Rezaul Karim

Tumor-expressed B7-H1 and B7-DC in relation to PD-1+ T-cell infiltration and survival of patients with cervical carcinoma.

Purpose: The interaction between programmed cell death 1 (PD-1), expressed by activated effector or regulatory T cells, and B7-H1 (PD-L1) and B7-DC (PD-L2) results in the inhibition of T-cell function. The aim of this study was to determine B7-H1, B7-DC, and PD-1 expression in cervical carcinoma. Experimental Design: A tissue microarray of a well-defined group of 115 patients was stained with antibodies against B7-H1 and B7-DC. Three-color fluorescent immunohistochemistry was used to study the number and phenotype of tumor-infiltrating T cells expressing PD-1. Additional analyses consisted of in vitro T-cell suppression assays. Results: B7-H1 was expressed in 19%, and B7-DC was expressed by 29% of the 115 tumors. PD-1 was expressed by more than half of both the infiltrating CD8+ T cells and CD4+Foxp3+ T cells, irrespective of B7-H1 or B7-DC expression by tumors. The expression of B7-H1 did not show a direct impact on patient survival. However, subgroup analysis revealed that patients with a relative excess of infiltrating regulatory T cells displayed a better survival when the tumor was B7-H1 positive (P = 0.033). Additional studies showed that the presence of B7-H1 during the activation of CD4+Foxp3+ regulatory T cells impaired their suppressive function in a functional in vitro assay. Conclusions: B7-H1 is expressed on only a minority of cervical cancers and does not influence the survival of patients with cervical cancer. PD-1 is expressed by a vast number of infiltrating CD8 T cells, suggesting that blocking of PD-1 could have therapeutic potential in cervical cancer patients. (Clin Cancer Res 2009;15(20):6341–7)

Human Papillomavirus Deregulates the Response of a Cellular Network Comprising of Chemotactic and Proinflammatory Genes

Despite the presence of intracellular pathogen recognition receptors that allow infected cells to attract the immune system, undifferentiated keratinocytes (KCs) are the main targets for latent infection with high-risk human papilloma viruses (hrHPVs). HPV infections are transient but on average last for more than one year suggesting that HPV has developed means to evade host immunity. To understand how HPV persists, we studied the innate immune response of undifferentiated human KCs harboring episomal copies of HPV16 and 18 by genome-wide expression profiling. Our data showed that the expression of the different virus-sensing receptors was not affected by the presence of HPV. Poly(I:C) stimulation of the viral RNA receptors TLR3, PKR, MDA5 and RIG-I, the latter of which indirectly senses viral DNA through non-self RNA polymerase III transcripts, showed dampening in downstream signalling of these receptors by HPVs. Many of the genes downregulated in HPV-positive KCs involved components of the antigen presenting pathway, the inflammasome, the production of antivirals, pro-inflammatory and chemotactic cytokines, and components downstream of activated pathogen receptors. Notably, gene and/or protein interaction analysis revealed the downregulation of a network of genes that was strongly interconnected by IL-1β, a crucial cytokine to activate adaptive immunity. In summary, our comprehensive expression profiling approach revealed that HPV16 and 18 coordinate a broad deregulation of the keratinocytes inflammatory response, and contributes to the understanding of virus persistence.

Human Papillomavirus (HPV) Upregulates the Cellular Deubiquitinase UCHL1 to Suppress the Keratinocyte's Innate Immune Response

