Navigating patient journey in early diagnosis of lung cancer in India.

Lung cancer (LC) is one of the leading causes of cancer deaths worldwide. In India, the incidence of LC is increasing rapidly, and a majority of the patients are diagnosed at advanced stages of the disease when treatment is less likely to be effective. Recent therapeutic developments have significantly improved survival outcomes in patients with LC. Prompt specialist referral remains critical for early diagnosis for improved patient survival. In the Indian scenario, distinguishing LC from benign and endemic medical conditions such as tuberculosis can pose a challenge. Hence, awareness regarding the red flags-signs and symptoms that warrant further investigations and referral-is vital. This review is an effort toward encouraging general physicians to maintain a high index of clinical suspicion for those at risk of developing LC and assisting them in refering patients with concerning symptoms to specialists or multidisciplinary teams as early as possible.

Recurrent osteosarcoma with calcified liver metastases: Uncommon development of a common disease.

Osteosarcoma is the commonest primary malignant bone tumor. Since bones lack a lymphatic system, metastatic spread in these tumors is exclusively hematogenous, the commonest sites being lungs and bone. We report a case of osteosarcoma humerus which recurred locally after primary therapy consisting of neoadjuvant chemotherapy and limb salvage surgery, who developed calcified liver metastases in addition to local and pulmonary relapse. Liver, though a common site of hematogenous spread in most solid tumors, has rarely been reported to be involved in metastatic osteosarcomas.

Outcomes of thymoma treated with multimodality approach: a tertiary cancer center experience of 71 patients.

AIMS: To explore the demographics and clinical outcome of patients with thymoma treated with a multimodality approach at our institute. METHODS: A total of 71 patients with thymoma (Masaoka stage II-IV and WHO subtype AB-B3) treated from 1999-2013 were included in this retrospective analysis. Age, stage, WHO subtypes, details of surgery, radiotherapy, and chemotherapy were noted. Progression-free survival (PFS) was estimated using Kaplan-Meier method and SPSS (version 21.0) was used for statistical analysis. RESULTS: Male:female ratio was 56:15 with median age at presentation of 41 years. Stage-wise distribution was 6:46:19 for stage II, stage III, and stage IV, respectively. A total of 31 patients (44%) had associated myasthenia gravis and 3 had pure red cell aplasia. A total of 57 patients (80%) underwent radical thymectomy and all of these patients received adjuvant radiotherapy. A total of 15 patients and 7 patients received adjuvant chemotherapy and neoadjuvant chemotherapy, respectively. At median follow-up of 19.3 months (range 7.9-72.3 months), 2-year and 3-year PFS rate for the entire cohort was 78.3% and 57.1%, respectively. On univariate analysis, surgery (hazard ratio [HR] 3.881; 95% confidence interval [CI] 1.784-19.220; p = 0.006) and stage (HR 5.457; 95% CI 1.567-18.996; p = 0.0001) were significant prognostic factors and association with myasthenia gravis (HR 0.404; 95% CI 0.151-1.078; p = 0.078) trended towards better PFS. Stage retained its prognostic significance (HR 5.501; 95% CI 2.076-14.573; p = 0.0006) on multivariate analysis. CONCLUSIONS: Multimodality management of locally advanced thymoma yields decent survival outcomes. Masaoka stage is an independent prognostic factor for survival and radical surgery should be contemplated in all cases of locoregionally limited thymoma.

Patterns of care and survival among small cell lung cancer patients: Experience from a tertiary center in India.

BACKGROUND/PURPOSE: Lung cancer is the commonest malignancy and the most common cause of cancer related mortality in males worldwide. Non-small cell lung cancer (NSCLC) is the commonest histology while small cell lung cancer (SCLC) contributes to only 15% of all cases of lung cancer. This report intended to present the patterns of care, survival outcomes and prognostic factors of SCLC treated in a tertiary care institute. RESULTS: A total of 85 patients of SCLC were registered in radiotherapy unit I during the period January, 2005 to December, 2012. The median age of the cohort was 56.5years (95% CI 34-72). The majority of the patients were male with a male:female ratio of 6.7:1. Sixty eight percent of the patients were smokers. Sixty percent patients presented with extensive stage disease. Radiotherapy (RT) was used in 76% of the patients while chemotherapy was used in 75% of the patients. Platinum Etoposide was the most common regimen which was used in 70% of the patients who received chemotherapy. The median progression free survival (PFS) of the entire cohort was 11.4months (95% CI 9.11-13.58months). Stage, performance status, and use of chemotherapy were found to be significant factors affecting survival outcome in patients with SCLC. CONCLUSION: The pattern of care and survival outcomes in the present study parallels that of the various published retrospective reviews. Basic research and development of targeted agents may be the way forward in improving the outcome of patients with SCLC.

