Clustered papulonodular lesions in an infant.

Non-Langerhans cell histiocytosis is a collective term encompassing a vast group of benign proliferative disorders of histiocytes, macrophages and dendritic cells that do not meet the criteria of Langerhans cell histiocytosis. We describe a case of juvenile xanthogranuloma with an unusual clustered distribution.

Intraepithelial tumour infiltrating lymphocytes are associated with absence of tumour budding and immature/myxoid desmoplastic reaction, and with better recurrence-free survival in stages I-III colorectal cancer.

AIMS: Tumour budding (TB), desmoplastic reaction (DR) and intraepithelial tumour infiltrating lymphocytes (iTILs) are recently recognised prognostic factors in colorectal cancer (CRC). In this study, we evaluated their significance and relationship to each other and their cumulative effect on survival. METHODS AND RESULTS: A total of 372 stages I-III CRC cases from 2013 to 2016 were included. Low TB was identified in 302 (81%) cases, immature/myxoid DR in 67 (18%) cases and iTILs in 130 (35.0%) cases. iTILs was associated with low budding (P = 0.0247), non-myxoid DR (P = 0.0004), poorly differentiated histology (P = 0.0015), absence of perineural invasion (P = 0.0367) and loss of mismatch repair proteins (P = 0.0002). Absence of iTILs and presence of immature/myxoid DR were associated with a worse recurrence-free survival (RFS) [hazard ratio (HR) = 2.191, 95% confidence interval (CI) = 1.232-3.895; and HR = 5.706, 95% CI = 3.632-8.964, respectively]. A competing risk analysis showed statistically significant prognostic groups combining iTILs and TB (P < 0.0001). Cases with iTILs and low TB were associated with better RFS compared to cases without iTILs and with intermediate/high TB (HR = 0.214, 95% CI = 0.109-0.421). Similarly, combining iTILs and DR revealed statistically significant prognostic groups (P < 0.0001). Cases with iTILs and a non-myxoid DR had better RFS compared to cases without iTILs and immature/myxoid DR (HR = 0.113, 95% CI = 0.056-0.230). On multivariate cause-specific analysis, patients' age (P = 0.0045), iTILs (P = 0.0345), DR (P < 0.0001) and pTNM prognostic groups (P < 0.0001) were associated with RFS. CONCLUSIONS: Our study validates the association of iTILs and DR as independent prognostic finding in CRC, and propose a prognostic model using the combinations of iTILs with TB and stromal reaction in CRC.

Severe epidermolysis bullosa/Kindler syndrome-like phenotype of an autoinflammatory syndrome in a child.

A 5-year-old boy presented with generalized cutaneous erosions, severe scarring, depigmentation and contractures affecting major joints. The lesions had initially affected his ears, nose, feet, and the genital and ocular mucosa, leading to significant depigmentation, scarring, contractures and mutilation. The whole of the trunk and limbs were involved at the time of presentation, with the exception of some islands of spared skin on the proximal thighs, legs, nipples and external genitalia. Electron microscopy revealed a split in the sublamina densa with the absence of anchoring fibrils, suggestive of dystrophic epidermolysis bullosa (EB). Immunofluorescence antigen mapping demonstrated a broad reticulate pattern of staining with collagen IV, VII, and laminin 332 in the floor of the blister, suggestive of Kindler syndrome. Next-generation sequencing revealed a de novo heterozygous missense mutation (a variant of unknown significance) in exon 22 of the phospholipase-C gamma 2 gene (PLCG2), which resulted in a substitution of serine by asparagine at codon 798 (p.Asp798Ser), a result that was validated using Sanger sequencing. The child was diagnosed with PLCG2-associated antibody deficiency and immune dysregulation (PLAID)/autoinflammation and PLCG2-associated antibody deficiency and immune dysregulation (APLAID) syndrome. The cutaneous and corneal erosions, inflammation and scarring of this magnitude, and the eventual result of death have not been described previously for the PLAID/APLAID spectrum previously. In conclusion, this was an unusual acquired autoinflammatory severe EB-like disease that may be associated with de novo PLCG2 mutation.

Primary papillary epithelial tumour of the sella: expanding the spectrum of TTF-1-positive sellar lesions.

