Co-relation of Portal Vein Tumour Thrombus Response With Survival Function Following Robotic Radiosurgery in Vascular Invasive Hepatocellular Carcinoma.

Background/aims: The aim of this study was to prospectively evaluate stereotactic body radiotherapy (SBRT) with robotic radiosurgery in hepatocellular carcinoma patients with macrovascular invasion (HCC-PVT). Materials and methods: Patients with inoperable HCC-PVT, good performance score (PS0-1) and preserved liver function [up to Child-Pugh (CP) B7] were accrued after ethical and scientific committee approval [Clinical trial registry-India (CTRI): 2022/01/050234] for treatment on robotic radiosurgery (M6) and planned with Multiplan (iDMS V2.0). Triple-phase contrast computed tomography (CT) scan was performed for contouring, and gross tumour volume (GTV) included contrast-enhancing mass within main portal vein and adjacent parenchymal disease. Dose prescription was as per risk stratification protocol (22-50 Gy in 5 fractions) while achieving the constraints of mean liver dose <15 Gy, 800 cc liver <8 Gy and the duodenum max of <24 Gy). Response assessment was done at 2 months' follow-up for recanalization. Patient- and treatment-related factors were evaluated for influence in survival function. Results: Between Jan 2017 and May 2022, 318 consecutive HCC with PVT patients were screened and 219 patients were accrued [male 92%, CP score: 5-7 90%, mean age: 63 years (38-85 yrs), Cancer of the Liver Italian Program <3: 84 (40%), 3-6117 (56%), infective aetiology 9.5%, performance status (PS): 0-37%; 1-56%]. Among 209 consecutive patients accrued for SBRT treatment (10 patients were excluded after accrual due to ascites and decompensation), 139 were evaluable for response assessment (>2 mo follow-up). At mean follow-up of 12.21 months (standard deviation: 10.66), 88 (63%) patients expired and 51 (36%) were alive. Eighty-two (59%) patients had recanalization of PVT (response), 57 (41%) patients did not recanalize and 28 (17%) had progressive/metastatic disease prior to response evaluation (<2 months). Mean overall survival (OS) in responders and non-responders were 18.4 [standard error (SE): 2.52] and 9.34 month (SE 0.81), respectively (P < 0.001). Mean survival in patients with PS0, PS1 and PS2 were 17, 11.7 and 9.7 months (P = 0.019), respectively. OS in partial recanalization, bland thrombus and complete recanalization was 12.4, 14.1 and 30.3 months, respectively (P-0.002). Adjuvant sorafenib, Barcelona Clinic Liver Classification stage, gender, age and RT dose did not influence response to treatment. Recanalization rate was higher in good PS patients (P-0.019). OS in patients with response to treatment, in those with no response to treatment, in those who are fit but not accrued and in those who are not suitable were 18.4, 9.34, 5.9 and 2.6 months, respectively (P-<0.001). Thirty-six of 139 patients (24%) had radiation-induced liver disease (RILD) [10 (7.2%) had classic RILD & 26 (19%) had non-classic RILD]. Derangement in CP score (CP score change) by more than 2 was seen in 30 (24%) within 2-month period after robotic radiosurgery. Eighteen (13%) had unplanned admissions, two patients required embolization due to fiducial-related bleeding and 20 (14%) had ascites, of which 9 (6%) patients required abdominocentesis. Conclusion: PVT response or recanalization after SBRT is a statistically significant prognostic factor for survival function in HCC-PVT.

Evaluation of premetastatic changes in lymph nodes(pN0) of oral tongue tumour: A prospective observational Study.

