The UK Divide: Does Having a Pembrolizumab-Chemotherapy Option in Head and Neck Cancer Matter? Real-world Experience of First-line Palliative Pembrolizumab Monotherapy and Pembrolizumab-Chemotherapy Combination in Scotland.

AIMS: The Scottish Medical Consortium recently approved first-line pembrolizumab monotherapy or in combination with chemotherapy for head and neck squamous cell carcinoma in the palliative setting, contrasting with the decision made by the National Institute for Health and Care Excellence, who approved monotherapy alone in England and Wales. The aim of this study was to provide real-world performance data for first-line pembrolizumab-containing treatments for head and neck squamous cell carcinoma in the palliative setting in Scotland. MATERIALS AND METHODS: We analysed the electronic records of patients who started pembrolizumab-containing treatment between 1 March 2020 and 30 September 2021. Outcomes included overall survival, progression-free survival (PFS), the duration of response and the disease control rate. Data were compared with the KEYNOTE-048 study and clinical factors were evaluated for association with survival. RESULTS: Our cohort included 91 patients (median follow-up 10.8 months). Patient characteristics were similar to those in the KEYNOTE-048 study, although our cohort had a higher proportion of patients with newly diagnosed, non-metastatic disease. For patients receiving monotherapy (n = 76), 12- and 24-month overall survival were 45% and 27%, respectively. For patients receiving pembrolizumab-chemotherapy (n = 15), 12-month overall survival was 60% (24-month overall survival had not yet been reached). Experiencing one or more immune-related adverse event (irAE; versus no irAEs), of any grade, was associated with favourable overall survival and PFS for patients receiving monotherapy in both univariable Log-rank analysis (median overall survival 17.4 months versus 8.6 months, respectively, P = 0.0033; median PFS 10.9 months versus 3.0 months, respectively, P < 0.0001) and multivariable analysis (Cox proportional hazards regression: overall survival hazard ratio 0.31, P = 0.0009; PFS hazard ratio 0.17, P < 0.0001). CONCLUSION: Our real-world data support the KEYNOTE-048 study findings and the value of combination treatment options. Additionally, our data show that irAEs of any grade, as reported in routine clinical records, are associated with better outcomes in this patient group, adding to the growing body of evidence showing that irAEs are generally a positive marker of programmed death-ligand 1 (PD-L1) inhibitor response.

Randomized controlled trial of sustained release tacrolimus vs twice daily tacrolimus in adult living donor liver transplantation.

BACKGROUND: To compare the safety and efficacy of once-daily tacrolimus (ODT) versus twice-daily tacrolimus (BDT) in adult live donor liver transplantation (LDLT). METHODS: In this open-labelled randomized trial, 174 adult patients undergoing LDLT were randomized into ODT or BDT, combined with basiliximab induction and mycophenolate mofetil (steroid-free regimen). Tacrolimus was started at a total dose of 1 mg and the trough level was aimed at 3-7 ng/ml. The primary endpoint was eGFR at 1,3- and 6 months post-transplant, using CKD- EPI equation. Secondary endpoints included biopsy-proven acute rejection (BPAR), metabolic complications, post-operative bilio-vascular complications and patient survival. RESULTS: There was no statistically significant difference in eGFR between the two groups at 6 months (ODT -96 ± 19, BDT -91 ± 21, p value-0.164). BPAR was comparable (18/84 in ODT, 19/88 in BDT, p value-0.981). For a similar dosage of tacrolimus, the median trough tacrolimus levels attained were significantly lower for ODT than BDT during the first-month post-transplant (p value-0.001). Metabolic complications due to immunosuppression, post-operative bilio-vascular complications and patient survival was similar between the two groups at 6 months. CONCLUSION: Once-daily tacrolimus has similar renal safety and efficacy as twice-daily tacrolimus when used in combination with basiliximab induction and mycophenolate in adult LDLT.

Intensive Blood Pressure Management Preserves Functional Connectivity in Patients with Hypertension from the Systolic Blood Pressure Intervention Randomized Trial.

