Immunogenic cell death in colorectal cancer: a review of mechanisms and clinical utility.

Colorectal cancer (CRC) is a major cause of cancer-related morbidity and mortality worldwide. Despite several clinical advances the survival of patients with advanced colorectal cancer remains limited, demanding newer approaches. The immune system plays a central role in cancer development, propagation, and treatment response. Within the bowel, the colorectal mucosa is a key barrier and site of immune regulation that is generally immunosuppressive. Nonetheless, within this tumour microenvironment, it is evident that anti-neoplastic treatments which cause direct cytotoxic and cytostatic effects may also induce immunogenic cell death (ICD), a form of regulated cell death that leads to an anti-tumour immune response. Therefore, novel ICD inducers and molecular biomarkers of ICD action are urgently needed to advance treatment options for advanced CRC. This article reviews our knowledge of ICD in CRC.

Postmenopausal hyperandrogenism due to an ovarian sex cord-stromal tumour causing elevated dehydroepiandrosterone sulphate: a case report.

BACKGROUND: The source of excess androgen can be obscure in postmenopausal women with new-onset hyperandrogenism. If serum dehydroepiandrosterone sulphate (DHEAS) is raised, it is presumed to be of adrenal origin because DHEAS is exclusively produced from adrenal cortical cells. This reports an elderly female presenting with new-onset hyperandrogenism due to an ovarian sex cord-stromal tumour, associated with increased serum DHEAS levels. CASE DESCRIPTION: A 76-year-old female with long-standing diabetes and hypertension presented with hirsutism and male type alopecia for six months. She had menopause at 55 years of age. There was a pelvic mass on examination. Total testosterone was 6.106 ng/ml (0.124-0.357) and DHEAS was > 1000 µg/dL (35-430). Contrast-enhanced computed tomography of the abdomen and pelvis showed a heterogeneously enhancing complex mass measuring 11 × 8 cm in the left adnexal region. Adrenal glands were normal. She underwent total abdominal hysterectomy, bilateral salphingo-oophorectomy, and omentectomy. Both testosterone and DHEAS normalised following surgery. Histology revealed a sex cord-stromal tumour, likely a steroid cell tumour with malignant potential. Fluorodeoxyglucose-Positron emission tomography did not show any additional lesions. CONCLUSIONS: Due to the lack of sulfotransferase in ovarian tissue, markedly elevated DHEAS originating from an ovarian neoplasm is unusual. This phenomenon has not been described except in a patient with a steroid cell tumour causing Cushing syndrome and hyperandrogenism. The mechanism of this rare occurrence remains elusive. Knowledge of this unusual presentation would enable the clinicians to be cautious in localising the androgen source in women with hyperandrogenism.

Modeling the association between socioeconomic features and risk of flood damage: A local-scale case study in Sri Lanka.

Floods cause severe damage to people as well as to properties. The same flood can cause different levels of damage to different households, but investigations into floods tend to be conducted on regional and national scales, thereby missing these local variations. It is therefore necessary to understand individual experiences of flood damage to implement effective flood management strategies on a local scale. The main objectives of this study were to develop a model that represents the relationship between socioeconomic conditions and flood damage at a local scale, and to understand the socioeconomic factors most closely tied to flood damage. The analysis is novel in that it considers not only the impact of flood characteristics, but also the impact of social, economic, and geographic factors on flood damage. This analysis derives from a quantitative modeling approach based on community responses, with the responses obtained through questionnaire surveys that consider four consecutive floods of differing severity. Path analysis was used to develop a model to represent the relationships between these factors. A randomly selected sample of 150 data points was used for model development, and nine random samples of 150 data points were used to validate the model. Results suggest that poor households, located in vulnerable, low-lying areas near rivers, suffer the most from being exposed to frequent, severe floods. Further, the results show that the socioeconomic factors with the most significant bearing on flood damage are per capita income and geographic location of the household. The results can be represented as a cycle, showing that social, economic, geographic, and flood characteristics are interrelated in ways that influence flood damage. This empirical analysis highlights a need for local-scale flood damage assessments, as offered in this article but seldom seen in other relevant literature. Our assessment was achieved by analyzing the impact of socioeconomic and geographic conditions and considering the relationship between flood characteristics and flood damage.

