Background

The programmed cell death-1 (PD-1) receptor and its ligands PD-L1 and PD-L2 are immune checkpoints that suppress anti-cancer immunity. Typically, cancer cells express the PD-Ls that bind PD-1 on immune cells, inhibiting their activity. Recently, PD-1 expression has also been found in cancer cells. Here, we analysed expression and functions of PD-1 in thyroid cancer (TC).

Methods

PD-1 expression was evaluated by immunohistochemistry on human TC samples and by RT-PCR, western blot and FACS on TC cell lines. Proliferation and migration of TC cells in culture were assessed by BrdU incorporation and Boyden chamber assays. Biochemical studies were performed by western blot, immunoprecipitation, pull-down and phosphatase assays. TC cell tumorigenicity was assessed by xenotransplants in nude mice.

Results

Human TC specimens (47%), but not normal thyroids, displayed PD-1 expression in epithelial cells, which significantly correlated with tumour stage and lymph-node metastasis. PD-1 was also constitutively expressed on TC cell lines. PD-1 overexpression/stimulation promoted TC cell proliferation and migration. Accordingly, PD-1 genetic/pharmacologic inhibition caused the opposite effects. Mechanistically, PD-1 recruited the SHP2 phosphatase to the plasma membrane and potentiated its phosphatase activity. SHP2 enhanced Ras activation by dephosphorylating its inhibitory tyrosine 32, thus triggering the MAPK cascade. SHP2, BRAF and MEK were necessary for PD-1-mediated biologic functions. PD-1 inhibition decreased, while PD-1 enforced expression facilitated, TC cell xenograft growth in mice by affecting tumour cell proliferation.

Conclusions

PD-1 circuit blockade in TC, besides restoring anti-cancer immunity, could also directly impair TC cell growth by inhibiting the SHP2/Ras/MAPK signalling pathway.

Objectives: The 8th edition of the AJCC has introduced a new nodal staging system for head and neck cancers. Alternate nodal staging systems exist, however they have not been compared to the current AJCC staging system.Materials and methods: A retrospective analysis of 643 patients with oral squamous cell carcinoma (OSCC) treated with surgery ± adjuvant therapy in a single institution between 2004 and 2014 was undertaken. Nodal staging was performed using AJCC 8th edition (AJCC8), number of positive lymph nodes (PN), log odds of positive lymph nodes (LODDS) and lymph node ratio (LNR). Survival analyses for disease free survival (DFS) and overall survival (OS) were performed with the different staging systems and they were compared on the basis of hazard consistency, hazard discrimination, explained variation and likelihood difference.

Results: Overall, PN and LNR best predicted OS and DFS in our cohort of patients. AJCC8 had poor dis- crimination between sub-stages of pN2.
Conclusion: PN and LNR provided the most accurate prediction of OS and DFS for patients with OSCC.

Objectives: To study the determinants of locoregional control (LRC) on stage I/II oral squamous cell carcinoma (OSCC) classified by AJCC 8th edition.

Methods: Retrospective analysis from 296 patients of pT1-2N0 oral OSCC treated with surgery (wide local excision and selective neck dissection). Those receiving adjuvant therapy were excluded. Multivariate analysis was performed for impact of adverse pathological features (APFs) on LRC.

Results: In stage I, LRC was impacted by perineural invasion (PNI) (HR 7.72, p=0.010, 95% CI 1.64-36.26) and moderate/poor differentiation (MD/PD) (HR 3.04, p=0.049, 95% CI 0.99-9.25). In stage II, LRC was impacted by depth of invasion (DOI) (HR 1.59, p=0.014, 95% CI 1.099-2.32), PNI (HR=2.86, p=0.005, 95% CI 1.36-5.98). Combined MD/PD and PNI were associated with worse LRC than either feature individually (HR=4.12, p<0.001, 95% CI 2.16-7.85).

Conclusion: PNI and differentiation accurately predict LRC in AJCC 8th edition classified stage I/II OSCC. PNI was a stronger predictor of locoregional failure than DOI in stage II disease. By incorporating these parameters, we can improve precision in staging of early OSCC and identify potential candidates for treatment escalation to improve outcomes.