BACKGROUND AND PURPOSE: The Systolic Blood Pressure Intervention (SPRINT) randomized trial demonstrated that intensive blood pressure management resulted in slower progression of cerebral white matter hyperintensities, compared with standard therapy. We assessed longitudinal changes in brain functional connectivity to determine whether intensive treatment results in less decline in functional connectivity and how changes in brain functional connectivity relate to changes in brain structure. MATERIALS AND METHODS: Five hundred forty-eight participants completed longitudinal brain MR imaging, including resting-state fMRI, during a median follow-up of 3.84 years. Functional brain networks were identified using independent component analysis, and a mean connectivity score was calculated for each network. Longitudinal changes in mean connectivity score were compared between treatment groups using a 2-sample t test, followed by a voxelwise t test. In the full cohort, adjusted linear regression analysis was performed between changes in the mean connectivity score and changes in structural MR imaging metrics. RESULTS: Four hundred six participants had longitudinal imaging that passed quality control. The auditory-salience-language network demonstrated a significantly larger decline in the mean connectivity score in the standard treatment group relative to the intensive treatment group (P = .014), with regions of significant difference between treatment groups in the cingulate and right temporal/insular regions. There was no treatment group difference in other networks. Longitudinal changes in mean connectivity score of the default mode network but not the auditory-salience-language network demonstrated a significant correlation with longitudinal changes in white matter hyperintensities (P = .013). CONCLUSIONS: Intensive treatment was associated with preservation of functional connectivity of the auditory-salience-language network, while mean network connectivity in other networks was not significantly different between intensive and standard therapy. A longitudinal increase in the white matter hyperintensity burden is associated with a decline in mean connectivity of the default mode network.

Neoadjuvant tyrosine kinase inhibitor therapy in locally advanced differentiated thyroid cancer: a single centre case series.

OBJECTIVE: Primary surgical resection remains the mainstay of management in locally advanced differentiated thyroid cancer. Tyrosine kinase inhibitors have recently shown promising results in patients with recurrent locally advanced differentiated thyroid cancer. This study discussed four patients with locally advanced differentiated thyroid cancer managed with tyrosine kinase inhibitors used prior to surgery in the 'neoadjuvant' setting. METHOD: Prospective data collection through a local thyroid database from February 2016 identified four patients with locally advanced differentiated thyroid cancer unsuitable for primary surgical resection commenced on neoadjuvant tyrosine kinase inhibitor therapy. RESULTS: All cases had T4a disease at presentation. Three cases tolerated tyrosine kinase inhibitor therapy for more than 14 months while the last case failed to tolerate treatment at 1 month. All patients subsequently underwent total thyroidectomy to facilitate adjuvant radioactive iodine treatment. Disease-specific survival remains at 100 per cent currently (range, 29-75 months). CONCLUSION: Neoadjuvant tyrosine kinase inhibitors in locally advanced differentiated thyroid cancer can be effective in reducing primary tumour extent to potentially facilitate a more limited surgical resection for local disease control.

Building capacity for cancer care infrastructure in Karnataka - the present and the future.

BACKGROUND: Cancer mortality has doubled in India, a lower and middle-income country, from 1990 to 2016, depicting the ever-increasing burden of non-communicable disease. Karnataka, situated in the south of India, is one of the states with a rich medical college and hospital milieu. We present the status of cancer care across the state from the data collected by the investigators through public registries and personal communication to the concerned units to know the distribution of various services across the districts and give probable directives to improve on the present situation with emphasis on radiation therapy. This study may be taken as a bird's eye view of the situation across the country and form a basis based on which future planning of services and areas to emphasize on, may be considered. PURPOSE: The establishment of a radiation therapy center holds the key to the establishment of comprehensive cancer care centers. The existing situation of such centers and the need and scope for inclusion and expansion of cancer units is presented in this article.

Expert opinion: Stepwise ultrasound assessment of suspected placenta accreta spectrum using 2D, Doppler and 3D imaging.

