant patients.

Lytic Bone Lesions as a Prominent Feature in Waldenstrom's Macroglobulinemia.

We report a patient with Waldenstrom's macroglobulinemia who had diffuse plasmacytoid infiltration in the bone marrow, immunoglobulin M monoclonal gammopathy, wide-spread osteolytic lesions, recurrent pathologic fractures, and diffuse subcutaneous soft tissue calcifications. The bony lesions were even more pronounced than those usually seen with multiple myeloma and are a rare manifestation of this disease. Such malignant plasma-cell dyscrasia with macroglobulinemia and lytic osseous lesions is best handled clinically according to its general presenting features rather than according to whether it is Waldenstrom's macroglobulinemia or an immunoglobulin M myeloma. The bone lesions may require local palliative radiotherapy and orthopedic measures.

How well have diagnostic tests and therapies for gout been evaluated?

The first descriptions of gout can be traced to the dawn of recorded medical history, yet a number of controversies and unanswered questions remain regarding diagnosis and treatment of gout. Questions can still be posed about the need for crystal identification of all cases, the utility of a 24-hour urine collection for uric acid, and even the difficulty of choosing a technique for measurement of uric acid. Some time has elapsed since Mesner stated in 1623, "Love and gout are incurable." How far have we come? How have we evaluated different treatments for gout? Ongoing reviews of the Cochrane collaboration show that there is still very little reliable information based on randomized controlled trials on which to base treatment decisions in acute and chronic gout.

Acute gouty arthritis is seasonal.

OBJECTIVE: Information regarding effect of weather conditions on gout is sparse. We conducted a study in the USA to examine whether gout is seasonal. METHODS: We reviewed synovial fluid (SF) analyses from our laboratory during 1990-1995 and identified 359 patients who had acute gouty attacks. All fluids of patients with acute gout had intracellular monosodium urate crystals and SF leukocyte counts > 2000/mm3 or more than 10 leukocytes per high power field (HPF). Retrospective chart review of all patients was performed to confirm a clinical picture of acute gout. A control group included 76 patients with acute pseudogout whose SF were analyzed during the same period and who had intracellular calcium pyrophosphate crystals and inflammatory leukocyte counts as in patients with gout. RESULTS: Acute gout was most common during the spring; n = 115 (32%). Ninety (25%) patients had acute gout attacks in the fall; 81 (23%) had acute attacks during the summer; 73 (20%) had acute attacks in the winter. One-way analysis of variance (ANOVA) was used to compare the overall frequency of acute gout during the months and seasons. Using ANOVA, there was no overall statistically significant difference in the incidence of gout per season (p = 0.07), although it approached statistical significance. Acute gouty attacks were more common in the spring compared with winter (p = 0.002) and summer (p = 0.015). There was a trend but no statistically significant difference compared with fall. Winter was the season in which the fewest acute gouty cases were seen, although it was not statistically significant. No seasonal difference was seen in the pseudogout group. There was no correlation between either mean monthly temperature or humidity and the incidence of acute gouty attacks. CONCLUSION: Acute gout attacks are significantly more common in the spring. No seasonal variation was seen in patients with acute pseudogout attacks.