Keywords: oral squamous cell carcinoma, adverse pathological feature, perineural invasion, differentiation, AJCC 8th edition. 

Background: Plasminogen activator inhibitor-1 (PAI-1) is corelated with inflammation and tumorigenesis. We investigated the role of PAI-1 in tumor regulating immune component of tumor microenvironment.

Methods: Protein expression data proteins and phosphoproteins, tumor infiltrating immune cells with relative fraction of immune cell types and major clinical outcome endpoints were obtained from The Cancer Genome Atlas project. A statistical correlation analysis was performed between the expression and distribution of PAI-1, immune checkpoint expression, tumor infiltrating immune cells fraction and their distribution in each tumor. We used Cox proportional hazards model to evaluate the association of PAI-1 with clinical survival outcomes.

Results: The expression and distribution patterns of PAI-1 was measured in 7858 samples from 32 cancer type. PAI-1 had an enrichment in the squamous cancers. Increased expression of PAI-1 was associated with higher tumor stage and grade. Analyses of the tumor microenvironment revealed unanticipated correlation of PAI-1 with immune checkpoint expression and infiltrating immune cells. PAI-1 expression was tightly correlated to TGF-beta response (corr=0.40; p < 0.01), tumor leucocyte fraction (corr=0.33; p < 0.01) and PD-L1 expression (corr=0.29; p < 0.01). PAI-1 was positively corelates with intra-tumor heterogeneity (p < 0.01), proliferation(p < 0.01), stroma fraction (p < 0.01) and macrophages (p < 0.01). PAI-1 was also negatively correlated with lymphocyte fraction, activate CD4 cells, T cells (FH, gamma-delta and CD8). These correlations were also found with individual cancer type. PAI-1 was associated with poor Overall survival (Hazards ratio (HR)= 1.4; p < 0.01), Progression free interval (HR = 1.3; p < 0.01), disease free interval (HR = 1.26; p < 0.01) and disease specific survival (HR = 1.42; p < 0.01). PAI-1 was also associated with poor clinical outcomes in individual cancer type.

Legal entity responsible for the study: Narender Kumar.

Background: Incidence of Oropharyngeal Cancer varies greatly worldwide showing an increasing trend. This increasing trend in epidemiology of Oropharyngeal Cancer has been attributed to the infection by human papillomavirus [HPV]. In this study we aimed to determine the impact of the presence of HPV DNA and p16 in oropharyngeal cancer on response to treatment and toxicity in patients receiving radical chemo-radiotherapy at regional cancer center.

Methods: 80 patients of squamous cell carcinoma of oropharynx were enrolled. HPV DNA and p16 status of all patients was evaluated using polymerase chain reaction and immunohistochemistry. The selected patients for this study were treated with concurrent chemoradiation therapy with weekly cisplatin.

Results: Among 80 cases, 17cases (21.2%) shows positive results for p16 P16 was positive in 64.7 % cases of males and 35.3% cases of female on the other hand in p16 negative cases 84.1% cases were male while 15.9% cases were female. Overall, 83.8% of patients were tobacco users (smoking, n = 30 (44.8%); smokeless, n = 18 (26.9%), both, n = 19 (28.3%)). Tonsils (70%) is the most common site involved. Response of treatment was evaluated after 6 weeks of concurrent chemoradiation. Complete response was observed in 14 patients which were p16 positive and 47 patients which were p16 negative. Partial response in 3 (p16 positive) and 15 patients (p16 negativity). Stable disease was observed in 1 patient (p16 negative) and no cases with progression of disease was evaluated in response to treatment. Evaluation of toxicity was done and toxicity was graded in both HPV positive and HPV negative cases according to CTC. In both p16 positive and negative stomatitis (p = 0.75) was the most common adverse event. Oral stomatitis of Grade 1&2 (100% in p16 +ve and 96.8% in p16 -ve patients) and grade 3&4 (58.8% in p16+ and 49.20% in p16_ patients).

Conclusions: We concluded that patients with HPV positive and p16 positive OPSCC show better response to treatment. Risk of severe late toxic effect is low after treatment of oropharynx cancer as due to the escalation of therapy risk of late toxic effects are decreased. This may have implication in doing p16 routinely in clinical practice and implication while considering for treatment de-intensification strategies.

