The Clinical Value of Measuring Circulating HPV DNA during Chemo-Radiotherapy in Squamous Cell Carcinoma of the Anus.

BACKGROUND AND PURPOSE: Circulating tumor DNA (ctDNA) is investigated in various cancers. In squamous cell carcinoma of the anus (SCCA) infection with human papilloma virus (HPV) is found in around 90% of cases and here, plasma HPV (pHPV) can be used as ctDNA. Preliminary data have proved the ability to detect pHPV16 and -18 in SCCA. We have developed a highly sensitive method for measurement of six relevant pHPV subtypes, to investigate the elimination pattern of pHPV during chemo-radiotherapy (CRT) for SCCA and its clinical value. MATERIAL AND METHODS: Patients treated at Aarhus University Hospital from 2016-2020 were included. P16 status in the primary biopsy was measured and 82% of patients had P16 positive tumor. Blood samples were collected prior to treatment (PT), mid treatment (MT), end of therapy (EOT), and during follow-up (FU). An in-house multiplex digital droplet PCR method measured pHPV subtypes 16, 18, 31, 33, 51, 58. RESULTS: Samples from 88 patients were drawn PT (n = 73), MT (n = 72), EOT (n = 64) and during FU (n = 41). Plasma HPV was detectable in 52 patients and PT pHPV levels correlated to tumor stages. Three elimination patterns were observed during CRT with correlation to outcome: fast responders with no local or distant failures (0/12); slow responders with high risk of local failures (4/20), no distant failures; persistent molecular responders with high risk of distant failures (4/13), but no local failures, p < 0.01. CONCLUSION: During CRT, pHPV can divide patients with SCCA into three groups with significantly different risk of failure. The use of pHPV can potentially assist in clinical treatment decision.

Significant Individual Variation Between Pathologists in the Evaluation of Colon Cancer Specimens After Complete Mesocolic Excision.

BACKGROUND: After the introduction of complete mesocolic excision, a new pathological evaluation of the resected colon cancer specimen was introduced. This concept has quickly gained acceptance and is often used to compare surgical quality. The grading of colon cancer specimens is likely to depend on both surgical quality and the training of the pathologist. OBJECTIVE: The purpose of this study was to validate the principles of the pathological evaluation of colon cancer specimens. DESIGN: This was an exploratory study. SETTINGS: The study was conducted in Aarhus, Denmark, and Leeds, United Kingdom. PATIENTS: Colon cancers specimens were used. MAIN OUTCOME MEASURES: The agreement of gradings between participants was of interest. Four specialist GI pathologists and 2 abdominal surgeons evaluated 2 rounds of colon cancer specimens, each at 2 separate time points. Each round contained 50 specimens. After the first round, a protocol of detailed principles for the grading procedure was agreed on. Results from an experienced pathologist were considered as the reference results. RESULTS: In the first round, the distribution of gradings between participants showed substantial variation. In the second round, the variation was reduced. Intraobserver agreement was mostly fair to good, whereas interobserver agreement was frequently poor. This did not significantly change from round 1 to round 2. LIMITATIONS: The small sample size of 100 specimens provided a very small number of specimens resected in the muscularis propria plane, which renders the evaluation of this group potentially unreliable. The evaluations were made on photos and not on fresh specimens. CONCLUSIONS: This study demonstrates significant variation in the pathological evaluation of colon cancer specimens. It demonstrates that it cannot be used in clinical studies, and care should be taken when comparing results between different hospitals.

The relation between histopathological classification and renal outcome, ANCA subtype and treatment regimens in ANCA-associated vasculitis.