Phosphorylated Tau protein in the myenteric plexus of the ileum and colon of normothermic rats and during synthetic torpor.

Tau protein is of primary importance for neuronal homeostasis and when hyperphosphorylated (PP-Tau), it tends to aggregate in neurofibrillary tangles, as is the case with tauopathies, a class of neurodegenerative disorders. Reversible PP-Tau accumulation occurs in the brain of hibernating rodents and it was recently observed in rats (a non-hibernator) during synthetic torpor (ST), a pharmacological-induced torpor-like condition. To date, the expression of PP-Tau in the rat enteric nervous system (ENS) is still unknown. The present study immunohistochemically investigates the PP-Tau expression in the myenteric plexus of the ileum and colon of normothermic rats (CTRL) and during ST, focusing on the two major subclasses of enteric neurons, i.e., cholinergic and nitrergic.Results showed that both groups of rats expressed PP-Tau, with a significantly increased percentage of PP-Tau immunoreactive (IR) neurons in ST vs. CTRL. In all rats, the majority of PP-Tau-IR neurons were cholinergic. In ST rats, the percentage of PP-Tau-IR neurons expressing a nitrergic phenotype increased, although with no significant differences between groups. In addition, the ileum of ST rats showed a significant decrease in the percentage of nitrergic neurons. In conclusion, our findings suggest an adaptive response of ENS to very low core body temperatures, with changes involving PP-tau expression in enteric neurons, especially the ileal nitrergic subpopulation. In addition, the high presence of PP-Tau in cholinergic neurons, specifically, is very interesting and deserves further investigation. Altogether, these data strengthen the hypothesis of a common cellular mechanism triggered by ST, natural hibernation and tauopathies occurring in ENS neurons.

Drinking Water and CKD of Unknown Etiology in Sri Lanka: A Community Perspective.

People's belief that polluted drinking water is the principal medium through which environmental toxins are absorbed into the bodies of CKD of unknown etiology (CKDu) patients in the CKDu-endemic areas in Sri Lanka has been the subject of extensive epidemiological and medical research. This study examines (a) the people's perception and experience that polluted drinking water is the cause of CKDu, (b) how the government responded to people's demands for potable water, and (c) the impact of the use of alternative drinking water sources on the health of CKDu patients and their families, and on the progression of the disease in CKDu patients. Data were collected in 2013 and 2019 in Anuradhapura and Polonnaruwa districts in North Central Province of Sri Lanka. People's agitation, activism, and lobbying, together with the media's work in bringing the issue of polluted water to the forefront of political discourse, have prompted the government, private sector agencies, and community organizations to supply clean water to affected communities. A massive change in drinking water behaviors has occurred following the government's decision to supply reverse osmosis (RO) water to the affected communities. Informants perceived the provision of RO water as having brought about many positive outcomes in the health and disease progression of CKDu patients.

Bladder cancer in women: a Sri Lankan study

Introduction: Bladder cancer (BC) is the ninth commonest cancer globally, and ranks 19th among women. The literature on BC in women is sparse, and the knowledge on the variations of tumour characteristics in South Asian female BC is limited. The objective of this study was to describe the clinicopathological characteristics of BC in women and compare them with male BC. Methods: A retrospective analysis of all female patients with histopathologically proven newly diagnosed primary BC from January 2007 to January 2017 was done at the Urology Unit, National Hospital of Sri Lanka, and the findings were compared with men with BC during the same period. Results: There were 314 patients with primary BC, of which 55(17.5%) were women, with a male:female ratio of 4.7:1. Only 70.9% of women had haematuria at presentation. Forty-four women (80%) had urothelial bladder cancers(UBC). The mean age of women with UBC was 67±SD13.2 years, and for non-urothelial bladder cancers(NUBC) was 62.5±SD 12.7 years. NUBC in women accounted for a disproportionately higher percentage in comparison to men (20% vs.5.4%, p<0.001). Of the UBCs, muscle invasive BC accounted for 45.5% (20/44) in women as opposed to 33.5% (82/245) in men. Women had a significantly higher proportion of solid tumours (40%vs.22.8%,p=0.008) compared to men. Conclusion: Primary BC in women has a significantly higher proportion of NUBC and muscle invasive UBC, which are more aggressive cancers, compared to men. Furthermore, the lack of haematuria in >25%, and higher incidental diagnosis, with inherently thinner bladder wall, makes primary BC in women more likely to present late, in a more advanced state.