Background: DNA double-strand break (DSB) is the most critical type of genotoxic stress. Clinical studies have revealed a link between genomic instability and response to anti-PD-1/PD-L1 therapy in cancer management. We investigated role of DBS repair and ATR/Chk1 DNA damage checkpoint in regulating PD-L1 expression and their use in therapy selection and study design.

Methods: Protein expression data proteins and phosphoproteins with major clinical outcome endpoints were obtained from The Cancer Genome Atlas project. A statistical correlation analysis was performed between the expression and distribution DBS repair and ATR/Chk1 DNA damage checkpoint pathway and PD-L1. Signaling network was also analysed for of therapeutic target identification.

Results: The expression and distribution patterns of PD-L1 was measured in 7694 samples from 32 cancer type. Increased expression of PD-L1 was associated with higher tumor stage and grade. Analyses of the DNA damage ATR/Chk1 checkpoint signalling revealed strong correlation of PDL1 expression. PD-L1 expression in was upregulated in response to DSBs with strong correlation with MRE11 (correlation coefficient (r) =0.39, p < 0.01), RAD51 (r = 0.33, p < 0.01). This upregulation requires ATM/ATR/Chk1 kinases (Chk2_pt68; r = 0.36, p < 0.01 and Chk1_ps296; r = 0.33, p < 0.01). Interestingly Jab-1 expression was corelated with both Chk-1(r = 0.27, p < 0.01) and PD-L1 (r = 0.22, p < 0.01). We further investigate for the possible signaling mechanism for the correlation and found activation of oncogenic signaling in a cancer type specific manner. PI3K/AKT/mTOR/S6K, INFgamma/ JAK/STAT/IRF1 and Ras/BRAF/MEK/ERK were involved in mechanism of increased PD-L1 expression.

Conclusions: DSB-mediated immune activation is balanced by concomitant inhibitory signaling, via the checkpoint kinases ATM, ATR, and Chk1 drived PD-L1 expression in tumors. These observations have important clinical implications for therapy selection, particularly following progression on DNA damaging agents suggesting that PD-1/PD-L1 inhibitors may be a useful therapeutic strategy (with or without concurrent DNA damaging agents) for tumors.

Background: A dramatic improvement in the survival of acute lymphoblastic leukemia (ALL) patients in the last three decades has been observed. MCP 841 protocol is an old but effective tool with tolerable toxicities. The objective of this study was to estimate the relapse-free survival of ALL patients treated uniformly with MCP 841 protocol on the basis of various prognostic factors. Materials and Methods: The study design was retrospective and it was conducted in a regional cancer center of Northwest India. Three hundred and ten ALL patients who underwent treatment with MCP 841 protocol and regular follow-up for up to 5 years were selected for this study. Relapse-free survival was calculated by Kaplan-Meier analysis and Cox regression analysis was used to calculate the hazards ratio (HR) using Statistical Package for the Social Sciences (SPSS) software for windows version 20.0. Results: Fifty-four percent patients were <15 years of age and 69% were males. 53.2% patients were in remission at the end of 5 years of starting the treatment. Relapse-free survival at 5 years by Kaplan-Meir analysis for B-cell ALL was 62% [HR 0.67 {95% confidence interval (CI) 0.47-0.95}] with patients with unknown lineage taken as reference] while for T cell it was 28% [HR 1.41 (95% CI 1.19-1.63), P 0.001]. Patients with total leukocyte count (TLC) <1 lakh/cmm at presentation, relapse-free survival was 68% and those with TLC >1 lakh/cmm had 41% survival [HR 2.14 (1.76-2.48) with, P < 0.001]. Conclusion: MCP 841 protocol is a useful tool for the treatment of ALL in children when more aggressive protocols can not be used.

