Taxonomic reclassification of Kaposi Sarcoma identifies disease entities with distinct immunopathogenesis.

BACKGROUND: The taxonomy of Kaposi Sarcoma (KS) is based on a classification system focused on the description of clinicopathological features of KS in geographically and clinically diverse populations. The classification includes classic, endemic, epidemic/HIV associated and iatrogenic KS, and KS in men who have sex with men (MSM). We assessed the medical relevance of the current classification of KS and sought clinically useful improvements in KS taxonomy. METHODS: We reviewed the demographic and clinicopathological features of 676 patients with KS, who were referred to the national centre for HIV oncology at Chelsea Westminster hospital between 2000 and 2021. RESULTS: Demographic differences between the different subtypes of KS exist as tautological findings of the current classification system. However, no definitive differences in clinicopathological, virological or immunological parameters at presentation could be demonstrated between the classic, endemic or MSM KS patients. Reclassifying patients as either immunosuppressed or non-immunosuppressed, showed that the immunosuppressed group had a significantly higher proportion of adverse disease features at presentation including visceral disease and extensive oral involvement, classified together as advanced disease (chi2 P = 0.0012*) and disseminated skin involvement (chi2 P < 0.0001*). Immunosuppressed patients had lower CD4 counts, higher CD8 counts and a trend towards higher HHV8 levels compared to non-immunosuppressed patients, however overall survival and disease specific (KS) survival was similar across groups. CONCLUSION: The current system of KS classification does not reflect meaningful differences in clinicopathological presentation or disease pathogenesis. Reclassification of patients based on the presence or absence of immunosuppression is a more clinically meaningful system that may influence therapeutic approaches to KS.

Local excision and treatment of early node-negative anal squamous cell carcinomas in a highly HIV prevalent population.

BACKGROUND: Anal squamous cell carcinoma (ASCC) is an uncommon cancer associated with human immunodeficiency virus (HIV) infection. There has been increasing interest in providing organ-sparing treatment in small node-negative ASCC's, however, there is a paucity of evidence about the use of local excision alone in people living with HIV (PLWH). The aim of this study was to evaluate the efficacy of local excision alone in this patient population. METHODS: We present a case series of stage 1 and stage 2 ASCC in PLWH and HIV negative patients. Data were extracted from a 20-year retrospective cohort study analysing the treatment and outcomes of patients with primary ASCC in a cohort with a high prevalence of HIV. RESULTS: Ninety-four patients were included in the analysis. Fifty-seven (61%) were PLWH. Thirty-five (37%) patients received local excision alone as treatment for ASCC, they were more likely to be younger (p = 0.037, ANOVA) and have either foci of malignancy or well-differentiated tumours on histology (p = 0.002, Fisher's exact test). There was no statistically significant difference in 5-year disease-free survival and recurrence between treatment groups, however, patients who had local excision alone and PLWH were both more likely to recur later compared to patients who received other treatments for ASCC. (72.3 months vs 27.3 months, p = 0.06, ANOVA, and 72.3 months vs 31.8 months, p = 0.035, ANOVA, respectively). CONCLUSIONS: We recommend that local excision be considered the sole treatment for stage 1 node-negative tumours that have clear margins and advantageous histology regardless of HIV status. However, PLWH who have local excision alone must have access to an expert long-term surveillance programme after treatment to identify late recurrences.

The prognostic and predictive role of hyponatremia in patients with advanced non-small cell lung cancer (NSCLC) with bone metastases.