Drinking water and chronic kidney disease of unknown aetiology in Anuradhapura, Sri Lanka.

This paper examines how people in Anuradhapura District in Sri Lanka affected by endemic chronic kidney disease of unknown aetiology (CKDu) explain the factors causing the illness and their cultural meanings. The research found that the issue of contaminated water raised by the local community and the cultural meaning of water have influenced the government policy, health programmes, research agendas and the work of the media. Media reports on sociocultural, biomedical and epidemiological research into the aetiology of kidney disease have strengthened the perspective of the villagers who believe that polluted water has a direct relationship to kidney disease. This new understanding among villagers in Anuradhapura District has led to changes in their behaviours relating to the use and consumption of water, an important factor that has reinforced existing social hierarchies.

Embolizing pulmonary aspergillosis, mycobacterial & aspergillous splenic abscess and cytomegalovirus co-infection following steroid induced immunosuppression: a case report.

BACKGROUND: Aspergillosis is a serious infection particularly affecting the immunodeficient host. Its co-infection with tuberculosis and cytomegalovirus has not been reported before. Embolic events are well recognized with aspergillous endocarditis and aortitis. Splenic abscess is a rare serious complication of disseminated aspergillosis and is difficult to treat. We report the first case of multiple embolic events and splenic abscess in a patient with pulmonary aspergillosis and cytomegaloviral and tuberculous co-infection, without endocarditis or aortitis. CASE PRESENTATION: Thirty-year-old male presented with fever and non-productive cough while on glucocorticoids for glomerulonephritis. He was found to have pulmonary aspergillosis and subsequently developed bilateral lower limb and cerebral fungal emboli and fungal abscess in the spleen. He had IgM and B cell deficiency and cytomegalovirus (CMV) and tuberculous co-infections. He recovered after prolonged course of antimicrobials, splenectomy and cessation of glucocorticoid therapy which also lead to the resolution of immune deficiencies. CONCLUSION: This report illustrates rare combination of B and T cell suppressive effects of glucocorticoids leading to co-infections with CMV, Mycobacterium tuberculosis and Aspergillus and systemic fungal embolization from pulmonary aspergillosis.

Star fruit nephrotoxicity: a case series and literature review.

BACKGROUND: Star fruit is a popular medicinal fruit in the tropics. Its hypoglycaemic properties are considered useful in achieving glycaemic control in diabetes. Star fruit induced nephrotoxicity is a rare cause of acute kidney injury in individuals with both normal and reduced baseline renal function. We present three cases of acute kidney injury due to star fruit nephrotoxicity from Sri Lanka, and discuss the published literature on this topic. CASE PRESENTATION: Three Sri Lankan patients, all with a background of diabetes, presented to us with acute nausea and anorexia following recent consumption of star fruit. Two patients complained of diarrhoea and one patient complained of intractable hiccoughs. They all had elevated serum creatinine on admission. Two were known to have normal baseline serum creatinine levels. On renal biopsy two had evidence of oxalate crystal deposition. One did not show crystal deposition but had acute interstitial nephritis for which no alternate cause could be identified. Two were treated with short courses of prednisolone and two required acute haemodialysis. All recovered renal function, with both patients with known baselines approaching their premorbid serum creatinine levels. CONCLUSION: Consumption of star fruit, especially on an empty stomach or in a state of dehydration may precipitate acute kidney injury. A history of star fruit ingestion must be actively looked for in patients presenting with unexplained acute kidney injury. The use of star fruit as a therapy for diabetes should be discouraged.

In situ immunopathological changes in cutaneous leishmaniasis due to Leishmania donovani.

