Lymphoma incidence, survival and prevalence 2004-2014: sub-type analyses from the UK's Haematological Malignancy Research Network.

BACKGROUND: Population-based information about cancer occurrence and survival are required to inform clinical practice and research; but for most lymphomas data are lacking. METHODS: Set within a socio-demographically representative UK population of nearly 4 million, lymphoma data (N=5796) are from an established patient cohort. RESULTS: Incidence, survival (overall and relative) and prevalence estimates for >20 subtypes are presented. With few exceptions, males tended to be diagnosed at younger ages and have significantly (P<0.05) higher incidence rates. Differences were greatest at younger ages: the <15 year male/female rate ratio for all subtypes combined being 2.2 (95% CI 1.3-3.4). These gender differences impacted on prevalence; most subtype estimates being significantly (P<0.05) higher in males than females. Outcome varied widely by subtype; survival of patients with nodular lymphocyte predominant Hodgkin lymphoma approached that of the general population, whereas less than a third of those with other B-cell (e.g., mantle cell) or T-cell (e.g., peripheral-T) lymphomas survived for ≥5 years. No males/female survival differences were detected. CONCLUSIONS: Major strengths of our study include completeness of ascertainment, world-class diagnostics and generalisability. The marked variations demonstrated confirm the requirement for 'real-world' data to inform aetiological hypotheses, health-care planning and the future monitoring of therapeutic changes.

Drug Permeability - Best Practices for Biopharmaceutics Classification System (BCS)-Based Biowaivers: A workshop Summary Report.

The workshop "Drug Permeability - Best Practices for Biopharmaceutics Classification System (BCS) Based Biowaivers" was held virtually on December 6, 2021, organized by the University of Maryland Center of Excellence in Regulatory Science and Innovation (M-CERSI), and the Food and Drug Administration (FDA). The workshop focused on the industrial, academic, and regulatory experiences in generating and evaluating permeability data, with the aim to further facilitate implementation of the BCS and efficient development of high-quality drug products globally. As the first international permeability workshop since the BCS based biowaivers was finalized as the ICH M9 guideline, the workshop included lectures, panel discussions, and breakout sessions. Lecture and panel discussion topics covered case studies at IND, NDA, and ANDA stages, typical deficiencies relating to permeability assessment supporting BCS biowaiver, types of evidence that are available to demonstrate high permeability, method suitability of a permeability assay, impact of excipients, importance of global acceptance of permeability methods, opportunities to expand the use of biowaivers (e.g. non-Caco-2 cell lines, totality-of-evidence approach to demonstrate high permeability) and future of permeability testing. Breakout sessions focused on 1) in vitro and in silico intestinal permeability methods; 2) potential excipient effects on permeability and; 3) use of label and literature data to designate permeability class.

In vivo image-guided (1)H-magnetic resonance spectroscopy of the serial development of hepatocarcinogenesis in an experimental animal model.

Histology on a core or open biopsy is considered the gold standard for the diagnosis of tumours. While the non-invasive technique of magnetic resonance imaging can direct some of the decision diagnostic making, it has limitations and disadvantages, that can be partly overcome with the use of in vivo magnetic resonance spectroscopy (MRS). In vivo MRS is able to provide a specific biochemical profile on tumour tissue, compared with normal tissue. The capability of this technique is demonstrated here by the long-term development of hepatocellular carcinoma in an animal model. It allows the observation of the biochemical changes that occur in tumour tissue during its progression from preneoplastic nodules to hepatocellular carcinoma. Specifically the changes in the lipid profiles of tumour tissue at various stages of development are observed with proton ((1)H) MRS. Significant increases occurred in the lipid acyl chain methylene and methyl hydrogens during the early developmental stages of hepatocarcinogenesis, whereas during later stages associated with tumour development there was a significant increase in the levels of olefinic acyl chain hydrogens from unsaturated lipids. It is anticipated that this model will precede the application of the same technology to the non-invasive diagnosis and grading of human hepatocellular carcinoma.

Cortical processing of visceral and somatic stimulation: differentiating pain intensity from unpleasantness.