Persistent infection of basal keratinocytes with high-risk human papillomavirus (hrHPV) may cause cancer. Keratinocytes are equipped with different pattern recognition receptors (PRRs) but hrHPV has developed ways to dampen their signals resulting in minimal inflammation and evasion of host immunity for sustained periods of time. To understand the mechanisms underlying hrHPVs capacity to evade immunity, we studied PRR signaling in non, newly, and persistently hrHPV-infected keratinocytes. We found that active infection with hrHPV hampered the relay of signals downstream of the PRRs to the nucleus, thereby affecting the production of type-I interferon and pro-inflammatory cytokines and chemokines. This suppression was shown to depend on hrHPV-induced expression of the cellular protein ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) in keratinocytes. UCHL1 accomplished this by inhibiting tumor necrosis factor receptor-associated factor 3 (TRAF3) K63 poly-ubiquitination which lead to lower levels of TRAF3 bound to TANK-binding kinase 1 and a reduced phosphorylation of interferon regulatory factor 3. Furthermore, UCHL1 mediated the degradation of the NF-kappa-B essential modulator with as result the suppression of p65 phosphorylation and canonical NF-κB signaling. We conclude that hrHPV exploits the cellular protein UCHL1 to evade host innate immunity by suppressing PRR-induced keratinocyte-mediated production of interferons, cytokines and chemokines, which normally results in the attraction and activation of an adaptive immune response. This identifies UCHL1 as a negative regulator of PRR-induced immune responses and consequently its virus-increased expression as a strategy for hrHPV to persist.

CXCR7 expression is associated with disease-free and disease-specific survival in cervical cancer patients.

Background:The CXC chemokine receptor (CXCR)7 is involved in tumour development and metastases formation. The aim of the present study was to determine protein expression of CXCR7, its putative co-receptors epidermal growth factor receptor (EGFR) and CXCR4, its predominant ligand CXCL12, their co-dependency and their association with survival in cervical cancer patients.Methods:CXC chemokine receptor 7, EGFR, CXCR4 and CXCL12 expression were determined immunohistochemically in 103 paraffin-embedded, cervical cancers. Subsequently, associations with patient characteristics were assessed and survival analyses were performed.Results:CXC chemokine receptor 7 was expressed by 43% of tumour specimens, in a large majority of cases together with either EGFR or CXCR4 (double positive), or both (triple positive). The CXCR7 expression was associated with tumour size (P=0.013), lymph node metastasis (P=0.001) and EGFR expression (P=0.009). CXC chemokine receptor 7 was independently associated with disease-free survival (hazard ratio (HR)=4.3, 95% confidence intervals (CI) 1.7–11.0, P=0.002), and strongly associated with disease-specific survival (HR=3.9, 95% CI 1.5–10.2, P=0.005).Conclusion:CXC chemokine receptor 7 expression predicts poor disease-free and disease-specific survival in cervical cancer patients, and might be a promising new therapeutic marker. In a large majority of cases, CXCR7 is co-expressed with CXCR4 and/or EGFR, supporting the hypothesis that these receptors assist in CXCR7 signal transduction.

Surgery for Spinal Tuberculosis: A Multi-Center Experience of 582 Case

Introduction Tuberculosis of the spine is a common form of TB infection for 50% to 60% of osseous tuberculosis. Although uncommon, spinal TB still occurs in both developed and developing countries. The diagnosis of spinal tuberculosis is difficult and it commonly presents at an advanced stage. Delays in establishing diagnosis and management result in complications such as spinal cord compression and spinal deformity. Material and Methods A total of 582 patients with tuberculosis of the cervical, thoracic and lumbar spine with moderate to severe cord compression were studied. Variable degrees of neurological deficit with deformity were treated from January, 2003 to July, 2014. Thoracotomy along with anterolateral decompression and autogenous strut bone grafting with simultaneous fixation by screws and rods were done in 113 cases. Posterior decompression, posterior interbody and posterolateral fusion by bone graft with stabilization by transpedicular screws and rods were done in the remaining 469 cases. Appropriate anti TB drugs were given to all patients for 18–24 months. The follow-up period was 3 months to 10 years. Results The average age was 32.5 years. All patients survived surgery. There were 7 cases of superficial infections (1.2%) while there were 4 cases (0.7%) of deep infections. Revision surgery was performed in 6 patients (1.0%). Implant failure occurred in 4 cases (0.7%) while malposition of screws occurred in 12 cases (2.1%). Perioperative bleeding complications were reported for 4 patients (0.7%). Neurological improvement occurred in all patients except for 2 cases (0.3%). Preoperatively, the majority of patients (n = 221, 38%) were classified with Class A on the American Spinal Injury Association (ASIS) neurological impairment scale. This was significantly reduced postoperatively to 0.4%. Conclusion For patients with spinal tuberculosis anterior debridement, auto graft bone fusion, anterior or posterior fixation appears to be effective in arresting disease, correcting kyphotic deformity and maintaining correction until solid spinal fusion.