Cutaneous leishmaniasis in Sri Lanka is a newly established parasitic disease caused by the usually visceralizing Leishmania donovani. Skin lesions manifest as non-itchy, non-tender papules, nodules or ulcers. In situ cytokine expression provides clues for immunopathogenesis of this localized form of disease. Skin biopsies from 58 patients were analyzed for histological appearance and in situ cytokine expression of T-helper 1 (Th1) and T-helper 2 (Th2) cytokines, namely interferon (IFN)-γ, interleukin (IL)-12A, tumor necrosis factor (TNF)-α, IL-4 and IL-10 by real-time RT-PCR. Significant up-regulation of the Th1 cytokine IFN-γ and down-regulation of the Th2 cytokine IL-4 were seen in patients compared to healthy controls. Significantly elevated tissue expression of IFN-γ and TNF-α was seen in lesions that presented later than 6 months from the time of onset, while IL-4 expression was more prominent in lesions that responded poorly to antimony therapy. A prominent Th1 response appears to support resolving of lesions, whereas a Th2-biased milieu tends to favor poor responsiveness to antimony and delayed lesion healing in L. donovani infections in Sri Lanka.

How many Medical specialists do Ministry of Health- Sri Lanka need by 2025: Use of system dynamics modelling for policy decisions

Introduction: The Ministry of Health is the largest health care provider in Sri Lanka in terms of funding, coverage and human resources. Long duration and high training cost of a medical specialist highlights the importance of health human resource planning. Ministry of Health, Sri Lanka has no scientific cadre planning for medical specialists. Methods: System dynamics, an analytical modelling approach and a methodology for studying complex feedback systems was used. Two sub models of "need" and "supply" were developed and simulated over a period of 10 years from 2016 to 2025. Results: By December 2015 there were 1860 clinician medical specialists with an average age of 46.8 years, in the government hospitals in Sri Lanka. In the surgical group of specialties the Proposed Training Rate is more than Current Training Rate while in Medical and Paediatric groups and in Radiology, Anaesthesiology, Psychiatry, Dermatology and Hematology Proposed Training Rate is less than the Current Training Rate. Conclusions: In Surgical specilities the number of trainees enrolled in the Pre-MD programme should be increased from 55 to 71 and while in Medical specilaities the number of trainees enrolled in Pre- MD programmes should be reduced from 107 to 68 and in the Paediatric specialities from 47 to 39. During the 2016-2025 period, 765 specialists will be lost to the Ministry of Health costing nearly Rs 7.6 billion and there will be 4050 consultants by 2025, which is a 120% increase.

Metabolic equivalent determination in the cultural dance of hula.

Ethnic minorities share an unequal burden of cardiometabolic syndrome. Physical activity (PA) has been shown to be an important factor for improving the outcomes of these diseases. While metabolic equivalents (METs) have been calculated for diverse activities, most cultural activities have not been evaluated. Hula, the traditional dance of Native Hawaiians, is practiced by men and women of all ages but its MET value is unknown. To our knowledge, this is the first scientific evaluation of energy expenditure of hula. 19 competitive hula dancers performed 2 dance sets of low- and high-intensity hula. METs were measured with a portable indirect calorimetry device. Mean and standard deviations were calculated for all the variables. A 2-way ANOVA was conducted to identify differences for gender and intensity. The mean MET were 5.7 (range 3.17-9.77) and 7.55 (range 4.43-12.0) for low-intensity and high-intensity, respectively. There was a significant difference between intensities and no significant difference between genders. This study demonstrates that the energy expenditure of both low- and high-intensity hula met the recommended guidelines for moderate and vigorous intensity exercise, respectively, and that hula can be utilized as a prescribed PA.

Translation, cross-cultural adaptation, and validation of the Duke Activity Status Index (DASI) to Sinhala language.