Visceral and somatic pain perception differs in several aspects: poor localization of visceral pain and the ability of visceral pain to be referred to somatic structures. The perception of pain intensity and affect in visceral and somatic pain syndromes is often different, with visceral pain reported as more unpleasant. To determine whether these behavioral differences are due to differences in the central processing of visceral and somatic pain, non-invasive imaging tools are required to examine the neural correlates of visceral and somatic events when the behavior has been isolated and matched for either unpleasantness or pain intensity. In this study we matched the unpleasantness of somatic and visceral sensations and imaged the neural representation of this perception using functional magnetic resonance imaging in 10 healthy right-handed subjects. Each subject received noxious thermal stimuli to the left foot and midline lower back and balloon distension of the rectum while being scanned. Stimuli were matched to the same unpleasantness rating, producing mild-moderate pain intensity for somatic stimuli but an intensity below the pain threshold for the visceral stimuli. Visceral stimuli induced deactivation of the perigenual cingulate bilaterally with a relatively greater activation of the right anterior insula-i.e. regions encoding affect. Somatic pain induced left dorso-lateral pre-frontal cortex and bilateral inferior parietal cortex activation i.e. regions encoding spatial orientation and assessing perceptual valence of the stimulus. We believe that the observed patterns of activation represent the differences in cortical process of interoceptive (visceral) and exteroceptive (somatic) stimuli when matched for unpleasantness.

Evidence that portal tract microvascular destruction precedes bile duct loss in human liver allograft rejection.

In liver allograft rejection, interlobular bile ducts are thought to be the main target of rejection. In contrast, in other organ allografts the capillary bed of the graft appears to be the primary target. To determine whether portal tract microvasculature is destroyed in liver allografts during rejection, we have identified portal tract microvasculature in 11 normal livers and 38 liver allograft biopsy specimens using monoclonal antibodies to capillary endothelium in immunohistochemical staining. E1.5, CD31 and EL-4 antibodies identified portal microvascular endothelium in normal liver that had the morphology of capillaries. In allograft biopsies the number of microvascular structures per portal tract was reduced markedly in acute cellular rejection to 1.1 +/- 0.6 (n = 25) and to 0.65 +/- 0.9 (n = 15) in chronic ductopenic rejection compared with nonrejecting allografts (2.8 +/- 0.6) (n = 4) or normal liver (3.8 +/- 0.7) (n = 11). To determine whether loss of microvascular structures preceded bile duct destruction in rejection, sections were double-stained to identify both microvasculature and bile ducts. The number of microvascular structures per bile duct was significantly lower in acute cellular rejection (0.5 +/- 0.4) (n = 18) or chronic rejection (0.3 +/- 0.4) (n = 8) compared with normal liver (2.3 +/- 0.6) (n = 7) (P < 0.0001), demonstrating that components of the portal vasculature are destroyed prior to bile ducts. There was a correlation between the severity of rejection and the loss of microvascular structures per bile duct (P < 0.001). In conclusion, in common with other allografted organs, the microvasculature of liver allografts appears to be an early target of rejection.

Use of liver allografts from carbon monoxide poisoned cadaveric donors.

Carbon monoxide (CO) inhalation leads to cerebral, cardiac, and, more rarely, liver damage. The use of liver allografts from CO poisoned donors with evidence of liver damage has not previously been reported. In this report we describe two recipients, both in fulminant hepatic failure, who received liver grafts from such donors. One donor had markedly abnormal liver function tests (LFTS), and in the other LFTS were mildly abnormal. In both, the liver appeared normal at procurement. There was satisfactory early function of both allografts, although marked patchy necrosis was seen on the postreperfusion biopsy (case 1), and on a 10 day postoperative biopsy (case 2). In both cases the changes were considered to be related to damage sustained from CO inhalation. Both allografts soon achieved normal function and both recipients are well. We conclude that CO poisoning can cause liver damage that can recover completely following liver transplantation.

Vascular endothelial growth factor expression in human chronic renal allograft rejection.

BACKGROUND: Chronic renal allograft rejection is characterized by interstitial fibrosis and vasculopathy. Vascular endothelial growth factor (VEGF) is an endothelial mitogen with increased expression in inflammation and vasculopathy. METHODS: Renal tissue from 17 patients with chronic rejection was examined for VEGF protein and the presence of CD 68-positive macrophages, and compared to biopsies from patients with temporary allograft dysfunction, acute rejection, and native kidneys with thin membrane disease. RESULTS: In the chronic rejection group, there was markedly increased expression of VEGF protein in the interstitium (P<0.0001). In serial sections, VEGF colocalized with the expression of CD 68-positive macrophages. Significantly more macrophages were in the tubulointerstitium in tissue with chronic rejection than in those with temporary allograft dysfunction (P<0.005). Additionally, VEGF protein expression in the glomeruli and the vascular compartment of patients with chronic rejection was increased. CONCLUSION: The up-regulation of VEGF in chronic renal allograft rejection may be important in inflammation and development of fibrosis.

