Rare T-Cell Subtypes.

There are a number of rare T-cell lymphoma subtypes that may be encountered in clinical practice. In recent years, improved immunohistochemical techniques and molecular tumor profiling have permitted refinement of some of the diagnostic categories in this group, as well as the recognition of distinct conditions not previously well elucidated. In this chapter, we cover the diagnostic and clinical features of some of the more common of these conditions, including subcutaneous panniculitis-like T-cell lymphoma, cutaneous gamma-delta T-cell lymphoma, enteropathy-associated T-cell lymphoma, monomorphic epitheliotropic intestinal T-cell lymphoma, primary cutaneous CD8-positive aggressive epidermotropic cytotoxic T-cell lymphoma, CD4-positive small/medium T-cell lymphoproliferative disorder, and acral CD8-positive T-cell lymphoma. Given the rarity of these conditions, optimal treatments approaches are not always well established, not least as data from large-scale clinical trials are lacking. In this chapter, we aim to provide a summation of current thinking around best treatment, as well as highlighting some controversies in the management of these diagnoses.

Frailty predicts mortality in all emergency surgical admissions regardless of age. An observational study.

BACKGROUND: frail patients in any age group are more likely to die than those that are not frail. We aimed to evaluate the impact of frailty on clinical mortality, readmission rate and length of stay for emergency surgical patients of all ages. METHODS: a multi-centre prospective cohort study was conducted on adult admissions to acute surgical units. Every patient presenting as a surgical emergency to secondary care, regardless of whether they ultimately underwent a surgical procedure was included. The study was carried out during 2015 and 2016.Frailty was defined using the 7-point Clinical Frailty Scale. The primary outcome was mortality at Day 90. Secondary outcomes included: mortality at Day 30, length of stay and readmission within a Day 30 period. RESULTS: the cohort included 2,279 patients (median age 54 years [IQR 36-72]; 56% female). Frailty was documented in patients of all ages: 1% in the under 40's to 45% of those aged 80+. We found that each incremental step of worsening frailty was associated with an 80% increase in mortality at Day 90 (OR 1.80, 95% CI: 1.61-2.01) supporting a linear dose-response relationship. In addition, the most frail patients were increasingly likely to stay in hospital longer, be readmitted within 30 days, and die within 30 days. CONCLUSIONS: worsening frailty at any age is associated with significantly poorer patient outcomes, including mortality in unselected acute surgical admissions. Assessment of frailty should be integrated into emergency surgical practice to allow prognostication and implementation of strategies to improve outcomes.

Surveillance imaging with FDG-PET/CT in the post-operative follow-up of stage 3 melanoma.

Background: As early detection of recurrent melanoma maximizes treatment options, patients usually undergo post-operative imaging surveillance, increasingly with FDG-PET/CT (PET). To assess this, we evaluated stage 3 melanoma patients who underwent prospectively applied and sub-stage-specific schedules of PET surveillance. Patients and methods: From 2009, patients with stage 3 melanoma routinely underwent PET +/- MRI brain scans via defined schedules based on sub-stage-specific relapse probabilities. Data were collected regarding patient characteristics and outcomes. Contingency analyses were carried out of imaging outcomes. Results: One hundred and seventy patients (stage 3A: 34; 3B: 93; 3C: 43) underwent radiological surveillance. Relapses were identified in 65 (38%) patients, of which 45 (69%) were asymptomatic. False-positive imaging findings occurred in 7%, and 6% had treatable second (non-melanoma) malignancies. Positive predictive values (PPV) of individual scans were 56%-83%. Negative scans had predictive values of 89%-96% for true non-recurrence [negative predictive values (NPV)] until the next scan. A negative PET at 18 months had NPVs of 80%-84% for true non-recurrence at any time in the 47-month (median) follow-up period. Sensitivity and specificity of the overall approach of sub-stage-specific PET surveillance were 70% and 87%, respectively. Of relapsed patients, 33 (52%) underwent potentially curative resection and 10 (16%) remained disease-free after 24 months (median). Conclusions: Application of sub-stage-specific PET in stage 3 melanoma enables asymptomatic detection of most recurrences, has high NPVs that may provide patient reassurance, and is associated with a high rate of detection of resectable and potentially curable disease at relapse.