Background: Tongue tumors show intra and inter-tumoral heterogenicity with high incidence, relapse and mortality rates necessitating further research.  Recurrence/metastasis that occurs  after surgical resection of primary cancer is often the reason for poor survival in these patients.  Lymph nodes are the most common site of metastasis in tongue tumors. Therefore, premetastatic molecular changes can be best evaluated in lymph nodes which may epitomize the earliest events in the metastasis cascades. The presence of circulating tumor cells(CTCs) in the absence of nodal disease (N0) may represent tumor aggressiveness, suggesting an immune escape which may have high metastatic potential. This trial  was developed  to investigate the earliest pre-metastatic changes which may regulate tumor dormancy and predict metastasis. A better understanding of organotropism or pre-metastatic changes can help in theragnostic, thereby  preventing the outbreak of overt metastasis.  Methods: A single-institutional prospective observational cohort study. This trial will be conducted at a tertiary care Centre (Amrita Institute of Medical Sciences Kochi).  Eligible patients will be enrolled after obtaining informed consent. The dissected lymph nodes will  be subjected to histopathological and immunohistochemical analyses for premetastatic niche (PMN) formation. In addition, circulating tumor cells will be evaluated before treatment and 6 months after treatment. The patients will be followed  up for a period of two years to correlate the findings with the recurrence-free survival. Expected results:  The pre-metastatic changes, if detected will  be  a predictive biomarker. It may help to define future drug targets for metastasis chemoprevention   . CTCs may  define the tumor aggressiveness ,there by  prognostication  and helps in better disease management. Ethics and dissemination: The study has received the following approval: Ethics Committee of Amrita School of Medicine (ECASM-AIMS-2022-048).Trial Registered Prospectively( CTRI/2022/03/041256 ) on 22/03/2022 under Clinical Trial Registry of India.

5-FU mediated depletion of myeloid suppressor cells enhances T-cell infiltration and anti-tumor response in immunotherapy-resistant lung tumor.

Tumor microenvironment (TME) is a heterogeneous system consisting of both cellular and acellular components. The growth and progression of tumors rely greatly on the nature of TME, marking it as an important target in cancer immunotherapy. Lewis Lung Carcinoma (LLC) is an established murine lung cancer model representing immunologically 'cold' tumors characterized by very few infiltrated cytotoxic T-cells, high levels of Myeloid-Derived Suppressor Cells (MDSCs) and Tumor-Associated Macrophages (TAMs). Here, we report various strategies we applied to reverse the non-immunogenic character of this cold tumor by imparting: a) immunogenic cell death using Hypericin nanoparticle-based photodynamic therapy (PDT), b) repolarising TAM using a TLR7/8 agonist, resiquimod, c) immune checkpoint inhibition using anti-PD-L1 and d) depleting MDSCs using low-dose 5-fluorouracil (5-FU) chemotherapy. Interestingly, the nano-PDT, resiquimod or anti-PD-L1 treatment had no major impact on tumor growth, whereas low-dose 5-FU-mediated depletion of MDSCs showed significant anti-tumor effect, primarily caused by the increased infiltration of CD8+ cytotoxic T-cells (∼96%). Though we have tested combining PDT with resiquimod or 5-FU for any synergistic effect, low-dose 5-FU alone showed better response than combinations. In effect, we show that depletion of MDSCs using low-dose 5-FU was one of the best methods to augment infiltration of CD8+ cytotoxic T-cells into a cold tumor, which is resistant to conventional therapies including immune checkpoint inhibitors.

Prospective Evaluation of Response to Treatment, Survival Functions, Recurrence Pattern and Toxicity Profile in Indian Patients with Oligo-Brain Metastasis Treated with Only SRS.