Early up-regulation of macrophages and myofibroblasts: a new marker for development of chronic renal allograft rejection.

BACKGROUND: Increased numbers of macrophages and myofibroblasts are observed to occur in chronic renal allograft rejection (CR). The aim of this study was to examine the expression of cellular markers for the macrophage and myofibroblast in early renal transplant biopsy specimens and correlate these findings with allograft outcome. METHODS: The first postengraftment biopsy specimens from 53 patients who underwent renal transplantation between January 1993 and December 1995 were studied using immunohistochemistry with antibodies to alpha-smooth muscle actin, which identifies myofibroblasts and CD68, a marker for monocytes and macrophages. Patients were followed until December 1998 (mean follow-up 4.7+/-1.2 years). RESULTS: Nine patients had progressed to CR by the time of the study, whereas 44 patients continued to have stable renal function. A marked increase in both macrophages (P=0.02) and myofibroblasts (P=0.04) was noted in the first biopsy specimen obtained after engraftment in the patients who developed CR compared with those with stable allograft function. There was a positive correlation between alpha-smooth muscle actin and collagen expression (P=0.0001). CONCLUSION: Significant increases in macrophages and myofibroblasts occur in the first renal biopsy specimen in those patients who later develop CR.

A large, single center investigation of the immunogenetic factors affecting liver transplantation.

BACKGROUND: Reports on the relevance of immunogenetic factors in liver transplantation are often conflicting or inconclusive. We have, therefore, investigated a range of factors that may underlie liver graft survival. METHODS: The influences of HLA, flow cytometric, and enhanced cytotoxic crossmatching and immunoglobulin (Ig)A levels on graft survival, and acute and chronic rejection were investigated for a single center involving 446 patients over 13 years. RESULTS: The effect of HLA mismatching on graft survival was significant (P<10(-2)) and was reversed in recipients with autoimmune diseases (P<0.5x10(-2)), whereas the effect of HLA mismatches on the level of acute rejection was detrimental in all recipients. There was a significant effect of a positive cytotoxic crossmatch on 3-month (P<10(-5)) and 1-year (P<10(-4)) graft survival, and an additional effect of the flow cytometric crossmatch was seen for chronic rejection (P<10(-2)) and acute rejection (P<10(-2)). Recipients with HLA-A1,B8,DRB1*0301 had higher levels of acute rejection (P<0.5x10(-2)), and recipients who received an ABO compatible-nonidentical transplant have a significantly higher risk (P<10(-2)) of developing chronic rejection. Finally, the beneficial effect of high serum IgA and, specifically, IgA anti Fab, seen in renal transplants was not evident in liver transplants, and in fact the opposite may be true, at least for acute rejection (P<0.5x10(-2)). CONCLUSIONS: By separating the recipients with autoimmune disease from other patients and by including acute and chronic rejection as outcome parameters, we have used the power of a large single-centre study to delineate the significance of some of the important immunogenetic factors involved in liver transplantation.

A giant multiacinar macroregenerative nodule in an explanted liver.

Macroregenerative nodules (MRN) have been detected with increased incidence in explanted livers since orthotopic liver transplantation (OLTx) has become a routine treatment for end-stage liver disease. Autopsy series suggest that MRN may be more common than once thought, and several studies point to the malignant potential of these lesions. With increasing waiting times for OLTx, the propensity for these premalignant lesions to arise in cirrhotic livers has important implications for the supervision of patients on OLTx waiting lists. We present here a striking example of a MRN and review a topic that is generating considerable interest.

Four-vessel umbilical cord associated with multiple congenital anomalies.

A case is described in which it was found at autopsy that the umbilical cord of a macerated stillborn infant had four patent vessels (two arteries and two veins) throughout its length. This was due to a rare persistence of the caudal portion of the right umbilical vein. The infant had multiple congenital anomalies including complete thoracic ectopia cordis, a symmetrical bifid liver, severe bilateral cleft lip and palate with absent soft palate and uvula , and cecum mobile. The autopsy findings are detailed and the relevant literature and embryology briefly discussed.

The pathological assessment of ovarian neoplasms V: The germ cell tumours.

All neoplasms of the ovary encountered in a 25-yr study period of King George V Memorial Hospital were classified according to the World Health Organisation (WHO) Histological Classification of Ovarian Tumours. Of just fewer than 1700 tumours, 467 fell into the category designated as germ cell tumours: 4 dysgerminomas, one endodermal sinus tumour, one primary choriocarcinoma, 6 immature and 454 mature teratomas and one mixed malignant germ cell tumour. Two additional cases of gonadoblastoma with associated dysgerminoma were encountered and included for discussion. A detailed histological assessment is presented and the major clinical correlates are documented.