Global patterns of care in advanced stage mycosis fungoides/Sezary syndrome: a multicenter retrospective follow-up study from the Cutaneous Lymphoma International Consortium.

BACKGROUND: Advanced-stage mycosis fungoides (MF)/Sézary syndrome (SS) patients are weighted by an unfavorable prognosis and share an unmet clinical need of effective treatments. International guidelines are available detailing treatment options for the different stages but without recommending treatments in any particular order due to lack of comparative trials. The aims of this second CLIC study were to retrospectively analyze the pattern of care worldwide for advanced-stage MF/SS patients, the distribution of treatments according to geographical areas (USA versus non-USA), and whether the heterogeneity of approaches has potential impact on survival. PATIENTS AND METHODS: This study included 853 patients from 21 specialist centers (14 European, 4 USA, 1 each Australian, Brazilian, and Japanese). RESULTS: Heterogeneity of treatment approaches was found, with up to 24 different modalities or combinations used as first-line and 36% of patients receiving four or more treatments. Stage IIB disease was most frequently treated by total-skin-electron-beam radiotherapy, bexarotene and gemcitabine; erythrodermic and SS patients by extracorporeal photochemotherapy, and stage IVA2 by polychemotherapy. Significant differences were found between USA and non-USA centers, with bexarotene, photopheresis and histone deacetylase inhibitors most frequently prescribed for first-line treatment in USA while phototherapy, interferon, chlorambucil and gemcitabine in non-USA centers. These differences did not significantly impact on survival. However, when considering death and therapy change as competing risk events and the impact of first treatment line on both events, both monochemotherapy (SHR = 2.07) and polychemotherapy (SHR = 1.69) showed elevated relative risks. CONCLUSION: This large multicenter retrospective study shows that there exist a large treatment heterogeneity in advanced MF/SS and differences between USA and non-USA centers but these were not related to survival, while our data reveal that chemotherapy as first treatment is associated with a higher risk of death and/or change of therapy and thus other therapeutic options should be preferable as first treatment approach.

High HIV incidence in men who have sex with men attending for postexposure prophylaxis: a service evaluation.

BACKGROUND/AIMS: There are limited outcome data for men who have sex with men (MSM) who have received HIV postexposure prophylaxis (PEP). The objective of this service evaluation was to determine HIV incidence and repeat PEP use among MSM PEP recipients in London, UK. METHODS: Retrospective electronic case-note review of all MSM who were prescribed PEP between January and April 2013 at a central London sexual health service. RESULTS: 530 MSM received PEP between 1 January and 30 June 2013. Of these, 449 had more than 30 days subsequent follow-up at our service. Median age was 31 years. PEP indication was unprotected anal intercourse, 98% (receptive 88% and insertive 10%) and other, 2%. Up to 1 November 2015, total follow-up was 756 person-years. 183 users received repeat PEP. The total number of repeat PEP courses was 442. 57 MSM newly acquired HIV: the HIV incidence was 7.6 per 100 person-years. CONCLUSIONS: PEP was associated with a high risk of subsequent HIV seroconversion in this cohort; this group may be appropriate candidates for pre-exposure prophylaxis.

Neuropsychological and social cognitive function in young people at genetic risk of bipolar disorder.

BACKGROUND: Impairments in key neuropsychological domains (e.g. working memory, attention) and social cognitive deficits have been implicated as intermediate (endo) phenotypes for bipolar disorder (BD), and should therefore be evident in unaffected relatives. METHOD: Neurocognitive and social cognitive ability was examined in 99 young people (age range 16-30 years) with a biological parent or sibling diagnosed with the disorder [thus deemed to be at risk (AR) of developing BD], compared with 78 healthy control (HC) subjects, and 52 people with a confirmed diagnosis of BD. RESULTS: Only verbal intelligence and affective response inhibition were significantly impaired in AR relative to HC participants; the BD participants showed significant deficits in attention tasks compared with HCs. Neither AR nor BD patients showed impairments in general intellectual ability, working memory, visuospatial or language ability, relative to HC participants. Analysis of BD-I and BD-II cases separately revealed deficits in attention and immediate memory in BD-I patients (only), relative to HCs. Only the BD (but not AR) participants showed impaired emotion recognition, relative to HCs. CONCLUSIONS: Selective cognitive deficits in the capacity to inhibit negative affective information, and general verbal ability may be intermediate markers of risk for BD; however, the extent and severity of impairment in this sample was less pronounced than has been reported in previous studies of older family members and BD cases. These findings highlight distinctions in the cognitive profiles of AR and BD participants, and provide limited support for progressive cognitive decline in association with illness development in BD.