PURPOSE: Hyponatremia and bone metastasis (BMs) are known as negative prognostic factors in patients affected by metastatic non-small cell lung cancer (NSCLC). Hyponatremia is associated with higher risk of osteoporosis and bone fracture, but no data are available about the relationship between hyponatremia and bone metastasis. This study aims to analyze the prognostic impact of hyponatremia in NSCLC patients with bone metastases. METHODS: We retrospectively collected data about advanced NSCLC patients. Survival curves were estimated using Kaplan-Meier method, and comparisons were made using chi-square test. RESULTS: Six hundred forty-seven patients were enrolled into the study. BMs were present in 264 patients (41%) at diagnosis, while hyponatremia appeared in 237 (37%) patients during the first-line treatment. Patients without BMs had a median overall survival (mOS) of 15.9 months (95% CI 14.1-17.9) versus 11.4 months (95% CI 9.4-13.4) for patients with BMs (p = 0.001). Eunatremic patients had a better outcome (mOS 16.3 months, 95% CI 14.6-18.0 vs 10.3 months, 95% I 7.6-12.8, p = 0.003). Considering the two variables, patients with BMs and hyponatremia had a mOS of 10.1 months (95% CI 4.3-15.9), patients with hyponatremia without BMs 11.9 months (95% CI 11.4-12.4), while mOS was 13.1 months (95% CI 12.0-14.2) for eunatremic patients with BMs versus 17.1 months (95% CI 15.2-19.1) in eunatremic patients without BMs (p = 0.0020). Hyponatremic patients developed metachronous BMs significantly earlier (3.73 vs 5.76 months, p = 0.0187). CONCLUSIONS: Our study showed that hyponatremia is an important prognostic factor and it should be necessarily considered to enhance the management of NSCLC patients with BMs.

The extent of B-cell activation and dysfunction preceding lymphoma development in HIV-positive people.

OBJECTIVES: B-cell dysfunction and activation are thought to contribute to lymphoma development in HIV-positive people; however, the mechanisms are not well understood. We investigated levels of several markers of B-cell dysfunction [free light chain (FLC)-κ, FLC-λ, immunoglobulin G (IgG), IgA, IgM and IgD] prior to lymphoma diagnosis in HIV-positive people. METHODS: A nested matched case-control study was carried out within the EuroSIDA cohort, including 73 HIV-positive people with lymphoma and 143 HIV-positive lymphoma-free controls. Markers of B-cell dysfunction were measured in prospectively stored serial plasma samples collected before the diagnosis of lymphoma (or selection date in controls). Marker levels ≤ 2 and > 2 years prior to diagnosis were investigated. RESULTS: Two-fold higher levels of FLC-κ [odds ratio (OR) 1.84; 95% confidence interval (CI) 1.19, 2.84], FLC-λ (OR 2.15; 95% CI 1.34, 3.46), IgG (OR 3.05; 95% CI 1.41, 6.59) and IgM (OR 1.46; 95% CI 1.01, 2.11) were associated with increased risk of lymphoma > 2 years prior to diagnosis, but not ≤ 2 years prior. Despite significant associations > 2 years prior to diagnosis, the predictive accuracy of each marker was poor, with FLC-λ emerging as the strongest candidate with a c-statistic of 0.67 (95% CI 0.58, 0.76). CONCLUSIONS: FLC-κ, FLC-λ and IgG levels were higher > 2 years before lymphoma diagnosis, suggesting that B-cell dysfunction occurs many years prior to lymphoma development. However, the predictive value of each marker was low and they are unlikely candidates for risk assessment for targeted intervention.

The albumin-bilirubin grade uncovers the prognostic relationship between hepatic reserve and immune dysfunction in HIV-associated hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is a leading cause of liver-related mortality in people living with HIV, where co-infection with hepatotropic viruses accelerates the course of chronic liver disease. AIM: To evaluate whether the albumin-bilirubin (ALBI) grade, a more accurate marker of liver dysfunction in HCC, might identify patients with progressive liver dysfunction in the context of HIV/hepatitis co-infection. METHODS: Using uni- and multi-variable analyses, we studied the albumin-bilirubin grade as a predictor of overall survival (OS) in a large, multi-center cohort of patients with HIV-associated HCC recruited from 44 centres in 9 countries within the Liver Cancer in HIV study group. Patients who underwent liver transplantation were excluded. RESULTS: A total of 387 patients, predominantly HCV co-infected (78%) with balanced representation of all Barcelona Clinic Liver Cancer (BCLC) stages (A = 33%, B = 18%, C = 37%, D = 12%) were recruited. At HCC diagnosis, 84% had been on anti-retrovirals for a median duration of 8.8 years. The albumin-bilirubin grade identified significant differences in median survival of 97 months for grade 1 (95% CI 13-180 months), 17 months for grade 2 (95% CI 11-22 months) and 6 months for grade 3 (95% CI 4-9 months, P < .001). A more advanced albumin-bilirubin grade correlated with lower CD4 counts (464/373/288 cells/mm3 for grades 1/2/3) and higher HIV viraemia (3.337/8.701/61.845 copies/mL for grades 1/2/3, P < .001). CONCLUSIONS: In this large, multi-center retrospective study, the albumin-bilirubin grade highlights the interplay between liver reserve and immune dysfunction as prognostic determinants in HIV-associated HCC.