Background: Prospective analysis of oligo-brain metastasis in Indian patients treated with SRS-only treatment. Methods: Between January 2017 and May 2022, 235 patients were screened and 138 histologically proven and radiologically confirmed. One to five brain metastasis patients aged more than 18 years with good Karnofsky performance status (KPS >70) accrued in ethical and scientific committee-approved prospective observational study protocol for treatment with only radiosurgery (SRS) with robotic radiosurgery (CyberKnife, CK) [AIMS IRB: 2020-071; CTRI No: REF/2022/01/050237]. Immobilization was performed with a thermoplastic mask, contrast CT simulation was performed with 0.625 mm slices, fused with T1 contrast/T2 FLAIR MRI images for contouring. Planning target volume (PTV) margin of 2-3 mm and a dose of 20-30 Gy in 1-5 fractions. Response to treatment, new brain lesions free survival, overall survival, and toxicity profile after CK were evaluated. Results: In total,: 138 patients with 251 lesions were accrued (median age 59 years (interquartile range [IQR] 49-67 years; female 51%; headache in 34%, motor deficit in 7%, KPS >90 in 56%; lung primary in 44%, breast in 30%; oligo-recurrence in 45%; synchronous oligo-metastases in 33%; adenocarcinoma primary in 83%). One hundred seven patients (77%) received upfront Stereotactic radiotherapy (SRS), 15 (11%) received postoperative SRS, 12 (9%) received whole brain radiotherapy (WBRT) before SRS, and 3 (2%) received WBRT plus SRS boost. The majority had solitary (56%) brain metastasis, 28% had two to three lesions, and 16% had four to five brain lesions. Frontal (39%) was the most common site. Median PTV was 15.5 mL (IQR - 8.1-28.5 mL). Seventy-one (52%) patients were treated with single fractions, 14% with three, and 33% with five fractions. Fraction schedules were 20-2 4 Gy/1fr; 27 Gy/3fr, and 25 Gy/5 fractions (mean BED 74.6 Gy [SD ± 48.1; mean MU 16608], mean treatment time was 49 min (range 17-118 min]. Twelve Gy normal brain volume was 40.8 mL (3.2%) (range 19.3-73.7 mL). At a mean follow-up of 15 months (SD 11.9 months; max 56 months), the mean actuarial OS after SRS-only treatment was 23.7 months (95% confidence interval [CI] 20-28). Further 124 (90%) patients had >3 months, 108 (78%) had >6 months, 65 (47%) had >12 months, and 26 (19%) had >24 months follow-up. Intracranial disease and extracranial disease were controlled in 72 (52.2%) and 60 (43.5%), respectively. "In-field" recurrence, "out-of-field," and "both in and out-of-field" recurrences were in 11%, 42%, and 46%, respectively. At the last follow-up, 55 patients (40%) were alive, 75 (54%) died due to disease progression, and the status of 8 (6%) patients was not known. Among 75 patients who died, 46 (61%) had extracranial disease progression, 12 (16%) had only intracranial progression, and 8 (11%) had unrelated causes. Also, 12/117 (9%) had radiological confirmation of radiation necrosis. Prognostication based on western patients (primary tumor type, number of lesions extracranial disease) showed similar outcomes. Conclusions: SRS alone in brain metastasis is feasible in the Indian subcontinent with similar survival outcomes, recurrence patterns, and toxicity as published in the western literature. Patient selection, dose schedule, and planning need to be standardized to have similar outcomes. WBRT can be safely omitted in Indian patients with oligo-brain metastasis. Western prognostication nomogram is applicable in the Indian patient population.

Analysis of the Mortality Trends of 23 Major Cancers in the Indian Population Between 2000 and 2019: A Joinpoint Regression Analysis.

PURPOSE: Cancer mortality trends have not been documented across the population of India. We, therefore, analyzed the overall and individual cancer mortality trends for 23 major cancers between 2000 and 2019 on the basis of Global Health Observatory (GHO) database. MATERIALS AND METHODS: This study examined cancer mortality trends for 23 major cancer sites on the basis of 12.85 million cancer deaths obtained from the GHO of the WHO between 2000 and 2019. A joinpoint regression model was used to analyze the long-term trends of cancer mortality. Annual percentage change (APC) and average APC were estimated for various cancer sites. RESULTS: Between 2000 and 2019, 12.85 million deaths occurred in India from 23 major cancers. The most common lethal cancers were mouth and oropharyngeal (15.6%), stomach (10.6%), lung (9.6%), breast (9%), and colorectal (8%) cancers. The mortality trend decreased by 0.19% annually among men and increased nonsignificantly by 0.25% among women; an increase of 0.02% was observed among combined sexes. Increasing mortality trends were seen among cancers of the lung, breast, colorectum, lymphoma, multiple myeloma, gallbladder, pancreas, kidney, and mesothelioma between 2000 and 2019. The highest annual increase in mortality was observed in pancreatic cancer among both sexes: 2.7%, 2.1% among men, and 3.7% in women. The cancers of the stomach, esophagus, leukemia, larynx, and melanoma showed a declining cancer mortality trend irrespective of sex. CONCLUSION: A multifaceted strategy is required to tackle the rising cancer mortality rates in India; the best long-term strategy could be implementing awareness on cancer symptoms among the population as well as cancer prevention policies with improved health infrastructure and specifically dedicated human resources.