BACKGROUND: Duke Activity Status Index (DASI) is a widely used tool to assess functional capacity among patients, but there is no Sinhala version validated for patients in Sri Lanka. This study aimed to cross-culturally adapt and test the validity and reliability of the Sinhala version of DASI (DASI-S). METHODS: The translation and cross-cultural adaptation of the DASI questionnaire were conducted following the standard guidelines. It was pre-tested on ten pre-operative patients and further modified. The construct validity and reliability of DASI-S were evaluated by administering the modified final DASI-S, which comprised 12 items, along with the physical functioning sub-scale of the 36-item short-form health survey (SF-36), consisting of 10 items to eighty-one patients who were awaiting non-cardiac surgeries at university surgical wards, National Hospital of Sri Lanka (NHSL), and Colombo North Teaching Hospital (CNTH), Sri Lanka. Reliability was assessed through Cronbach alpha, while the validity was evaluated using factor analysis and Spearman's correlation. The ethical approval was obtained from the Ethics Review Committee, Faculty of Medicine, University of Colombo, Sri Lanka. RESULTS: The mean age of the participants was 46.2 (± 16.6) years and the majority were females (54.3%). The mean height, weight, and body mass index of the sample were 160.5 (± 9.6) cm, 60.3 (± 11.9) kg, and 23.4 (± 4.5) kgm-2 respectively. The Cronbach's alpha coefficient for the internal consistency of DASI-S was 0.861. The concurrent validity of DASI-S was substantiated by positively correlating (p < 0.01, rs = 0.466) with the physical sub-scale of SF-36. There was a significant difference (p < 0.01) in the total score of DASI-S between the two age groups. CONCLUSIONS: Sinhala version of the DASI appears to be a valid, reliable and easy-to-administer tool to assess functional capacity among patients who are awaiting non-cardiac surgeries.

Polyphyly of the Dinurinae Looss, 1907 (Digenea: Hemiuridae) and resurrection of the Mecoderinae Skrjabin & Guschanskaja, 1954 based on novel collection of Tubulovesicula laticaudi Parukhin, 1969 from marine elapid snakes in Sri Lanka.

With one exception, the only known hemiurid trematodes that do not use teleost fishes as definitive hosts instead occur in marine elapid snakes. These comprise six species across four genera and three subfamilies, and so presumably indicate at least three independent invasions of marine snakes from teleost fishes. Here, one of these taxa, Tubulovesicula laticaudi Parukhin, 1969 (= T. orientalis Chattopadhyaya, 1970 n. syn.) is reported from Sri Lanka, collected from Shaw's sea snake Hydrophis curtus (Shaw) (Elapidae: Hydrophiinae: Hydrophinii), the annulated sea snake H. cyanocinctus Daudin and the yellow sea snake H. spiralis (Shaw) off Nayaru in the Bay of Bengal, and from H. spiralis in Portugal Bay, Gulf of Mannar. Novel molecular data, for COI mtDNA and ITS2 and 28S rDNA, are the first for a species of Tubulovesicula Yamaguti, 1934. Nominally, Tubulovesicula belongs in the Dinurinae Looss, 1907, but in phylogenetic analyses based on 28S rDNA, our sequences for T. laticaudi resolved relatively distant from that for representatives of Dinurus Looss, 1907, the type-genus, rendering the subfamily polyphyletic. Tubulovesicula laticaudi resolved closest to data for the type-species of the Plerurinae Gibson & Bray, 1979, but that subfamily is also polyphyletic. These findings lead us to re-evaluate an alternative classification considered by Gibson & Bray (1979). We propose restricting the Dinurinae for forms with a permanent sinus-organ (Dinurus, Ectenurus Looss, 1907; Erilepturus Woolcock, 1935; Paradinurus Vigueras, 1958; Qadriana Bilqees, 1971) and resurrect the Mecoderinae Skrjabin & Guschanskaja, 1954 for forms with a temporary sinus-organ (Mecoderus Manter, 1940, Allostomachicola Yamaguti, 1958, Stomachicola Yamaguti, 1934 and Tubulovesicula).

Single-centre experience with peptide receptor radionuclide therapy for neuroendocrine tumours (NETs): results using a theranostic molecular imaging-guided approach.

AIM: To summarise our centre's experience managing patients with neuroendocrine tumours (NETs) in the first 5 years after the introduction of peptide receptor radionuclide therapy (PRRT) with [177Lu]Lu-DOTA-octreotate (LUTATE). The report emphasises aspects of the patient management related to functional imaging and use of radionuclide therapy. METHODS: We describe the criteria for treatment with LUTATE at our centre, the methodology for patient selection, and the results of an audit of clinical measures, imaging results and patient-reported outcomes. Subjects are treated initially with four cycles of ~ 8 GBq of LUTATE administered as an outpatient every 8 weeks. RESULTS: In the first 5 years offering LUTATE, we treated 143 individuals with a variety of NETs of which approx. 70% were gastroentero-pancreatic in origin (small bowel: 42%, pancreas: 28%). Males and females were equally represented. Mean age at first treatment with LUTATE was 61 ± 13 years with range 28-87 years. The radiation dose to the organs considered most at risk, the kidneys, averaged 10.6 ± 4.0 Gy in total. Median overall survival (OS) from first receiving LUTATE was 72.5 months with a median progression-free survival (PFS) of 32.3 months. No evidence of renal toxicity was seen. The major long-term complication seen was myelodysplastic syndrome (MDS) with a 5% incidence. CONCLUSIONS: LUTATE treatment for NETs is a safe and effective treatment. Our approach relies heavily on functional and morphological imaging informing the multidisciplinary team of NET specialists to guide appropriate therapy, which we suggest has contributed to the favourable outcomes seen.