Surgical excision alone for stage T1 anal verge cancers in people living with HIV.

INTRODUCTION: Anal cancer accounts for a small percentage of colorectal malignancies. Early stage (T1N0M0) cancers of the anal verge have been treated with local surgical excision alone in individuals without human immunodeficiency virus (HIV) infection. The risk of anal cancer is higher in people living with HIV (PLWH). We present results of the outcomes of T1 anal verge cancers treated by local excision only in a series of PLWH. METHODS: Demographic and clinicopathological data was prospectively collected from all HIV positive individuals with anal cancer, treated between 1986 and 2015. The date from anal cancer diagnosis until the date of the last follow up were collected. RESULTS: Fifteen patients had T1N0M0 cancer of the anal verge from a total of 92 patients with HIV-associated anal cancer. The mean age was 49 years (range 36-57). The average age of HIV diagnosis was 35 years (range 19-48) and four patients had a diagnosis of AIDS prior to the diagnosis of anal cancer. All patients were surgically managed with complete local excision of the tumour. There were no complications or need for any adjuvant therapy. No patients have relapsed and at a median follow up of 4 years (range 3-15), the overall survival was 100%. CONCLUSION: Surgical resection for early stage anal verge cancers is an effective strategy in PLWH. Increasing awareness of anal cancer and anoscopy surveillance in PLWH will hopefully continue to identify anal cancers at an early stage that are amenable to minimally invasive surgical management.

The clinical application of plasma Kaposi sarcoma herpesvirus viral load as a tumour biomarker: results from 704 patients.

OBJECTIVES: The aim of the study was to evaluate the role of plasma Kaposi sarcoma herpesvirus (KSHV) as a diagnostic and prognostic biomarker in people living with HIV (PLWH) and diagnosed with KSHV-associated diseases. METHODS: Using quantitative nested polymerase chain reaction (PCR) targeting the open reading frame-26 gene of KSHV, plasma levels of KSHV were measured in consecutive PLWH with KSHV-associated diseases or as part of the investigation of lymphadenopathy. RESULTS: Plasma KSHV assays were performed on samples from 684 PLWH and 20 HIV-seronegative people with KSHV-associated malignancies. In PLWH, plasma KSHV was detected in 39% of those with KS, 99% of those with multicentric Castleman disease (MCD), 9% of those with non-Hodgkin lymphoma (NHL), 2% of those with non-AIDS-defining malignancies and 0% of those with nonmalignant lymphadenopathy. There was no significant difference in plasma KSHV viral load among those with KS, MCD and KSHV-associated NHL. The 5-year overall survival rate from KS diagnosis of 335 PLWH was 95.2% (95% confidence interval 92.6-97.8%). Plasma KSHV viraemia did not predict overall survival in those with KS (P = 0.73), nor when those with T0 stage KS (P = 0.52) or T1 stage KS (P = 0.62) were analysed separately. CONCLUSIONS: Measuring the plasma levels of KSHV as a biomarker in KSHV-associated disease has a very limited value in either diagnosis or prognostication. The only potential role of clinical value is the suggestion that an undetectable plasma KSHV excludes a diagnosis of MCD in PLWH.

Liposomal anthracycline chemotherapy and the risk of second malignancies in patients with Kaposi's sarcoma (KS).