Interactome based identification and validation of prefoldin 5-α for prognosing CNS leukemia in B-ALL patients.

We report here the identification and validation of prefoldin 5-alpha (PFDN5-α) for the first time as prognostic biomarker for prediction of central nervous system (CNS) leukemia of B cell acute lymphoblastic leukemia (B-ALL) origin. Since cerebrospinal fluid (CSF) cytology being the gold standard of diagnosis for CNS leukemia with poor sensitivity, mandatory prophylactic intrathecal chemotherapy is administered irrespective of patients develop CNS leukemia. Thus, using interactome studies, we identified PFDN5-α as a prognostic biomarker for predicting CNS leukemia by interacting lymphoblastic proteins and CSF from B-ALL patients using far-western clinical proteomics approach. Validation by both western and ELISA methods confirmed our results. For further clinical translation, we performed Receiver Operating Characteristic (ROC) curve analysis generated from CNS +ve (n = 25) and -ve (n = 40) CSF samples from B-ALL patients and identified PFDN5-α-CSF reactivity cut-off value as 0.456. Values below 0.456 indicate the patient is at risk of developing CNS leukemia and suggestive of having intrathecal chemotherapy. Further flow cytometry validation for CNS leukemia positivity revealed that with increasing blast cells, a decrease in PFDN5-α-CSF reactivity confirming ELISA based PFDN5α-CSF reactivity assay. Predicting CNS leukemia development risk by ELISA based PFDN5-α-CSF reactivity assay could have potential in the clinical management of CNS leukemia.

Ribociclib-induced extensive vitiligo-like lesions: possible pathomechanisms with clinical, dermoscopic and histological correlation.

Cyclin dependent kinase (CDK) 4/6 inhibitors are targeted agents which act on cyclin-D and these combined with hormonal therapy have been approved for the treatment of locally advanced or metastatic breast cancer. CDK 4/6 inhibitors have been found to have a tolerable adverse event profile; however, they have been associated with various dermatological adverse events. We report a case of ribociclib-induced vitiligo and discuss the clinical, dermoscopic and histological features with a review of the various possible pathomechanisms involved.

Ribociclib-associated organising pneumonia.

A 63-year-old woman with grade 2 infiltrating left breast carcinoma who was started on ribociclib complained of exertional dyspnoea along with dry cough. There were bilateral interscapular crackles and chest X-ray evidence of bilateral mid and lower zone non-homogeneous opacity. The patient's pulmonary function test (PFT) showed moderate restrictions and desaturation. CT was suggestive of organising pneumonia and drug administration was stopped. The patient was treated with steroids in tapering doses, which led to improvements. The drug was restarted with the probability of other aetiologies for interstetial lung disease (ILD). It was also considered the superior efficacy of ribociclib in managing breast cancer. But due to evidence indicating the reappearance of organising pneumonia following drug administration, it was again stopped, and steroid use was restarted for treatment. The patient showed improvements in subsequent follow-ups.

Recurrence of renal cell carcinoma after three decades in an octogenarian: Small molecules adding life to years.

Renal cell carcinoma (RCC) is the most common primary renal neoplasm. About a half of our patients relapse after primary treatment. We present here a case of RCC with solitary metastasis to the pleura which occurred 32 years after nephrectomy. Our patient is an 86-year-old male who presented to us with a cough of 2 months and a history of having undergone a right nephrectomy 32 years back. Imaging of the chest showed left pleural effusion with a left pleural nodule. Computed tomography-guided fine-needle aspiration cytology from the pleural nodule was suggestive of malignancy with a clear cell morphology, suggestive of clear cell RCC. The patient was started on sunitinib 25 mg once daily. After the 1st month, the patient's performance status improved markedly, with no cough and improved appetite. He had developed Grade II hand-foot syndrome, which was managed conservatively, and the dose was deescalated to 25 mg once daily - 5 days on and 2 days off. An X-ray of the chest taken 6 weeks after the start of therapy showed complete resolution of the pleural fluid and regression of the pleural nodule. The patient is alive and well 5 years into therapy. The case highlights the unusual propensity for very late metastasis in RCC. Metastasis after 30 years is extremely rare. Another highlight of the case is the good tolerability of the dose-modified schedule of sunitinib. Wise patient selection and dose modification can certainly add "life to the years" in our very elderly patients.