Aim/Background: Selected patients with good responses to first-line chemotherapy, good performance status, and a long disease-free period between initial chemotherapy and relapse are the candidates for second-line chemotherapy with taxane based regimen. The aim of this study was to evaluate the efficacy of three weekly versus weekly paclitaxel as second line therapy in previously treated patients of advanced non small cell lung cancer (NSCLC) in patient population. Methods: Between October 2012 and December 2013, previously platinum based chemotherapy treated patients with stage IIIB/IV NSCLC were randomized 1:1 to three weekly paclitaxel (175 mg/m² for 4 cycles) or weekly paclitaxel (80 mg/m² for 3 months). The primary endpoint was the comparison of progression free survival (PFS) between the two arms and the secondary endpoints included overall survival (OS) and toxicity analyses. All statistical analyses were performed by using SPSS version 20.0. Results: 109 patients were enrolled in this study (median age: 59 years, males 78.8%, stage IV disease 70.6%, ECOG performance status 0/1: 66.9%). The patients were randomized in the three weekly paclitaxel (n = 55) and weekly paclitaxel (n = 54) arms. Median PFS for three weekly paclitaxel versus weekly paclitaxel was 3.1 vs. 4.3 months (hazard ratio [HR], 1.42; 95% CI, 1.07-1.75; P = 0.03), and median OS was 6.8 vs. 7.6 months (HR, 1.19; 95% CI, 0.79 to 1.29; P = 0.47), respectively. Weekly paclitaxel was well tolerated with grade 3-4 neutropenia (5.5% vs. 8.6%, P = 0.07) and grade 3-4 diarrhea (5.5% vs. 3.8%, P = 0.78). Conclusions: Weekly paclitaxel demonstrated better PFS in comparison to conventional three weekly paclitaxel as second line therapy in patients with advanced non small cell lung cancer with acceptable toxicity profile. However, it failed to reach the significance level for overall survival benefit.

Background: Nasopharyngeal carcinoma (NPC) is an aggressive tumor with a significant proportion of patients presenting with distant metastasis. The skeleton is one of the most common sites of distant failure. This retrospective study was performed to analyze the incidence and patterns of skeletal metastasis in NPC detected by bone scintigraphy in resource‑poor settings. Materials and Methods: We analyzed records of 301 NPC patients attending our oncology outpatient department from January 2002 to December 2012. Of these, 33 patients who presented with bony pain underwent bone scan (BS) for suspect of skeletal metastasis. In patients with positive scans, histological diagnosis to confirm metastasis was attempted. Results: Bone metastasis (BM) was found in 19 patients (57.6% of patients undergoing BS, 6.3% of total NPC patients). About 36.8% and 15.8% of BM cases were in the age group 20-29 and 30-39 years, respectively (P = 0.27). 63.1% of metastatic cases were of World Health Organization type‑II histology (P = 0.021). Of the patients diagnosed with BM, 52.6% belonged to stage IV at presentation (P = 0.022). Spine was involved in 56% of the positive cases, followed by the pelvis (32%), and ribs (24%). On univariate analysis, histology (P < 0.001), stage at diagnosis (P = 0.007) and age group (P = 0.001) were identified as significant factors affecting BM. However, on multivariate analysis, only stage (P = 0.001) was a significant factor. Conclusion: Bone scintigraphy can be considered in limited resource settings for the evaluation of distant metastasis in the patients of advanced NPC.

Neurofibromatosis is a genetic disorder of neural crestderived cells that predominantly affect growth and development of neural tissues. We report a case of 64 year old patient, had several soft tissue cutaneous nodules (neurofibroma) on the body including the face, head, and neck, extremities and multiple hyperpigmented macules on trunk and back (Caféaulait pigmentation), who was accidentally diagnosed as chronic myeloid leukemia, on routine investigation for surgical management. He did not have any systemic manifestation either of diseases.

Neurofibromatosis is a genetic disorder of neural crestderived cells that predominantly affect growth and development of neural tissues. We report a case of 64 year old patient, had several soft tissue cutaneous nodules (neurofibroma) on the body including the face, head, and neck, extremities and multiple hyperpigmented macules on trunk and back (Caféaulait pigmentation), who was accidentally diagnosed as chronic myeloid leukemia, on routine investigation for surgical management. He did not have any systemic manifestation either of diseases.