Placenta Accreta Spectrum (PAS) describes a spectrum of conditions ranging from 'sticky' placenta to placenta accreta, increta and percreta-each describing progressively deeper invasion into the uterus. It is a major contributor to maternal and perinatal morbidity particularly where clinical facilities are not immediately available. Hence accurate diagnosis is important in determining timing and place of delivery, and logistical arrangements of the clinical team and specialties. Although many different ultrasound features have been described, their relationship to the final operative diagnosis remains variably described. Ultrasound manufactures have developed new imaging techniques particularly in relation to Doppler and 3D processing techniques. We describe a standardized imaging approach employing new ultrasound modalities matched to the attributes unique to invasive placenta. The '3V' system describes the stages of placental invasion: namely low-flow Doppler techniques to delineate the vascular anatomy of the placenta and delineating its interface with the myometrium, and 3D 'context preserving' post processing technologies defining the placental interface with maternal structures (vesicular invasion and visceral extension). Used together with well characterized 2D imaging signs, we describe pictorially by reference to clinical cases how this standardized methodology allows new insights into the ultrasound diagnosis of PAS.

EBV-positive mucocutaneous ulceration.

Ulceration of the oral cavity is common and a frequent reason for referral to secondary and tertiary centres. Epstein-Barr virus (EBV)-related mucocutaneous ulceration, however, is a rare cause of oral ulceration that has been described only recently. Histologically these lesions resemble lymphomas; however, their management and prognosis differ significantly. We present a case of EBV-induced oral ulceration and discuss the diagnosis and management of and available literature for the condition, which was treated successfully through conservative measures alone.

GeneXpert assay - A cutting-edge tool for rapid tissue diagnosis of tuberculous lymphadenitis.

BACKGROUND: The most prevalent clinical entity of extra pulmonary tuberculosis is tuberculous lymphadenitis. However, it resembles other granulomatous conditions pathologically and obtaining tissue for microbiological diagnosis is also difficult. Thus it is a challenging task for diagnosis and early initiation of management. Fine needle aspiration cytology and biopsy are the diagnostic methods generally used to obtain the lymph node samples for histopathological and microbiological diagnosis. Mycobacterium culture on Lowenstein-Jensen medium remains the gold standard for definitive diagnosis, but its major limitations is a prolonged turn-around time of 2-4 weeks. The GeneXpert Mtuberculosis/RIF assay is a novel molecular diagnostic method for rapid diagnosis of tuberculosis and rifampicin resistance in clinical specimens. METHODS: This was a cross sectional analytical study conducted on 67 cases of suspected tubercular lymphadenitis at R.L Jalappa Hospital and Research Centre, Tamaka, Kolar. The study was carried out between December 2017 to June 2019. The samples were collected using excision biopsy and subjected to GeneXpert Mtuberculosis/RIF assay and histopathology. Further, sensitivity, specificity, positive predictive value and negative predictive value was measured and compared with histopathology. RESULTS: The average age of the patients was 37.04 ± 19.27 and majority was males. The lymph nodes were predominantly present in cervical region. Histopathology analysis reveals 46 positive cases of tuberculosis Lymphadenitis and GeneXpert Mtuberculosis/RIF assay detects 42 cases of tuberculosis Lymphadenitis. In the present study, GeneXpert Mtuberculosis/RIF assay had a sensitivity of 82.60% and specificity of 85% when compared to histopathology. Further the PPV and NPV was found to be 92.68% and 68% respectively. GeneXpert Mtuberculosis/RIF showed 2 cases of rifampicin resistance out of 67 cases. In this study, the GeneXpert Mtuberculosis/RIF showed the results in 0.79 days. CONCLUSION: The present study showed that GeneXpert Mtuberculosis/RIF is a simple and reliable technique for diagnosing tuberculosis Lymphadenitis with high specificity and sensitivity as compared histopathology. Further, the methods elicit rapid diagnosis and also detected rifampicin resistance. It is thus a reliable and useful diagnostic modality in rapid detection of the causative agent and initiation of appropriate category anti-tubercular therapy when necessary.

[Pott's puffy tumour: innovative technique in calvarial reconstruction].

BACKGROUND: Pott's puffy tumour is a rare complication of sinusitis. This osteomyelitis can affect the outer and inner tables of the frontal sinus. The treatment of Pott's puffy tumour combines medical and surgical approaches. Surgical approaches have traditionally been open, but endoscopic techniques have been adopted recently in select cases. The bony defect from debridement can be left alone, or closed with autografts or allografts. OBJECTIVE: To describe a technique for the reconstruction of a large skull vault after the debridement of extensive osteomyelitis of the anterior cranial vault. METHODS: Modified distraction osteogenesis is used in the cranial vault, to induce new bone formation. This is customarily used to lengthen long bones. The advantages of this technique include avoiding autologous grafts or alloplastic cranioplasty in the infected surgical bed, and allowing primary closure. RESULTS: Early post-operative imaging results have been encouraging, with no reported complications. CONCLUSION: Modified distraction osteogenesis is a novel technique in the primary reconstruction of calvarial bone.