Three Column Fixation: A Dynamic Method in Scoliosis Surgery

Introduction Scoliosis is a complex three dimensional deformity characterized by coronal, sagittal and horizontal plane deviation. Non operative treatment is a widely accepted approach. A significant number of cases need surgical intervention. Revolutionary design & capability of spinal instruments have drastically changed the principle of scoliosis correction by surgical intervention. Material and Methods During the period February 2009 to November 2014, 64 cases of different types of Scoliosis underwent surgical intervention at NITOR, BSOH and other private hospitals in Dhaka. 45 were female and 19 were male and age ranged from 14 to 38 years. Results The pedicle is a power nucleus of the vertebra and offers a secure grip of all 3 columns. Pedicle screw instrumentation has advantages of rigid fixation with improved 3D correction and it has been accepted as a reliable method with a high margin of safety. Accurate placement of the pedicle screws is important to reduce possible irreversible complication. So, all cases were corrected by transpedicular screws and rods and 1 case stabilized by sub laminar wring. 61 cases were managed by only posterior approaches and 3 cases required both anterior releases, costoplasty, posterior stabilization as well. In every case fusion was done in selected segments. Conclusion Total follow up time was ~5 years (6 months-5yrs). All patients were assessed in terms of correction of deformities, cosmesis, and functional outcome. 64 patients had average coronal plane cobbs angle measuring ~70 degree pre-operatively and 17.12 degree immediate post-operative period. 4 patients (5.7%) developed neurological deficit. 3 regained completely but another one regaining her neurological deficit very slowly. There were malposition of screws in 9 (14%) cases, Painful prominence of screws in 6 cases (9%), full flexion lack in 8 cases (12.5%) & superficial infection in 1 case (1.5%). 80% patients improved cosmetically.

Anterior Cervical Decompression, Fusion, and Stabilization by Cervical Plate and Screw for Traumatic Lower Cervical Spinal Injury: A Series of 62 Patients

Introduction Acute cervical spinal injury is one of the most common causes of severe disability and death following trauma. Though treatment of cervical spine injury is controversial but anterior cervical surgery has still a better outcome then any other method. Material and Methods A prospective study was done in NITOR and other private clinics at Dhaka from July 2009 - September 2014. Discectomy or corpectomy was done for decompression, tricortical bone graft or cage with bone graft was used for fusion. Cervical plate was used in all. Total case was 62 (M-46, F-16). Age ranging from 14 – 52 years. Total follow up time was 3 Months to 48 Months. Quantification of deficit and neurological outcome was rated by ASIA impairment scale. Results The results shows that peak incidence was in 3rd decade. Falling due to slip while carrying heavy load on head was the most common cause. The commonest skeletal level was C5/C6. Among 62, during the pre operative period, 6 patients had ASIA impairment scale A, 25 patients had ASIA impairment scale B, 28 had ASIA impairment scale C & 3 had ASIA impairment scale D. At follow up, 22 of ASIA B changed to ASIA D, 3 of ASIA B changed to ASIA E, 18 of ASIA C changed to ASIA D, 10 of ASIA C changed to ASIA E, 3 of ASIA D changed to ASIA E & 6 of ASIA A remain unchanged. None had worsening of neurodeficit due to surgery. Conclusion For better outcome, proper selection of case is very important. As no neurological recovery occurs in complete lesion but for early mobilization and prevention of further complication- surgery may be considered.