Frequency and Prognosis of Epidermal Growth Factor Receptor Variant III Mutations in Glioblastoma Multiforme among Indian Patients: A Single-Institution Study.

Background Glioblastoma multiforme (GBM) is a disease with poor outcome. Alterations or mutations in epidermal growth factor receptors (EGFRs) are found in GBM and may be targeted to improve outcomes. Aims We analyzed the frequency of EGFR variant III (vIII) mutations in patients with GBM and their outcomes after standard treatment. Materials and Methods This is a retrospective study conducted in a single tertiary cancer center in south India. Forty patients with GBM who had their entire treatment done at this center were identified, and their primary tumor tissue blocks were retrieved. Genomic DNA was extracted, and molecular analysis was performed and analyzed. The results of mutational analysis were correlated with treatment outcome of the patients. Statistical Analysis Survival outcome was analyzed using the Kaplan-Meier method. The log-rank test was used to assess the association between the groups and various parameters. Results Our study showed a similar incidence of EGFR vIII alterations as published in world literature, but we did not find any difference in overall survival (OS) and progression-free survival (PFS) in patients with EGFR vIII mutation compared with nonmutant cohort. Conclusions Contrary to the existing literature which indicated EGFR vIII alterations to be a negative prognostic indicator, our study did not find it to be an independent predictor of prognosis among Indian GBM patients treated with present standard of care.

Pathological Complete Response in Locally Advanced Breast Cancer after Neoadjuvant Chemotherapy: Survival Outcome and Its Relevance as a Surrogate End Point.

Background Pathological complete response (pCR) to neoadjuvant chemotherapy has emerged as a reliable surrogate marker for improved survival in breast cancer (BC), but its role as a surrogate end point is still controversial. Aims and Objectives The aim of the study is to investigate the clinical course of BC patients with pCR and to evaluate the relevance of pCR as a surrogate end point for survival. Materials and Methods This was a single-institution retrospective analysis done at Amrita Institute of Medical Sciences. Records of BC patients from 2004 to 2014 were analyzed. Disease-free survival (DFS) and overall survival (OS) were compared using the Kaplan-Meier method and log-rank test, respectively. pCR and survival association were evaluated using regression analysis ( R 2 ). Results Of 224 patients included in the study pCR rate was 15.2%. The median duration of follow-up was 61 months (range: 3-151 months). DFS (73.4 vs. 46.1%, p = 0.032) and OS (82.5 vs. 56.4%, p = 0.022) of pCR cohort was significantly higher than non-pCR cohort. Recurrence rate was significantly lower in the pCR cohort at: All distant sites ( p = 0.01 3), visceral sites ( p = 0.007), both bone and visceral sites ( p = 0.007), and nodal sites ( p = 0.007). There was no difference in the bone-only recurrence ( p = 0.3 15). Death rate was significantly lower in pCR cohort ( p = 0.007). The R2 value for pCR as a surrogate for DFS and OS was 0.006 and 0.004, respectively. Conclusion pCR is a favorable prognostic factor associated with improved survival. However, there is no association between pCR and survival.

Concurrent chemoradiotherapy for head and neck cancers in older patients: Outcomes and their determinants.

INTRODUCTION: Meta-analyses have shown concurrent chemoradiotherapy (CCRT) provides no survival benefit over radiotherapy in patients of head and neck squamous cell carcinoma (HNSCC) aged over 70 years. This study was performed to determine the adverse-effect profile, compliance, functional and oncological outcomes in patients of HNSCC over 70 years of age treated with CCRT. MATERIALS AND METHODS: Retrospective analysis of stage III/IV HNSCC in patients above 70 years of age who received CCRT at our institution (n = 57). Cox-proportional hazards regression model was used for statistical analysis. RESULTS: There were 57 patients of stage III/IV HNSCC who underwent curative CCRT. 61% completed chemotherapy with no deaths and acceptable toxicity. The predictors of recurrence were poorer performance status (P = 0.031) and treatment breaks (P = 0.04). Tube dependence was associated with 2.7 times higher risk of mortality (P = 0.005). CONCLUSION: CCRT should be considered standard of care in those over seventy with good performance status. Patients with tube dependence have a higher risk of persistent disease or treatment related mortality.