PURPOSE: People living with HIV (PLWH) are at increased risk of cancer, both non-AIDS- and AIDS-defining malignancies (NADM and ADM). Systemic chemotherapy also predisposes to secondary cancers. The potential contribution of systemic liposomal anthracycline chemotherapy (SLAC) to the development of second cancers in PLWH is unknown. METHODS: Since 1998, we have treated 495 PLWH and Kaposi's sarcoma (KS) with a stage-stratified approach including 163 who received SLAC as first-line treatment for KS. Subsequent ADM and NADM diagnosed in this population were recorded. RESULTS: More patients who received SLAC had T1 stage disease (p < 0.0001) and lower CD4 cell counts (p < 0.0001) in line with the stage-stratified treatment, but there were no significant differences in age (p = 0.29), gender (p = 0.18), prior AIDS-defining illness (p = 0.45), plasma HIV viral load (p = 0.15), or HHV8 viral load (p = 0.39) between the two groups. During a median follow-up of 4.6 years (maximum 15 years) from KS diagnosis, 28 patients developed a second cancer (5 ADM and 23 NADM). The 5-year cumulative risk of second cancer is 5.8 % (95 % CI 3.0-8.6 %), and there is no significant difference in the rate between those treated with SLAC and those not (log rank p = 0.19). Most patients (n = 131) were treated with daunoxome (liposomal daunorubicin) chemotherapy, and there was no significant correlation between risk of second cancer and cumulative dose of daunoxome (p = 0.23). CONCLUSION: Although the risk of second cancer after a diagnosis of KS in PLWH is high, systemic liposomal anthracycline chemotherapy does not appear to increase the risk.

Salvage surgery for residual primary and locally recurrent anal squamous cell carcinoma after chemoradiotherapy in HIV-positive individuals.

BACKGROUND: The treatment of anal cancer in human immunodeficiency virus (HIV) patients-as in the general population-is primarily with chemoradiotherapy (CRT), and abdominoperineal resection of residual or recurrent primary disease. The aim of this study was to evaluate the extent of residual primary disease and local recurrence as well as the outcome of salvage surgery after CRT for anal carcinoma in HIV-positive individuals. METHODS: We retrospectively studied HIV-positive anal carcinoma patients treated between February 1989 and November 2012 in a specialist London unit. Extent of residual primary disease, local recurrence after CRT, postoperative complications, and survival after salvage surgery were evaluated. RESULTS: Complete response was experienced in 44 of 53 (83%) of HIV patients treated with CRT for anal carcinoma. One patient (2.3%) developed local recurrence. Nine patients (eight residual primary disease after CRT and one local recurrence) underwent salvage surgery after CRT. There were no perioperative deaths, and perioperative CD4 counts were sustained. Complications occurred in five patients (55%). Median interval to complete perineal healing was 4 months (range 2-11 months), and median hospital stay was 29 days. Survival (median 16 months) was 25% at 2 years from salvage surgery. CONCLUSIONS: Results in HIV-positive patients receiving highly active antiretroviral therapy (HAART) suggest that loss of HIV sensitivity to HAART can be avoided, but that there is increased postoperative morbidity that may be related to HIV disease. Survival was comparable to that for salvage therapy after optimal CRT in non-HIV anal carcinoma patients.

A systematic review of anal squamous cell carcinoma in inflammatory bowel disease.

AIM: The aim of this systematic review was to determine the incidence, aetiology and clinical characteristics of anal squamous cell carcinomas (SCC) presenting in patients with inflammatory bowel disease. METHOD: A systematic review of the literature was undertaken using Medline, Embase, Cochrane and Web of Science. RESULTS: A total of 33 cases of anal SCC were described, 7 in ulcerative colitis (UC) and 26 in Crohn's disease (CD). The annual incidence of anal SCCs was 0.9/100,000 and 2.0/100,000 in patients with UC and CD respectively. The gender ratio in CD was 3M:17F with a median age of 42 years, the main presenting symptom was anal pain and 85% of CD cases had peri-anal disease. No studies described anal intra-epithelial neoplasia. The human papilloma virus was found to be positive in 2 out of 5 (40%) cases. The majority of patients (73%) with CD received radical surgery as their first line treatment. The cumulative overall and disease free survival in CD was 37 per cent at five years. CONCLUSION: The findings of this review when contrasted with the data from cancer registries suggests that there is a higher incidence of anal SCC, an earlier age of presentation and poorer outcomes in patients with Crohn's disease compared to the general population implying a more aggressive neoplastic process. This review supports the hypothesis that peri-anal disease plays a contributing role in anal SCCs and as such targeted surveillance in patients with longstanding peri-anal disease should be considered.