AIM: To describe four novel primary epithelial tumours of the sella with papillary architecture and Thyroid Transcription Factor 1 (TTF-1) expression. METHODS: Paraffin-embedded tissue from the four cases and recurrence of patient 1 was investigated with haematoxylin-eosin, special histochemical stains, immunohistochemistry with a broad panel of antibodies and next-generation sequencing. The ultrastructure of one tumour was studied in tissue retrieved from paraffin. RESULTS: The lesions occurred in three females aged 20, 26 and 42 years and a male aged 49 years. They presented with signs and symptoms secondary to pituitary stalk compression. Preoperative neuroimaging documented mixed solid and cystic, enhancing sellar masses with suprasellar extension. Histologically, the tumours showed thin papillae lined by a single layer of cytokeratin and TTF-1-positive cuboidal and cylindrical cells with mildly atypical nucleus. Next-generation sequencing performed in three cases did not identify any mutations. The main differential diagnosis included metastasis from lung or thyroid carcinoma, extraventricular choroid plexus papilloma and sellar ependymoma. CONCLUSION: We suggest the descriptive term of primary papillary epithelial tumour of the sella (PPETS) for this entity and propose that it could represent the intracranial equivalent of thyroid-like low-grade nasopharyngeal papillary adenocarcinoma. The cell of origin of PPETS remains undetermined although the intense and ubiquitous expression of TTF-1 may suggest a derivation from the infundibulum or ventricular recess. Our study expands the spectrum of sellar TTF-1-positive tumour and challenges the view that they all derive from pituicytes.

A retrospective study of lichen planus pigmentosus with focus on palmoplantar involvement.

Lichen planus pigmentosus (LPP) is a rare disease characterized by persistent and asymptomatic slate-grey pigmentation, which mostly affects patients with skin types IV-VI. The face and neck are the most commonly involved sites, followed by the trunk and extremities. LPP is believed to spare the palms, soles and nails. In this report, we describe palmoplantar involvement in 10 (4.65%, 10/215) patients with LPP, and compare its clinicodemographic features with those of classic LPP. LPP lesions on the palms and soles present as asymptomatic, well-circumscribed, hyperpigmented, brown-black patches without any history of prior lichen planus lesions. They are mostly observed in young patients with rapidly spreading active disease, who often require systemic treatment to control the disease activity. Strikingly, palmoplantar involvement is frequently associated with other atypical LPP variants. It is important to identify palmoplantar involvement in LPP, as it has a different clinical course and associations compared with classic LPP.

Dermatoscopy in leprosy and its correlation with clinical spectrum and histopathology: a prospective observational study.

BACKGROUND: Leprosy, a chronic granulomatous infection has varied clinical presentations spanning across different spectrums. The scope of dermatoscopy is vast and has been studied for other granulomatous disorders like sarcoidosis. OBJECTIVES: The objective of this study was to describe the dermatoscopic features of the entire spectrum of leprosy and to correlate with clinical and histopathological findings. METHODS: This was a prospective observational study of treatment naïve leprosy patients over a period of 1 year. The study patients were categorized as per Ridley-Jopling classification based on clinical, slit skin smear and histopathological findings. Most representative lesions were photographed, evaluated by dermatoscopy and were biopsied. RESULTS: A total of 30 patients (21 males and 9 females) were recruited; 2 cases of tuberculoid leprosy, 12 cases of borderline tuberculoid (3 with type 1 reaction), 8 cases of borderline lepromatous, 6 cases of lepromatous leprosy (3 with type 2 reaction) and 2 cases of Histoid leprosy. The dermatoscopic featues consistently seen were yellowish orange areas and vascular structures like linear branching vessels and crown vessels correlating with the presence of dermal granulomas and dilated vessels. Broken pigment network, white chrysalis like areas were seen in addition. Tuberculoid spectrum also had absence of or diminished hair follicles and eccrine duct openings correlating with presence of peri-appendageal granuloma and appendageal destruction. Scaling and follicular plugs were other features in lesions of type 1 reaction. CONCLUSION: Yellowish-orange areas and vascular structures are the common dermatoscopic features of leprosy. Broken pigment network and paucity of appendageal structures are additional specific features.

Inter-relationship between intercepted radiation and rice yield influenced by transplanting time, method, and variety.