Background: Bone metastasis is a rare occurrence in head and neck squamous cell carcinoma (HNSCC). This retrospective study was performed to analyze the frequency and patterns of skeletal metastasis in HNSCC. Materials and Methods: We analyzed records of 8326 HNSCC patients attending our oncology outpatient department from January 2000 to December 2013. All statistical calculations were performed using MedCalc software for windows, version 12.5.0 (Osterd, Belgium). Results: Bone metastasis was found in 25 patients (0.3% of total HNSCC patients, nasopharynx excluded). 10 patients (0.66%) of carcinoma tonsil had skeletal metastasis. The patients of younger age groups had higher frequency of bone metastasis; 1.56% patients of age group 20–29 years while 0.26% patients of 60–69 years age group had skeletal metastasis (P < 0.001). However, no patient of >70 years age was found to have bone metastasis. Most common site of metastasis was spine (56%) followed by pelvis (32%). Isolated involvement of a single bony site was present in 64% of the metastatic cases. Conclusion: Bone metastasis though very rare, should be considered for evaluation in patients of HNSCC especially in younger patients.

Background: Palliative radiotherapy (PRT) is the eventual requirement in 30-50% of all cancer patients. PRT is primarily aimed to relieve pain and prevent/treat collapse or fracture in case of bone metastasis, to reduce edema in patients with cranial metastasis, and to control distressing symptoms of rapid primary growth. An audit of PRT planned in a busy cancer center can help in the characterization of the requirements of the patients and the formulation of institutional policies.
Materials and Methods: In total, 516 patients who received PRT in our regional cancer center from January 2012 to December 2012 and whose complete records were available for analysis were selected for this retrospective study. Medical records and radiotherapy files were analyzed to obtain data such as sociodemographic parameters, prescription of PRT, and follow up. Descriptive statistics were evaluated in terms of frequencies and percentages to allow comparisons.
Results: Of the 516 patients, 73% patients were male; the median age of the patients receiving PRT was 62 years (range 13-83 years). About 48% ( n = 248) patients received PRT at the primary site while rest (52%) were given PRT at the metastatic site. The most common indication of PRT was pain (56.8% cases), followed by cytostatic PRT (19.8%) and raised ICT (12.4%). The median dose prescribed was 30 Gy (range 8-36 Gy) delivered in 1-12 fractions over the duration of 1-18 days. The overall response rate was about 43% at 2 weeks of completion of PRT; the median follow-up of the patients was 154 days (range 9-256 days). The long-term symptom relief at median follow up was 8%.
Conclusions: Good clinical judgment and expertise is required in prescribing correct fractionation schedule to achieve effective symptom palliation with lowest possible cost and inconvenience to the patients and relatives. Hypofractionated radiotherapy is a feasible treatment option in patients with advanced incurable disease to achieve effective palliation.

Background The present study summarizes the results of treatment in the form of disease-free survival and overall survival in bulky stage IB2 and locally advanced (stages II–IVA) squamous cell carcinoma of the uterine cervix. The treatment has been given in the form of NACT followed by CCRT in one arm and CCRT in the other arm.

Materials and Methods This retrospective study analyzed 713 cervical cancer patients who were treated at our center during 2007 and 2008; out of 713 patients, data of 612 patients have been compared. The patients’ data were analyzed retrospectively. Patients had undergone PF 28.6 %, TPF 21.5 %, and only CCRT 49.9 %. Majority of patients were in the age group 41–50 years, while stage wise, mainly stage IIIb and IIb. Disease-free survival was observed on the basis of stage and NACT. The survival analyses were performed using the Kaplan–Meier method. All statistical calculations were done with SPSS Statistics version 20.0.

Results For cancer cervix NACT versus CCRT, the DFS rate was at 5 years (58.3 vs. 41.8 % p = 0.001). NACT followed by CCRT demonstrated significantly superior DFS as compared to definitive CCRT, respectively, TPF (hazard ratio (HR) = 0.248, 95 % confidence interval (CI) 0.123–0.500; p < 0.001), PF (HR = 0.445, 95 % CI 0.266–0.722; p = 0.002). The results of univariate stage, age, and multivariate study show that stage hemoglobin level, interval between external-intracavitary radiation, and type of neoadjuvant chemotherapy were the factors affected survival cervical patients treated with radiation. The grade 3/4 hematologic toxicities were more in the NACT group than CCRT (p < 0.001) while the non-hematological toxicity was not significant; the TPF group experienced more toxicity than PF (p = 0.029). This treatment regimen is feasible as evidenced by the acceptable toxicity of NACT and by the high compliance to radiotherapy. The grade 3/4 hematologic toxicities were more inNACT groups than CCRT (p < 0.001); the TPF group experienced more toxicity than PF (p = 0.029).