Randomised trial of cervical cerclage, with and without occlusion, for the prevention of preterm birth in women suspected for cervical insufficiency.

OBJECTIVE: To evaluate the effect of cerclage, with and without cervical occlusion. DESIGN: Multicentre, stratified, randomised controlled trial. SETTING: Hospital-based multicentre study with 18 tertiary centres from nine countries. POPULATION: Women with a history of cervical insufficiency (prophylactic trial) and women with a short cervix (therapeutic trial) were recruited from August 2006 to August 2011. METHODS: A centralised telephone randomisation service with a computer system was used to randomise women to cervical cerclage with or without cervical occlusion. Only the analyst performing the interim analyses was blinded. MAIN OUTCOME MEASURES: The take-home baby rate (number of infants discharged alive from the hospital), gestational age at delivery, and the number of days in the neonatal intensive care unit (NICU). RESULTS: Women (n = 309) were stratified into the prophylactic trial (n = 213) or the therapeutic trial (n = 96). The trial stopped early due to slow recruitment and an interim analysis showing no benefit of occlusion. Final analysis comprised 197 women in the prophylactic trial and 87 women in the therapeutic trial. No added effect of cervical occlusion was found in terms of the take-home baby rate in the prophylactic trial (92 versus 90%, RR 1.03, 95% CI 0.94-1.12) or in the therapeutic trial (81 versus 85%, RR 0.96, 95% CI 0.79-1.16). No effect of cervical occlusion was found in terms of gestational age at delivery and number of days the neonate spent in the NICU. Cervical occlusion was associated with no harm. CONCLUSIONS: Cervical occlusion with cerclage had no significant additional effect.

Cervical occlusion in women with cervical insufficiency: protocol for a randomised, controlled trial with cerclage, with and without cervical occlusion.

OBJECTIVE: To evaluate the effect of double cerclage compared with a single cerclage. DESIGN: Randomised, controlled multicentre trial. SETTING: Ten different countries are participating with both secondary and tertiary centres. The countries participating are Denmark, Sweden, Germany, United Kingdom, Spain, South Africa, Australia and India. This gives both a broad spectrum of diversity global and local. We expect a total of 242 women enrolled per year. POPULATION: Prophylactic study: 1. History of cervical incompetence/insufficiency. (Delivery 15 to <36 weeks.) 2. Congenital short cervix (secondary to maternal administration of diethyl stilbestrol) or traumatic/surgical damage rendering the vaginal approach difficult (e.g. conisation). 3. Cervical suture applied in previous pregnancy, successful outcome. 4. Previous failed cerclage. Therapeutic study: 5. Secondary cerclage: Short cervix, without the membranes being exposed to the vagina. 6. Tertiary cerclage: Short cervix, membranes exposed to the vagina. Observational study: Eligible women who refuse to be randomised will participate in an observational study. 7. Repeat/requested cervical occlusion. METHODS: The women will be randomised between a single (vaginal or abdominal) and a double cerclage. The cervical cerclage (McDonald or Shirodkar) as well as the abdominal suture will be performed with the same material and technique normally used by the participating department. Those randomised to the double cerclage will have their external os closed with a continuous nylon 2-0/3-0 suture, in addition to the standard single cerclage. Local guidelines concerning antibiotics, Heparin, bed rest, tocolytics etc. are followed and recorded in the follow-up form. MAIN OUTCOME MEASURES: Primary endpoint is take home baby rate. The secondary endpoints are gestational age at delivery, incidence of preterm birth (<34+0 days) and number of days in neonatal unit.