Therapeutic Prospects in Preeclampsia - A Mini-Review.

BACKGROUND: Preeclapmsia (PE) is characterized by early onset symptoms such as elevated blood pressure, proteinuria and edema in the pregnant woman, and may result in seizures in the affected female. Currently, there are no therapeutic drugs available to treat this condition, but there are interventions to regulate the symptoms based on the gestational period of the fetus, although the largely favored option is delivery of the fetus and placenta. OBJECTIVE: A search for biomolecules associated with PE was conducted so as to identify diagnostic markers and therapeutic leads. RESULTS: The literature search resulted in the identification of biomolecules such as Corin and Placental Protein 13 (PP13), among others that are associated with PE. Thereby, giving an insight into the various mechanistic pathways involved in the causation of PE. However, it is also evident that PE cannot be solely attributed to any single mechanism but is due to an interplay of different factors that have led to the development of this disease condition. CONCLUSION: The identified biomarkers would ultimately help in understanding this complex disease and perhaps lead to the discovery of potential effective molecular targets for clinical trials, thereby providing a valuable therapeutic option for affected pregnant women.

Gender and limb differences in temporal gait parameters and gait variability in ankle osteoarthritis.

BACKGROUND: The effects of ankle osteoarthritis on gait are noticeable in the clinic, but are difficult to quantify and score without detailed kinematic and kinetic analysis. Evaluationof temporal gait parameters and gait variability is a potential alternative. RESEARCH QUESTION: This study aimed to determine associations between limb and gender with temporal gait parameters and gait variability in ankle OA patients to evaluate the utility of these parameters for gait assessment in a clinical setting. METHODS: Following informed consent, 242 end-stage unilateral ankle OA patients walked at self-selected speed across force plates. Means and stride-to-stride standard deviations (SD) of stride, swing, stance, and double support times were determined for each patient. Limb x Gender ANCOVA models co-varying for walking speed were run for swing and stance times, while stride and double support times were only compared between genders. Statistical analysis was performed in SPSS (α = 0.05). RESULTS: Walking speed affected all measures of interest. After adjusting for walking speed, mean stride time, stride time SD, and stance time SD were 3.5%, 67% and 29% higher among women than men (p = 0.002, 0.035 and 0.02 respectively). Swing time was 12% higher and stance time was 6% lower on the affected side compared to the unaffected side (p < 0.001 for both). SIGNIFICANCE: Women have longer stride times and higher variability, which may indicate higher fall risk. Both genders minimized loading on the affected limb by increasing swing time and reducing stance time on the affected side. Simple, easy to record temporal gait patterns can provide useful insight into gait abnormalities in patients with ankle OA.

Magainin-AM2 improves glucose homeostasis and beta cell function in high-fat fed mice.

BACKGROUND: Magainin-AM2, a previously described amphibian host-defense peptide, stimulates insulin- and glucagon-like peptide-1-release in vitro. This study investigated anti-diabetic effects of the peptide in mice with diet-induced obesity and glucose intolerance. METHODS: Male National Institute of Health Swiss mice were maintained on a high-fat diet for 12-weeks prior to the daily treatment with magainin-AM2. Various indices of glucose tolerance were monitored together with insulin secretory responsiveness of islets at conclusion of study. RESULTS: Following twice daily treatment with magainin-AM2 for 15 days, no significant difference in body weight and food intake was observed compared with saline-treated high fat control animals. However, non-fasting blood glucose was significantly (P<0.05) decreased while plasma insulin concentrations were significantly (P<0.05) increased. Oral and intraperitoneal glucose tolerance and insulin secretion following glucose administration via both routes were significantly (P<0.05) enhanced. The peptide significantly (P<0.001) improved insulin sensitivity as well as the beta cell responses of islets isolated from treated mice to a range of insulin secretagogues. Oxygen consumption, CO2production, respiratory exchange ratio and energy expenditure were not significantly altered by sub-chronic administration of magainin-AM2 but a significant (P<0.05) reduction in fat deposition was observed. CONCLUSION: These results indicate that magainin-AM2 improves glucose tolerance, insulin sensitivity and islet beta cells secretory responsiveness in mice with obesity-diabetes. GENERAL SIGNIFICANCE: The activity of magainin-AM2 suggests the possibility of exploiting this peptide for treatment of type 2 diabetes.