Robot-assisted supine extraperitoneal retroperitoneal lymph node dissection: a novel approach for template dissection in post-chemotherapy residual mass in non-seminomatous germ cell tumours.

Robot-assisted retroperitoneal lymph node dissection (RA-RPLND) in testicular cancer is conventionally performed through transperitoneal route. We report a case of robot-assisted supine extraperitoneal RPLND (RASE-RPLND), not previously described in the literature, which was performed for post-chemotherapy residual mass in a case of non-seminomatous germ cell tumour (NSGCT). RASE-RPLND apart from providing the benefits of robotic assistance has a significant advantage over transperitoneal approach, as the procedure can be performed in supine position without any bowel handling. Herein, we provide a detailed description of the novel surgical technique employed by us in this case.

Pharmacogenetic landscape of DPYD variants in south Asian populations by integration of genome-scale data.

AIM: Adverse drug reactions to 5-Fluorouracil(5-FU) is frequent and largely attributable to genetic variations in the DPYD gene, a rate limiting enzyme that clears 5-FU. The study aims at understanding the pharmacogenetic landscape of DPYD variants in south Asian populations. MATERIALS & METHODS: Systematic analysis of population scale genome wide datasets of over 3000 south Asians was performed. Independent evaluation was performed in a small cohort of patients. RESULTS: Our analysis revealed significant differences in the the allelic distribution of variants in different ethnicities. CONCLUSIONS: This is the first and largest genetic map the DPYD variants associated with adverse drug reaction to 5-FU in south Asian population. Our study highlights ethnic differences in allelic frequencies.

Epidermal growth factor receptor (EGFR) structure-based bioactive pharmacophore models for identifying next-generation inhibitors against clinically relevant EGFR mutations.

Present work elucidates identification of next generation inhibitors for clinically relevant mutations of epidermal growth factor receptor (EGFR) using structure-based bioactive pharmacophore modeling followed by virtual screening (VS) techniques. Three-dimensional (3D) pharmacophore models of EGFR and its different mutants were generated. This includes seven 3D pharmacophoric points with three different chemical features (descriptors), that is, one hydrogen bond donor, three hydrogen bond acceptors and three aromatic rings. Pharmacophore models were validated using decoy dataset, Receiver operating characteristic plot, and external dataset compounds. The robust, bioactive 3D e-pharmacophore models were then used for VS of four different small compound databases: FDA approved, investigational, anticancer, and bioactive compounds collections of Selleck Chemicals. CUDC101 a multitargeted kinase inhibitor showed highest binding free energy and 3D pharmacophore fit value than the well known EGFR inhibitors, Gefitinib and Erlotinib. Further, we obtained ML167 as the second best hit on VS from bioactive database showing high binding energy and pharmacophore fit value with respect to EGFR receptor and its mutants. Optimistically, presented drug discovery based on the computational study serves as a foundation in identifying and designing of more potent EGFR next-generation kinase inhibitors and warrants further experimental studies to fight against lung cancer.

Advanced therapeutic options and importance of rebiopsy in epidermal growth factor receptor-tyrosine kinase inhibitor-progressed nonsmall cell lung carcinoma patients: An expert opinion.

Advanced nonsmall cell lung cancer (NSCLC) treatment is primarily based on platinum-based chemotherapy. Although epidermal growth factor receptor (EGFR) targeting has shifted the treatment paradigm toward personalized tyrosine kinase inhibitors (TKIs), resistance develops inevitably and EGFR T790M is the most common acquired resistance mechanism. Rebiopsy of resistant NSCLC cases can provide additional information on the underlying resistant mechanisms and therefore can help clinicians in taking better management decisions. An expert panel meeting of renowned cancer oncologists was held to discuss the management of advanced-stage NSCLC. The present paper is based on the recommendations made by the expert panel and is supported by an exhaustive literature search. It was suggested that identification of driver mutation leads to better treatment decisions. TKIs have proven to be better treatment option in EGFR-positive patients as compared to chemotherapy. Third-generation TKIs (osimertinib) promise to bring optimal and improved care for NSCLC cases failing first-line TKI treatment.