OBJECTIVES: ANCA-associated vasculitis (AAV) is associated with an increased risk of death and end stage renal disease (ESRD). The aim of this study was to examine the correlation between a histopathological classification and renal outcome and to describe the interaction with ANCA subtype and initial treatment. METHODS: Eighty-seven patients with AAV from 1999-2010 from two centres in Denmark were included in the study and had a 3 year follow-up. Data was collected retrospectively. The renal biopsies were reclassi ed into one of the following groups: crescentic, sclerotic, focal and mixed. RESULTS: Histopathologic groups were not associated with eGFR at three years. Age and baseline eGFR were independent prognostic for eGFR at three years. More patients in the crescentic group than in the mixed and focal groups developed ESRD (33%, 13% and 5% respectively). Patients reaching ESRD had few- er non-affected glomeruli (14 % vs. 34%, p=0.0014) and lower eGFR at baseline (7 vs. 21.7 ml/min/m(2), p<0.0001). At baseline MPO-ANCA positive patients were older, had more sclerotic glomeruli and had a lower eGFR after three years compared to PR3-ANCA positive patients. PR3-ANCA positive patients receiving plasma exchange (PE) improved eGFR more from baseline to three years than those not receiving PE (36 vs. 20 ml/min/m2, p=0.01). CONCLUSIONS: In our cohort most pa- tients in the crescentic group and fewer in the focal group reached ESRD. Age and baseline eGFR are prognostic of renal function after 3 years, as also in the PR3-ANCA positive subgroup initial treatment with PE.

Fast detection of renal ischemia in transplanted kidneys with delayed graft function-an experimental study.

BACKGROUND: The newly transplanted kidney is difficult to monitor with regard to postoperative vascular thrombosis, especially when there is delayed graft function. We evaluated microdialysis as a tool for early ischemia detection in porcine kidneys with delayed graft function early after transplantation. METHODS: Sixteen pigs were transplanted with 26-hr cold ischemia kidneys. A microdialysis catheter was placed in the lateral renal cortex. Five hours after graft reperfusion, the pigs were randomized to renal arterial clamping or open artery, n=8 in each group, and further observed for 2 hr. RESULTS: The diuresis and glomerular filtration rate were low and decreasing throughout the study, with no significant differences between groups. Until arterial clamping, there were no significant differences in the development of local renal metabolites between the two groups. Renal artery clamping immediately caused significantly different development of all metabolites (P<0.02 for all) compared to the open artery group. After clamping, levels of glutamate and glycerol were significantly increased within 30 min (P=0.0049 and P=0.0061, respectively). CONCLUSIONS: Microdialysis provided an early warning of arterial occlusion in transplanted grafts with delayed graft function. It may become a valuable tool for postoperative monitoring and detection of thrombosis after renal transplantation.

Early plasma exchange improves outcome in PR3-ANCA-positive renal vasculitis.

OBJECTIVES: Plasma exchange (PE) has been shown to improve renal outcome in anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) and severe renal failure; however the effect of PE in AAV with moderate renal impairment is controversial. METHODS: A single-centre, retrospective one-year follow-up study, including patients with renal AAV and eGFR <60 ml/min/1.73 m2. Since 2007, all patients with renal AAV and eGFR <60 ml/min/1.73 m2 had PE in addition to induction therapy with cyclophosphamide and prednisolone. Patients admitted from 1999 to 2007 that did not receive PE served as controls. The primary outcome was the combination of death, end-stage renal disease, and relapses after one year. RESULTS: A significant reduction in the primary endpoint was observed following the addition of PE (25% vs. 43%, p=0.04). Furthermore, a greater improvement in renal function after one year was observed among surviving PE treated patients not on dialysis (ΔeGFR 36.1 vs. 19.7 ml/min, p=0.03). There was a significant reduction in serious adverse events in the PE treated group (4% vs. 30%, p=0.02) despite no differences in types and doses of induction immunosuppressive therapy. The advantageous effect of PE was related to the presence of anti-proteinase3 (PR3)-antibodies and also evident among patients with plasma creatinine less than 500 µM. CONCLUSIONS: This study suggests the use of PE in addition to standard induction treatment with cyclophosphamide and glucocorticoids to patients with renal PR3-AAV and an estimated-GFR <60 ml/min/1.73m2.