"Hyperfrontality" as seen on FDG PET in unmedicated schizophrenia patients with positive symptoms.

INTRODUCTION: Decreased frontal activity has been reported widely in unmedicated schizophrenic patients with predominantly negative symptoms. Not many studies have assessed the frontal lobe status in unmedicated patients with positive symptoms. PATIENTS AND METHODS: Fifty-one patients with schizophrenia (all unmedicated, 38 never medicated) and 12 healthy age-matched controls were evaluated with FDG PET CT. The patients met ICD-10 and DSM-IV criteria for schizophrenia, and all reported psychotic, "positive" symptoms when tested. RESULTS: Schizophrenic patients with positive symptoms had a hypermetabolic frontal metabolic pattern on quantification by region to occipital ratio comparison. Associated statistically significant differences were also found when comparing ratios of occipital to thalamic, striatal and temporal cortex in schizophrenic patients. CONCLUSION: The finding of a hyperfrontality in unmedicated and never medicated psychotic schizophrenic patients is observed when there is a predominance of positive symptoms. There could be a possible disruption of cortico-striato-thalamic feedback loops causing hyperfrontality as seen in experimentally induced models of psychosis .

c-Abl and Arg are activated in human primary melanomas, promote melanoma cell invasion via distinct pathways, and drive metastatic progression.

Despite 35 years of clinical trials, there is little improvement in 1-year survival rates for patients with metastatic melanoma, and the disease is essentially untreatable if not cured surgically. The paucity of chemotherapeutic agents that are effective for treating metastatic melanoma indicates a dire need to develop new therapies. Here, we found a previously unrecognized role for c-Abl and Arg in melanoma progression. We demonstrate that the kinase activities of c-Abl and Arg are elevated in primary melanomas (60%), in a subset of benign nevi (33%) and in some human melanoma cell lines. Using siRNA and pharmacological approaches, we show that c-Abl/Arg activation is functionally relevant because it is requiredfor melanoma cell proliferation, survival and invasion. Significantly, we identify the mechanism by which activated c-Abl promotes melanoma invasion by showing that it transcriptionally upregulates matrix metalloproteinase-1 (MMP-1), and using rescue approaches we demonstrate that c-Abl promotes invasion through a STAT3 → MMP-1 pathway. Additionally, we show that c-Abl and Arg are not merely redundant, as active Arg drives invasion in a STAT3-independent manner, and upregulates MMP-3 and MT1-MMP, in addition to MMP-1. Most importantly, c-Abl and Arg not only promote in vitro processes important for melanoma progression, but also promote metastasis in vivo, as inhibition of c-Abl/Arg kinase activity with the c-Abl/Arg inhibitor, nilotinib, dramatically inhibits metastasis in a mouse model. Taken together, these data identify c-Abl and Arg as critical, novel, drug targets in metastatic melanoma, and indicate that nilotinib may be useful in preventing metastasis in patients with melanomas harboring active c-Abl and Arg.

Cryopreservation of mouse testicular tissue: prospect for harvesting spermatogonial stem cells for fertility preservation.

OBJECTIVE: To investigate the efficacy of vitrification, rapid freezing, and slow freezing in preserving testicular tissue for subsequent isolation of spermatogonial stem cells. DESIGN: Experimental study. SETTING: University-based laboratory. ANIMALS: Immature mouse testicular tissue. INTERVENTION(S): The tunica of the testis was manipulated before cryopreservation. The tunica was either breached with a fine needle or completely removed, or the testis was sectioned longitudinally into halves. MAIN OUTCOME MEASURE(S): Cell viability by Trypan blue exclusion test and flow cytometry analysis of live-dead cytotoxicity test, measurement of hormonal production, enrichment of spermatogonial stem cells with use of magnetic-activated cell sorting technology. RESULT(S): Samples with tunica minimally penetrated with a needle point gave the highest cell viability after freezing and thawing. Vitrification protocol with use of an ethylene glycol-sucrose-based vitrification solution (40% vol/vol ethylene glycol-0.6 mol/L sucrose) was able to maintain postwarming cell viability and functions similar to those of noncryopreserved controls and significantly better than both conventional slow and rapid freezing protocols. Primitive spermatogonial stem cells were enriched successfully from vitrified tissue via magnetic-activated cell sorting. CONCLUSION(S): Vitrification of testicular tissue is a time- and cost-efficient strategy to preserve spermatogonial stem cells for potential transplantation procedure.