Modelling the role of groundwater hydro-refugia in East African hominin evolution and dispersal.

Water is a fundamental resource, yet its spatiotemporal availability in East Africa is poorly understood. This is the area where most hominin first occurrences are located, and consequently the potential role of water in hominin evolution and dispersal remains unresolved. Here, we show that hundreds of springs currently distributed across East Africa could function as persistent groundwater hydro-refugia through orbital-scale climate cycles. Groundwater buffers climate variability according to spatially variable groundwater response times determined by geology and topography. Using an agent-based model, grounded on the present day landscape, we show that groundwater availability would have been critical to supporting isolated networks of hydro-refugia during dry periods when potable surface water was scarce. This may have facilitated unexpected variations in isolation and dispersal of hominin populations in the past. Our results therefore provide a new environmental framework in which to understand how patterns of taxonomic diversity in hominins may have developed.

Preoperative endoscopy may reduce the need for revisional surgery for gastro-oesophageal reflux disease following laparoscopic sleeve gastrectomy.

Laparoscopic sleeve gastrectomy is a safe and effective bariatric operation, but postoperative reflux symptoms can sometimes necessitate revisional surgery. Roux-en-Y gastric bypass is the preferred operation in morbidly obese patients with gastro-oesophageal reflux disease. In 2011, we introduced preoperative endoscopy to assess for hiatus hernia or evidence of oesophagitis in conjunction with an assessment of gastro-oesophageal reflux symptoms for all patients undergoing bariatric surgery with a view to avoid sleeve gastrectomy for these patients. A prospectively maintained database was used to identify patients who underwent sleeve gastrectomy before and after we changed the unit policy. The need for revisional surgery in patients with troublesome gastro-oesophageal reflux disease was examined. Prior to 2011, 130 patients underwent sleeve gastrectomy, and 11 (8.5%) of them required conversion to Roux-en-Y gastric bypass for symptomatic reflux disease. Following the policy change, 284 patients underwent sleeve gastrectomy, and to date, only five (1.8%) have required revisional surgery (p = 0.001). Baseline demographics were comparable between the groups, and average follow-up period was 47 and 33 months, respectively, for each group. Preoperative endoscopy and a detailed clinical history regarding gastro-oesophageal reflux symptoms may improve patient selection for sleeve gastrectomy. Avoiding sleeve gastrectomy in patients with reflux disease and/or hiatus hernia may reduce the incidence of revisional surgery.

Localized melanoma in older patients, the impact of increasing age and comorbid medical conditions.

BACKGROUND: Elderly patients experience a different spectrum of disease and poorer outcomes than younger patients. This study investigated the impact of age and medical comorbidities on the management and outcome of patients ≥65 years. METHODS: A retrospective review of all patients ≥65 years (481 patients with 525 primary melanomas) presenting with AJCC clinical stage I-II melanoma to an Australian cancer centre between 2000 and 2008. RESULT: The median age was 74 years (65-94) with a male predominance (313 males, 65.0%) and median tumour thickness of 1.90 mm (IQR = 0.40-2.90, T1 = 33%, T2 = 20%, T3 = 24%, T4 = 23%). Inadequate surgical margins of excision (<10 mm) were common in older patients independent of site, thickness and ulceration (OR = 1.04, 95%CI = 1.00-1.07, p = 0.038). Inadequate excision margins were strongly associated with time to local recurrence, independent of age, thickness, ulceration and mitotic rate (HR = 3.00, 95%CI = 1.49-6.03, p = 0.0021), but not time to progression (p = 0.10) or disease specific survival (DSS, p = 0.27). Overall survival (OS) was strongly related to increasing age (HR = 1.04, 95%CI = 1.01-1.07, p = 0.015) and comorbid medical conditions (HR = 1.26, 95%CI = 1.12-1.42, p < 0.001), as assessed by the Charlson comorbidity index (CCI). DSS was significantly related to CCI (HR = 1.20, 95%CI = 1.01-1.42, p = 0.041) and not age (p = 0.46), when adjusting for thickness, ulceration and mitotic rate on multivariate analysis. CONCLUSION: Older patients present with poor prognosis melanomas yet are less likely to receive adequate surgical excision margins resulting in higher rates of local recurrence. In melanoma patients ≥65 years, the increasing number of medical comorbidities explains much of the age related variations in OS and DSS and should be considered when planning treatment.