Photosynthetically active radiation (PAR) is one of the most important environmental factors that determine the productivity and grain quality of the crops. Continuous rainy days or cloudy weather throughout crop growth especially at critical stages often resulted in great loss of grain quality and yield in rice. Low light stress has rigorously constrained the rice production in various rice-growing regions, especially in Southeast Asia. Method and time of planting are the major management factors contributing to the higher yield potential of rice by influencing light harvesting and use efficiency. Present study was executed consecutively for 5 years (kharif seasons of 2012-2016) to determine whether planting time improves the radiation absorption and use efficiency in different duration rice cultivars. We evaluated the difference in plant growth and development leading to yield formation under different planting time which related to radiation incidence and interception. The results of the study revealed that PAR interception depends on morphological characters of cultivars and also with agronomic management such as transplanting time and method. Long duration cultivar intercepted more PAR but interception decreased due to late planting (3rd week of July), whereas short duration cultivars (Naveen) when planted earlier (1st week of June) could not effectively utilize intercepted PAR constraining the biomass accumulation and yield formation. Effect of planting density and crop architecture on PAR absorption was apparent among establishment methods as light interception at crop canopy was highest in the system of rice intensification and lowest in that of wet direct seeding. In general, Pooja as a long duration cultivar intercepted more PAR per day but when compared on same date of planting, the comparative absorption of radiation was 30.6% higher in Naveen. The lower yields in the wet season are attributed mostly to reduction in grain number per panicle or per unit land area, which is a consequence of high spikelet sterility. Grain yield of rice planted in July third week was reduced by 3.8, 12.3, and 6.9% over June first and third week and July first week, respectively, mainly due to spikelet sterility (26%) and lower grains per panicle (18%). Our results indicated that agronomic management like optimum time of sowing, cultivar duration, and establishment methods should be followed for yield improvement in tropical lowlands where light intensity is limiting due to prevailing weather situations.

Haemodynamic response to pre-hospital emergency anaesthesia in trauma patients within an urban helicopter emergency medical service.

PURPOSE: Pre-hospital emergency anaesthesia is routinely used in the care of severely injured patients by pre-hospital critical care services. Anaesthesia, intubation, and positive pressure ventilation may lead to haemodynamic instability. The aim of this study was to identify the frequency of new-onset haemodynamic instability after induction in trauma patients with a standardised drug regime. METHODS: A retrospective database analysis was undertaken of all adult patients treated by a physician-led urban pre-hospital care service over a 6-year period. The primary outcome measure was the frequency of new haemodynamic instability following pre-hospital emergency anaesthesia. The association of patient characteristics and drug regimes with new haemodynamic instability was also analysed. RESULTS: A total of 1624 patients were included. New haemodynamic instability occurred in 231 patients (17.4%). Patients where a full-dose regime was administered were less likely to experience new haemodynamic instability than those who received a modified dose regime (9.7% vs 24.8%, p < 0.001). The use of modified drug regimes became more common over the study period (p < 0.001) but there was no change in the rates of pre-existing (p = 0.22), peri-/post-anaesthetic (p = 0.36), or new haemodynamic instability (p = 0.32). CONCLUSION: New haemodynamic instability within the first 30 min following pre-hospital emergency anaesthesia in trauma patients is common despite reduction of sedative drug doses to minimise their haemodynamic impact. It is important to identify non-drug factors that may improve cardiovascular stability in this group to optimise the care received by these patients.

Prospective Phase II Study of Radiotherapy Dose Escalation in Grade 4 Glioma Using 68Ga-Pentixafor PET Scan.