Primary cervical lymphoma: a rare presentation to a genitourinary medicine clinic.

Primary non-Hodgkin's lymphoma of uterine cervix is a rare diagnosis. We present the case of a 47-year-old woman who presented to our genitourinary (GU) medicine service complaining of a malodorous discharge. Speculum examination revealed a necrotic mass on the cervix. She was referred urgently to gynaecology and subsequent histology revealed a diffuse large B-cell lymphoma. She received six cycles of RCHOP chemotherapy and is now in clinical remission. This case highlights the need for GU medicine physicians to remain vigilant with regard to possible gynaecological malignancies in all of our patients, the need for medical backup within GU medicine clinics and for clear pathways of referral to other specialists to exist.

Thoroughbred racehorse mitochondrial DNA demonstrates closer than expected links between maternal genetic history and pedigree records.

The potential future earnings and therefore value of Thoroughbred foals untested in the racing arena are calculated based on the performance of their forebears. Thus, lineage is of key importance. However, previous research indicates that maternally inherited mitochondrial DNA (mtDNA) does not correspond to maternal lineage according to recorded pedigree, casting doubt on the voracity of historic pedigrees. We analysed mtDNA of 296 Thoroughbred horses from 33 maternal lineages and identified an interesting trend. Subsequent to the founding of the Thoroughbred breed in the 16th century, well-populated maternal lineages were divided into sub-lineages. Only six in 10 of the Thoroughbreds sampled shared mitochondrial haplotype with other members of their maternal lineage, despite having a common maternal ancestor according to pedigree records. However, nine in 10 Thoroughbreds from the 103 sub-lineages sampled shared mtDNA with horses of their maternal pedigree sub-lineage. Thus, Thoroughbred maternal sub-lineage pedigree represents a more accurate breeding record than previously thought. Errors in pedigrees must have occurred largely, though, not exclusively, at sub-lineage foundation events, probably due to incomplete understanding of modes of inheritance in the past, where maternal sub-lineages were founded from individuals, related, but not by female descent.

The collagen prolyl hydroxylases are novel transcriptionally silenced genes in lymphoma.

BACKGROUND: Prolyl hydroxylation is a post-translational modification that affects the structure, stability and function of proteins including collagen by catalysing hydroxylation of proline to hydroxyproline through action of collagen prolyl hydroxylases3 (C-P3H) and 4 (C-P4H). Three C-P3Hs (nomenclature was amended according to approval by the HGNC symbols and names at http://www.genenames.org/ and Entrez database at http://www.ncbi.nlm.nih.gov/gene) leucineproline-enriched proteoglycan (leprecan) 1 (Lepre1), leprecan-like 1 (Leprel1), leprecan-like 2 (Leprel2) and two paralogs Cartilage-Related Protein (CRTAP) and leprecan-like 4 (Leprel4) are found in humans. The C-P4Hs are tetrameric proteins comprising a variable α subunit, encoded by the P4HA1, P4HA2 and P4HA3 genes and a constant ß subunit encoded by P4HB. METHODS: We used RT-PCR, qPCR, pyrosequencing, methylation-specific PCR, western blotting and immunohistochemistry to investigate expression and regulation of the C-P3H and C-P4H genes in B lymphomas and normal bone marrow. RESULTS: C-P3H and C-P4H are downregulated in lymphoma. Down-regulation is associated with methylation in the CpG islands and is detected in almost all common types of B-cell lymphoma, but the CpG islands are unmethylated or methylated at lower levels in DNA isolated from normal bone marrow and lymphoblastoid cell lines. Methylation of multiple C-P3H and C-P4H genes is present in some lymphomas, particularly Burkitt's lymphoma. CONCLUSIONS: Methylation of C-P3H and C-P4H is common in B lymphomas and may have utility in differentiating disease subtypes.