Circadian regulation of teleost retinal cone movements in vitro.

In the retinas of many species of lower vertebrates, retinal photoreceptors and pigment epithelium pigment granules undergo daily movements in response to both diurnal, and in the case of teleost cone photoreceptors, endogenous circadian signals. Typically, these cone movements take place at dawn and at dusk when teleosts are maintained on a cyclic light (LD) regime, and at expected dawn and expected dusk when animals are maintained in continuous darkness (DD). Because these movements are so strictly controlled, they provide an overt indicator of the stage of the underlying clock mechanism. In this study we report that both light-induced and circadian-driven cone myoid movements in the Midas cichlid (Cichlasoma citrinellum), occur normally in vitro. Many of the features of retinomotor movements found in vivo also occur in our culture conditions, including responses to light and circadian stimuli and dopamine. Circadian induced predawn contraction and maintenance of expected day position in response to circadian modulation, are also normal. Our studies suggest that circadian regulation of cone myoid movement in vitro is mediated locally by dopamine, acting via a D2 receptor. Cone myoid contraction can be induced at midnight and expected mid-day by dark culture with dopamine or the D2 receptor agonist LY171555. Further, circadian induced predawn contraction can be increased with either dopamine or LY171555, or may be reversed with the dopamine D2 antagonist, sulpiride. Sulpiride will also induce cone myoid elongation in retinal cultures at expected mid-day, but will not induce cone myoid elongation at dusk. In contrast, circadian cone myoid movements in vitro were unaffected by the D1 receptor agonist SCH23390, or the D1 receptor antagonist SKF38393. Our short-term culture experiments indicate that circadian regulation of immediate cone myoid movement does not require humoral control but is regulated locally within the retina. The inclusion of dopamine, or dopamine receptor agonists and antagonists in our cultures, has indicated that retinal circadian regulation may be mediated by endogenously produced dopamine, which acts via a D2 mechanism.

Illuminance threshold for maintenance of testes in Syrian hamsters (Mesocricetus auratus) is higher in continuous light than in long photoperiods.

The illuminance threshold for maintenance of testicular function was found to be considerably higher in Syrian hamsters kept in continuous light (LL) than in hamsters on long-day (14-hr) photoperiods (LD 14:10), or in a similar-length skeleton photoperiod (LDSK); the threshold lay between 3 and 30 lux in LL and at approximately 0.3 lux in LD 14:10 or LDSK. The threshold for testicular maintenance in LL was related to the capacity of LL to suppress nocturnal melatonin secretion: 400 lux totally suppressed, 30 or 3 lux partially suppressed, and 0.3 lux failed to suppress melatonin secretion. Hamsters in the LD and LDSK groups, whose locomotion was entrained into a pattern characteristic of long-day exposure, maintained full testicular function; those whose locomotion free-ran or assumed a pattern of entrainment characteristic of short-day exposure underwent testicular regression. These results suggest that light signals entrain the circadian rhythms of locomotion and melatonin secretion in a similar manner, and that LL is less effective than LD or LDSK in shortening the duration of melatonin secretion. For hamsters in LL, a direct relationship was seen between the free-running period (tau) of locomotion and log10 illuminance at 0.3, 3.0, and 30 lux, but tau at 400 lux was no longer than tau at 30 lux. Splitting of locomotion did not occur at 0.3 or 3.0 lux, and occurred in 43% and 62% of hamsters in 30 and 400 lux, respectively.

The effect of abrupt lengthening of the photoperiod on the onset of ovulation in gonadotrophin-treated immature rats.