Teratomas in childhood.

Of 107 teratomas in children, 86 were benign and 21 malignant. Sacrococcygeal and pelvic teratomas predominated (51 cases) and these fell into 3 groups: post sacral, dumb-bell and presacral. The 34 purely posterior tumours were always congenital and benign, whilst the incidence of malignancy in dumb-bell and presacral teratomas increased as the tumour became more internal. Malignant teratomas were carcinomas, usually containing glandular, papillary and clear-cell areas, and metastases were similar. Immature tissues in benign teratomas were usually neural or connective tissue. They did not give rise to neuroblastomas or sarcomas, and did not indicate a worse prognosis. Only 2 originally benign teratomas later developed malignancy.

Histopathological prediction of hepatitis B recurrence in liver allografts.

The aim of this study was to review the clinical, serological and histopathological features of 20 patients who underwent orthotopic liver transplantation for hepatitis B virus (HBV) related liver disease in an attempt to identify factors which predict recurrence of HBV infection, pattern of disease and disease severity. Hepatitis B recurrence occurred in 11 patients (55%). Positive immunoperoxidase staining for HBsAg and HBcAg of the hepatectomy specimen were shown to have a sensitivity (82% and 64% respectively) and specificity (55% and 66%) in predicting recurrence. This was comparable to serological markers such as HBV DNA (36% sensitivity and 89% specificity). The staining for HBcAg in some cases was weak, focal and had a reticular pattern. Therefore, examination of multiple blocks with a high magnification was necessary to detect HBcAg staining. Negative staining of multiple sections for HBsAg and HBcAg were shown to have a good correlation with clearing of HBV infection (5 out of 6 patients). If recurrence occurred, the range of histological and clinical patterns of HBV recurrence was varied, with severe disease occurring in 5 patients. Neither pre-transplant serology nor hepatectomy immunoperoxidase staining characteristics were shown to be of value in predicting the pattern or the severity of disease once HBV recurrence had occurred. This study indicates that lack of staining for HBV antigens on multiple sections of the native liver may predict a subgroup of HBsAg positive transplant patients who will not suffer from recurrent disease. Once disease did occur however, markers for severity of recurrence were not identified.

The limited (needle biopsy) autopsy and the acquired immunodeficiency syndrome.

It is often uncertain whether deaths that occur during active treatment for complications of AIDS result from diagnostic or therapeutic failure. Accurate diagnosis of infections is particularly important, and has relevance not only for the patient but also to partners, relatives, hospital staff and other patients. In the absence of adequate physical facilities and in view of the lack of success in obtaining formal autopsies in patients dying with AIDS, a limited autopsy protocol was devised for routine application at our hospital, beginning in 1989. The major aim of this protocol was to enable the safe collection of diagnostic material from patients who died despite active therapy, to ascertain unrecognized conditions and confirm existing diagnoses. We present findings from the first 16 limited autopsies which resulted in 12 additional diagnoses and a revision of the principal cause of death in 7 cases.

Hepatocellular carcinoma metastasizing to the orbit diagnosed by fine needle aspiration cytology.

Hepatocellular carcinoma (HCC) rarely metastasizes to the orbit. We report a case of a 78-year-old man with a past history of HCC, who presented with a periorbital mass, which was diagnosed as metastatic HCC by fine needle aspiration cytology (FNAC) and subsequently confirmed on excision biopsy. The cytological, histopathological and immunohistochemical findings are presented and the differential diagnosis is discussed. To our knowledge there has been no previously reported case of HCC metastatic to the orbit diagnosed by FNAC.

The pattern of glomerular disease in New Caledonia: preliminary findings.

Two hundred and two renal biopsies from 181 patients in New Caledonia were classified into either primary glomerulonephritis or glomerulopathy associated with systemic disease. These were then compared with 670 similar biopsies from 634 in-patients at Sydney's Royal Prince Alfred Hospital (RPAH). The most prevalent primary glomerular disease among the New Caledonian cases was focal segmental glomerulosclerosis, compared with IgA disease among the RPAH cases. Mesangiocapillary glomerulonephritis, post-infectious glomerulonephritis and minimal lesion nephropathy were all relatively commoner among the New Caledonian biopsies, but the numbers were small. The most prevalent systemic glomerulopathy in the New Caledonian cases were amyloidosis. This was the least common among our RPAH group. Diabetes mellitus and lupus nephritis were also slightly more common in the New Caledonian group. Focal necrotizing/crescentic glomerulonephritis was unusual in the New Caledonian samples, while it was the most common systemic glomerulopathy among the RPAH group.