Conclusion TPF/PF as NACT is feasible and produces impressive responses in cancer cervix.

Perivascular epithelioid cell tumor (PEComa) is a group of sarcomas that exhibit a myomelanocytic phenotype and possess a unique cell type in the perivascular epithelioid cell. Traditionally HMB-45 immunoreactivity is the first criteria required to consider a tumor to be PEComa. We report a case of multifocal PEComa with negative HMB-45 marker. The patient presented with three big ulceroproliferative lesions; two over right thigh and one over the scalp in the right frontal region. The patient was prescribed with oral sirolimus to which good response was seen. To the best of our knowledge, this is the first case of HMB-45 negative multifocal malignant PEComa from India.

Background: A prospective randomized study was done to determine the comparative effectiveness and safety of low dose weekly paclitaxel versus weekly cisplatin with concurrent radiation in the treatment of locally advanced head and neck cancer. 

Material and Method: The prospective single centered study was conducted on 122 patients in the department of radiation oncology in a tertiary care hospital from October 2010 to November 2011. All patients were histopathologically proved squamous cell carcinoma. Previously untreated one hundred eight randomly selected and patients were divided into two groups by computer generated programme. The study group received injection Paclitaxel 20 mg/m2 while control group received injection Cisplatin 30 mg/m2. All patients had received 66-70 Gy concurrent radiation at the rate of 2 Gy/day, 5 #/week, in 6-7 weeks by cobalt-60 Theratron -780 E/780C Teletherapy units. 

Result: Out of 122, 112 patients were men and 10 were women with a median age of 51 years range (30 - 65). 63 versus 59 patients were distributed on the basis of computer generated programme in Cisplatin and Paclitaxsel arm. There was no statistically significant difference in DFS in CDDP arm and Paclitaxel arm (χ.= 0.072; p value 0.789) at the 24 months. There was no statistically significant difference in OS in CDDP arm and Paclitaxel arm (χ.= 0.006; p value: 0.936) at the 24 months. The common adverse effect both in the CDDP arm and Paclitaxsel arm was oral mucosits. There was no significant difference in the incidence of mucositis and dermatitis between CDDP and Paclitaxsel arm. 

Conclusion: Low dose Paclitaxel weekly schedule is comparable to Cisplatin in locally advanced head and neck squamous cell carcinoma both in form of survival and toxicity.

Background: The aim of this study was to describe the prevalence of comorbidity in newly diagnosed female breast cancer patients in north-west India. The second end point of the study was compliance for multimodality treatment. Comorbidity assessed by counting the number of coexisting diseases diagnosed in a cancer patient or by using a comorbidity index that combines the number and severity of the diseases. The most widely used index is the Charlson Comorbidity Index (CCI). Materials and Methods: The data of female patients with breast cancer were recorded, having comorbidities during the cancer registration or comorbidities diagnosed during the treatment at the host institute between January and December 2012. The patients were distributed on the basis of physical parameters such as age, stage, tumor grade, hormone receptor status, ECOG status at diagnosis and CCI. Scores of CCI are summed to provide a total score to predict mortality. Results: During the period of January to December 2012, 156 biopsy-proven breast cancer patients were included in the study. During this period, female breast cancer patients enrolled were 13.94% out of total patient enrollment. The most prevalent comorbidities associated with breast cancer are hypertension (21.8%), chronic obstructive pulmonary disease (COPD) (19.9%), rheumatologic disease (18.6%), and diabetes mellitus (16.7%), all four conditions have been reported in around 75% of the cases. The planning of multimodality management in comorbidity arm was significantly lower (P > 0.01) as compared to patients without comorbidity. Conclusions: The planning of multimodality management in comorbidity arm was significantly lower as compared to patients without comorbidity. Because of the comorbid condition, the definitive treatment of breast cancer was not given so this will also affect the treatment of breast cancer. When the CCI score increases with an increase in the number of comorbidities will decrease survival.