Incidence of prostate cancer in Sri Lanka using cancer registry data and comparisons with the incidence in South Asian men in England.

OBJECTIVE: •To investigate the incidence of carcinoma of the prostate (CaP) in Sri Lanka and compare the rates with the migrant population in the UK. METHODS: •The Sri Lanka cancer registry data were used to determine the rates of CaP in Sri Lanka from 2001 to 2005. •The incidence of CaP in 8,426,000 men, aged ≥30 years, was analysed using 5-year age bands and age-standardized rates were calculated using European standard population data. •The relative risk was calculated by comparison with the South Asian migrant population in the UK using the Prostate Cancer in Ethnic Subgroups (PROCESS) study data, a population-based retrospective cohort study of 2140 men carried out over a 5-year period in four predefined areas of southern England. •Data from incidental findings of CaP in Sri Lanka on transurethral resection of the prostate (TURP) specimens were also analysed. RESULTS: •In all, 1378 new cases of CaP were diagnosed during the 5-year period with a mean age of 69.2 years at diagnosis. •Compared with the previous 5 years, the incidence of CaP had doubled to 5.7 per 100,000, but was significantly lower than in the PROCESS study (relative risk 0.25). •Districts with a higher population density had higher adjusted rates of CaP in Sri Lanka (5.8-12.4 per 100,000). •For TURP specimens, 16.8-18.75% had incidental diagnoses of CaP in Sri Lanka, higher than other published studies. CONCLUSIONS: •The Sri Lankan cancer registry data showed a low rate of CaP, similar to other South Asian countries, but the actual incidence of CaP in Sri Lanka is probably higher than reported, as seen in the densely populated districts and the high rate of incidental diagnosis of CaP in TURP specimens. •The incidence of CaP in migrant South Asians in the UK was much higher than in Sri Lanka. •Further studies are required to examine the environmental and genetic components which may be responsible for the low incidence of CaP in Sri Lanka.

Pulmonary langerhans cell histiocytosis masquerading as tuberculosis in an infant.

A 4-month-old infant presented with continued fever, unresolving bronchopneumonia and household contact with sputum-smear-positive tuberculosis (TB) and showed marginal improvement on anti-TB chemotherapy. Recurrent pneumothorax prompted the clinical diagnosis of TB to be revised. High-resolution CT scan of the chest and open lung biopsy confirmed the diagnosis of pulmonary Langerhans cell histiocytosis. Treatment with prednisolone and vinblastin resulted in settling of fever and resolution of respiratory symptoms and signs. In communities where the prevalence of TB is high, unusual presentations should prompt consideration of alternative diagnoses.

Case report: NTRK1-rearranged cervical sarcoma with fibrosarcoma like morphology presenting in a 13-year-old managed with a neo-adjuvant TRK-inhibitor and surgical excision.

This case report reviews the case of a 13-year-old patient who presented with a 9 cm NTRK1-rearranged cervical sarcoma with fibrosarcoma like morphology. At presentation the lesion filled her vagina and pelvis and any attempt at surgical removal would have been morbid and led to loss of fertility. These neoplasms are extremely rare with 18 cases of the uterine cervix reported in the literature, none of which have occurred in a paediatric patient, and none of whom have received neo-adjuvant therapy prior to excision. Based upon evidence that has shown good tolerability and responses of paediatric NTRK fusion-positive solid tumours to TRK inhibitors, both in the neo-adjuvant and upfront setting, this patient was managed with neo-adjuvant entrectinib. Following a dramatic reduction in tumour size confirmed by imaging, she underwent conservative fertility sparing surgery with final histopathology showing no residual disease.