Chromatin-remodelling proteins of the pea aphid, Acyrthosiphon pisum (Harris).

Aphids display extraordinary developmental plasticity in response to environmental cues. These differential responses to environmental changes may be due in part to changes in gene expression patterns. To understand the molecular basis for aphid developmental plasticity, we attempted to identify the chromatin-remodelling machinery in the recently sequenced pea aphid genome. We find that the pea aphid possesses a complement of metazoan histone modifying enzymes with greater gene family diversity than that seen in a number of other arthropods. Several genes appear to have undergone recent duplication and divergence, potentially enabling greater combinatorial diversity among the chromatin-remodelling complexes. The abundant aphid chromatin modifying enzymes may facilitate the phenotypic plasticity necessary to maintain the complex life cycle of the aphid.

Analysis of meiosis and cell cycle genes of the facultatively asexual pea aphid, Acyrthosiphon pisum (Hemiptera: Aphididae).

Phenotypic plasticity in response to environmental change is a common phenomenon, yet is poorly understood at the genetic and molecular level. Aphids exhibit a reproductive plasticity whereby seasonal changes result in asexual or sexual reproduction. To investigate the genetic basis of this reproductive plasticity, we assessed the meiosis and cell cycle gene repertoire in the genome of the pea aphid, Acyrthosiphon pisum. Aphids possess meiotic recombination genes and G1-to-S phase transition regulatory genes in gene copy numbers similar to other metazoans. However, mitotic and meiotic regulatory genes have duplicated, and several paralogues exhibit differential expression between reproductive morphs. Together, this suggests that cell cycle plasticity may be important in the evolution and mechanism of aphid reproductive plasticity.

Sphingosine kinase 1 is pivotal for Fc epsilon RI-mediated mast cell signaling and functional responses in vitro and in vivo.

Mast cell degranulation is pivotal to allergic diseases; investigating novel pathways triggering mast cell degranulation would undoubtedly have important therapeutic potential. FcepsilonRI-mediated degranulation has contradictorily been shown to require SphK1 or SphK2, depending on the reports. We investigated the in vitro and in vivo specific role(s) of SphK1 and SphK2 in FcepsilonRI-mediated responses, using specific small interfering RNA-gene silencing. The small interfering RNA-knockdown of SphK1 in mast cells inhibited several signaling mechanisms and effector functions, triggered by FcepsilonRI stimulation including: Ca(2+) signals, NFkappaB activation, degranulation, cytokine/chemokine, and eicosanoid production, whereas silencing SphK2 had no effect at all. Moreover, silencing SPHK1 in vivo, in different strains of mice, strongly inhibited mast cell-mediated anaphylaxis, including inhibition of vascular permeability, tissue mast cell degranulation, changes in temperature, and serum histamine and cytokine levels, whereas silencing SPHK2 had no effect and the mice developed anaphylaxis. Our data differ from a recent report using SPHK1(-/-) and SPHK2(-/-) mice, which showed that SphK2 was required for FcepsilonRI-mediated mast cell responses. We performed experiments in mast cells derived from SPHK1(-/-) and SPHK2(-/-) mice and show that the calcium response and degranulation, triggered by FcepsilonRI-cross-linking, is not different from that triggered in wild-type cells. Moreover, IgE-mediated anaphylaxis in the knockout mice showed similar levels in temperature changes and serum histamine to that from wild-type mice, indicating that there was no protection from anaphylaxis for either knockout mice. Thus, our data strongly suggest a previously unrecognized compensatory mechanism in the knockout mice, and establishes a role for SphK1 in IgE-mediated mast cell responses.