Immature female rats exposed daily to a-14 h photoperiod were induced to ovulate precociously by administering pregnant mares' serum gonadotrophin (PMS) at 30 days of age (day 30). In these rats ovulation occurs on day 33 between 0130 and 0330 (midpoint of photoperiod equals 1200). The acute effect on the timing of ovulation of abruptly lengthening the photoperiod by 6 h was investigated in this preparation. When compared with controls kept on a 14-h photoperiod, adding 6 h of light to the beginning of the daily photoperiod (i.e., AM light) advanced ovulation by 2 h; adding 6 h of light to the end of the photoperiod (i.e., PM light) delayed ovulation by 5.5 h; adding 3 h of light to the beginning and to the end of the photoperiod delayed ovulation by 2 h. These results suggest that the time of release of an ovulatory quota of pituitary gonadotrophin may be advanced by exposure to AM light and delayed by exposure to PM light, but the PM light appears to have a stronger effect on the time of gonadotrophin secretion.

Generation of soluble recombinant human acute phase serum amyloid A2 (A-SAA2) protein and its use in development of an A-SAA specific ELISA.

Human acute phase serum amyloid A (the A-SAA2 isoform) was expressed at high levels using the pGEX bacterial expression system. A-SAA2 protein was expressed in E. coli NM544 as part of a fusion protein facilitating rapid purification. A-SAA2 was cleaved from the fusion moiety in the presence of a non-ionic detergent (Triton X-100) to release a soluble A-SAA2. Further purification using ion exchange chromatography yielded a pure A-SAA2 (3 mg per litre of culture). Antibodies generated against recombinant A-SAA2 were specific for the acute phase SAAs, A-SAA1 and A-SAA2 and showed no cross-reactivity with the constitutively expressed SAA (C-SAA). These antibodies were used to develop a rapid enzyme-linked immunosorbent assay (ELISA) specific for the measurement of A-SAA in serum.

Light and circadian modulation of teleost retinal tyrosine hydroxylase activity.

PURPOSE: The authors examined the effects of both light and circadian phase on the synthetic activity of the dopamine producing enzyme, tyrosine hydroxylase (TH), in the retina of the Midas cichlid (Cichlasoma citrinellum). METHODS: TH activity was assayed in the retina-retinal pigment epithelium (RPE) complex of fish entrained to cyclic light regimens. The animals were killed throughout cyclic light and continuous dark cycles and after light exposure following short-term dark adaptation to assess the effects of both diurnal and circadian phase and light exposure on TH activity. Variations in retina-RPE TH activity were compared with cone retinomotor position. RESULTS: The authors report that TH activity was influenced both by light and by circadian phase. In both cyclic light and continuous darkness, TH activity fluctuated in cyclic fashion, increasing to peak values at night, declining through dawn, and reaching minimal values at midday. In continuous dark-adapted retinae, the peak activity at night was approximately sixfold greater than the minimum activity during the day. In cyclic light-adapted retinae at midday, the TH activity was 2.4-fold higher than that determined at the same time point in continuous dark-adapted retinae. Light onset enhanced the TH activity in previously dark-adapted animals by 2.2-fold at midday and 1.7-fold at dusk. Thus, retinal TH activity exhibits fluctuations of approximately sixfold in response to circadian signals and is stimulated approximately twofold by light. CONCLUSIONS: These observations indicate that dopamine production in the retina is regulated both by light and by circadian phase and that there are cyclic changes in dopamine production during the 24-hr cycle both in normal light and dark cycles and under conditions of constant darkness.

Parallel effects of light signals on the circadian rhythms of running activity and ovulation in rats.

Continuous monitoring of wheel-running activity and determination of the time of ovulation in rats by serial laparotomies revealed that ovulation followed the onset of running at prooestrus by approximately 9 h (range 7--1 h). This temporal relationship held in rats in which the period of the circadian rhythm had been modified (entrained) by daily exposure to 14 h photoperiods, and in rats in dim continuous light whose rhythms were non-entrained (free-running). Knowledge of this temporal relationship between the two rhythms made it possible to give bright light signals at known points in the circadian cycle of the rat and to observe the effects on the timing of running and ovulation in subsequent cycles. Giving daily light signals near the onset of running (i.e. at subjective dusk) delayed, whereas giving signals near the end of running (i.e. at subjective dawn) advanced, the time of running and ovulation in subsequent cycles. These results indicate that in rats exposed to the usual laboratory photoperiod the delaying effect of dusk light and the advancing effect of dawn light balance one another; thus the preovulatory surge of LH occurs at a relatively consistent time at prooestrus.