AIMS: Local failure remains the major concern in grade 4 glioma or glioblastoma (GBM). Pilot studies have shown a radiotherapy (RT) dose-response relationship in GBM. Here we present our preliminary data of RT dose escalation using 68Ga-Pentixafor PET scan. High 68Ga-pentixafor uptake in glioma cells helps in sharp demarcation between tumour and normal brain. MATERIALS AND METHODS: This phase II prospective study was conducted from 2018 to 2020. Thirty, biopsy-proven cases of grade 4 glioma were included. All patients underwent post-operative MRI of the brain and 68Ga-Pentixafor PET scan. RT was planned in 2-phases. Phase-1 GTV (GTV1) comprised of T2/flair abnormality, PET-avid disease and post-op cavity. A margin of 2cm was given to GTV-1 to create phase-1 CTV (CTV1), which was further expanded to 0.5cm to generate phase-1 PTV (PTV1). A radiation dose of 46Gy/23fr was prescribed to PTV-1. Phase-2 GTV (GTV2) consisted of CT/MRI contrast-enhancing lesion, PET avid disease and post-op cavity. A margin of 0.5 cm was given to GTV2 to create phase-2 CTV (CTV2) which was expanded to 0.5 cm to create phase-2 PTV (PTV2). RT dose of 14 Gy/7 fr was prescribed to PTV2. PET avid disease was delineated as GTV PET and a margin of 3mm was given to generate PTV-PET which received escalated RT dose of 21 Gy/7fr by simultaneous integrated boost (SIB) in phase 2 (Total dose to PTV PET = 67 Gy/30 fr). All patients received concurrent and adjuvant temozolomide. The data was prospectively maintained in Microsoft Excel sheet. SPSS v 23 was used for statistical analysis. The primary endpoints were estimation of the overall survival (OS) and progression-free survival (PFS), and secondary endpoint was to measure the incidence of radiation necrosis. Categorical variables were reported as frequency and percentage and quantitative variables were reported as median and range. RESULTS: Data from thirty patients were analysed. A median OS of 23 months was observed with estimated 1, 2 and 3 years OS of 90%, 40% and 17.8% respectively. A significant association of OS was seen with the extent of surgery (p = 0.04) and kernofsky performance status (p = 0.007). No patient developed significant radiation necrosis. CONCLUSIONS: The index study did not show any survival benefit from dose escalation RT. However, all of the patients tolerated the treatment well and none of them developed radiation necrosis. Considering the small sample size as a limitation of the index study, the role of 68Ga-pentixafor PET scan for radiation dose escalation should be further explored. CLINICAL TRIAL NUMBER: CTRI/2019/05/019146.

Heterogeneity of colorectal cancer (CRC) in reference to KRAS proto-oncogene utilizing WAVE technology.

BACKGROUND: New drugs targeting specific genes required for unregulated growth and metastases have improved survival rates for patients with metastatic colorectal cancer. Resistance to monoclonal antibodies specific for the epidermal growth factor receptor (EGFR) has been attributed to the presence of activating point mutations in the proto-oncogene KRAS. The use of EGFR inhibitor monotherapy in patients that have KRAS wild type has produced response rates of only 10-20%. The molecular basis for clinical resistance remains poorly understood. We propose two possible explanations to explain these low response rates; 1) levels of resistant CRC cells carrying mutated KRAS are below the sensitivity of standard direct sequencing modalities (<5%) or 2) the standard practice of analyzing a single area within a heterogeneous tumor is a practice that can overlook areas with mutated KRAS. METHODS: In a collaborative effort with the surgical and molecular pathology departments, 3 formalin fixed paraffin embedded tissue blocks of human CRC were obtained from the human tissue bank maintained by the Lifespan Pathology Department and/or the human tissue bank maintained by the Molecular Pathology Core of the COBRE for Cancer Research Development. The three specimens previously demonstrated KRAS mutations detected by the Applied Biosystems Kit. The Wave system 4500 (high performance ion-pairing liquid chromatography (IP-HPLC)) was utilized to evaluate tissue for the presence of KRAS proto-oncogene mutations at codons 12 and 13. RESULTS: Initially, the sensitivity of WAVE technology was compared with direct sequencing by evaluating a dilutional series. WAVE detected mutant alleles at levels of 2.5% compared to 20% performed with standard direct sequencing. Samples from three patients were evaluated by WAVE technology. Eight samples from patient 1 were analyzed. In two of eight samples, no mutations were detected at concentrations as low as 5%. In one sample a mutation was noted by WAVE and not by direct sequencing. All four samples from patient 2 tested positive for Exon 12/13 mutations. Of the seven samples from patient 3, five were positive for Exon 12/13 mutations and two were negative for Exon 12/13 mutations. CONCLUSION: In these studies the analysis of three patients' colorectal cancer tissues were analyzed utilizing the WAVE technology. Results demonstrated a greater degree of sensitivity in mutation detection when compared to standard sequencing. These studies also demonstrated heterogeneity of expression of KRAS mutations between areas of the tissue samples at a genomic level. The low clinical response rates to EGFR inhibition might be explained by the variation in mutation presence, which was dependent upon the region examined. The heterogeneity demonstrated in these studies provides another phenotypic variant that will impact clinical care.