Effects of short-term training on cardiac function during prolonged exercise.

To determine the relationship between the training-induced increases in plasma volume (PV) and alterations in cardiac performance during prolonged submaximal cycle exercise, seven male subjects were studied prior to and following a short-term (3 d) training period (2 h.d-1 at 65% VO2max). Mean (range) VO2max was 3.42 l.min-1 (2.96-3.87). Training resulted in a 20% increase (P less than 0.05) in plasma volume (PV) and a 12% increase (P less than 0.05) in total blood volume (TBV). In contrast, training had no effect (P greater than 0.05) in altering exercise VO2, VCO2, VE BTPS, or RER. Cardiac output (Q) was higher (P less than 0.05) posttraining at all exercise sampling times (30, 60, 90, and 120 min). The elevations in Q were accompanied by an average decrease (P less than 0.05) in stroke volume (SV) of 22 ml. Arteriovenous O2 (a-v O2) difference was depressed (P less than 0.05) during exercise following the training. Although elevations (P less than 0.05) in core temperature (degrees C) occurred during the exercise, the training-induced PV increases did not affect thermoregulatory behavior. These results indicate that an early adaptive response to exercise training is an elevation in Q, an increase in SV, and a reduction in HR. These effects persist during prolonged exercise in spite of the progressive increase in body heat content. It is proposed that the increase in Q serves primarily to increase muscle blood flow and maintain arterial O2 delivery, while the altered cardiodynamic behavior serves to increase cardiac reserve, providing a greater tolerance to prolonged heavy exercise.

Training-induced hypervolemia: lack of an effect on oxygen utilization during exercise.

To investigate the effect of training-induced increases in plasma volume on maximal aerobic power, 8 male subjects (age 19 to 24 yr) underwent a 4-d training program (2 h X d-1) at an estimated 71% maximal aerobic power. Following training, plasma volume measured using 131I-human serum albumin increased by 20.3% (P less than 0.01) whereas red cell volume remained unchanged and total blood volume increased by 12.3% (P less than 0.01). During progressive sub-maximal cycle exercise, oxygen consumption, carbon dioxide production, ventilation, and blood lactate concentration remained unchanged following the training whereas heart rate was significantly elevated (P less than 0.05). Significant post-training elevations were also noted in carbon dioxide production (P less than 0.05), blood lactate (P less than 0.01), and peak power output (P less than 0.05) during maximal exercise. Maximal aerobic power and ventilation were not altered. It is concluded that hypervolemia induced by short-term exercise training does not affect oxygen consumption either during sub-maximal or maximal exercise.

Histological tumour response to pre-operative combined modality therapy in locally advanced rectal cancer.

BACKGROUND: Pre-operative combined modality therapy (CMT) is used in locally advanced rectal cancer. Its use affects the clinicopathological staging based on the resected specimen. Assessment of the tumour response in the resected specimen may provide prognostic information. This study was undertaken to determine the histological response to pre-operative chemoradiation and to assess the interobserver reliability of a newly developed tumour response grading system for rectal cancer. METHODS: Pre-operative biopsy specimens and the resected specimens of 21 patients with low rectal cancer were assessed. The patients underwent pre-operative CMT consisting of radiotherapy (45 Gy) with 5-FU either as a continuous infusion or as a bolus intravenous infusion with leucovorin. After four to six weeks tumour response was assessed by comparing pre-operative transrectal ultrasound (TRUS) findings (uT1-4, uN0-1) with postoperative histopathological assessment (pT1-4, pN0-1) using UICC TNM characteristics. Tumour response was defined as a decrease in T status. The histological response to CMT was based on the tumour regression grade (TRG) and ranged from fibrosis extending through the rectal wall with no residual cancer (TRG 1), to no evidence of tumour response (TRG 5). Inter-observer reliability was assessed using weighted and unweighted kappa statistics. RESULTS: Local downstaging was demonstrated in 11/21 (52%) of patients. Three of 21 patients had a TRG 1 response. Thirteen of 21 (62%) patients had TRG 1-3 responses to CMT. There was no significant correlation between local downstaging and TRG. The interobserver correlation coefficient for assessment of TRG was 0.88 (unweighted kappa). CONCLUSIONS: Local downstaging by pre-operative CMT can be demonstrated if pre-operative TRUS staging is compared to standard pathology staging in patients with rectal cancer. Local downstaging is not directly related to histologic response as assessed by TRG. Inter-observer reporting of tumour regression grade (TRG) is reliable.