Clinicopathological characteristics, molecular subgrouping, and expression of miR-379/miR-656 cluster (C14MC) in adult medulloblastomas.

Medulloblastoma (MB) is a childhood tumor comprising four molecular subgroups: WNT, SHH, group 3 and group 4, with diagnostic and prognostic connotations. Very few studies are available on molecular subgrouping of adult MBs due to their rarity. Recently, loss of chromosome14q has been reported in SHH MBs, with downregulation of miR-379/miR-656 cluster (C14MC) in pediatric SHH MBs. Hence, the present study on adult MBs was undertaken to enumerate clinicopathological characteristics and molecular subgroups, and to analyze expression of C14MC and its transcriptional regulators, MEF2, JUN and ESRRG. Immunohistochemistry for ß-catenin, GAB1 and YAP1 was performed to identify molecular subgroups. MYC amplification was evaluated by FISH. Expression profiling of 47 miRNAs from C14MC was performed using customized Taqman low-density array. Expression of transcriptional regulators was examined using RT-PCR. Seventy-one adult MBs were analyzed. They had male predominance and majority were located laterally (52 %). A significant proportion of cases were of Desmoplastic/nodular histology (32 %); MBEN was not seen. WNT tumors constituted 4.2 %, SHH 62 %, and non-WNT/non-SHH 33.8 %. MYC amplification was identified in 11.1 % cases. Patient outcome was worse in adults. Significant downregulation of C14MC was observed in all MB subgroups, and MEF-2 expression was downregulated. Adult MBs are distinct from childhood MBs in terms of location, histopathological subtypes, molecular subgroups, as well as prognosis. Silencing of C14MC in all MB subgroups suggests its role as a tumor suppressor locus in tumorigenesis. Deregulation of C14MC can possibly be attributed to repression of MEF2.

Intracranial germ cell tumors: a multi-institutional experience from three tertiary care centers in India.

OBJECTIVE: Central nervous system germ cell tumors (CNS GCTs) are relatively rare neoplasms. Incidence of CNS GCTs in Western literature is low (0.3-0.6 %) as compared to East Asia (3-4 %). No large study is available on CNS GCTs from India. METHODS: Intracranial GCT cases were retrieved from databases of three tertiary care institutes in India; clinicopathological data was reviewed. RESULTS: Ninety-five intracranial GCT cases were identified, accounting for 0.43 % of CNS tumors. Median age was 12 years (range, birth to 48 years); male preponderance was noted (66 %). Most patients (86.3 %) were aged <18 years. Pineal location was most common (45 %) and was associated with male gender and age >14 years. Germinoma was the commonest histopathological type (63.2 %), followed by teratoma (20 %). Suprasellar location was associated with germinoma histology. Follow-up was available for 71 patients (median, 15 months). Of these, 48 received adjuvant chemotherapy and/or radiotherapy. At the last follow-up, 44 patients showed no evidence of disease. Age >10 years, male gender, pineal location, and germinoma histology were associated with favorable outcome. CONCLUSION: This is the first multicentric study from India establishing that incidence of CNS GCT in India is similar to that in the West and differs from that in East Asian countries. However, similar to both, germinoma is the commonest histological type, and pineal location is most frequent. Studies on molecular alterations based on ethnicity and geographical location are necessary to provide clarity on differences in incidence. Attention needs to be focused on decreasing treatment heterogeneity and minimizing treatment-related morbidity and mortality, improving the cure rate of these highly treatable tumors.

Molecular predictive and prognostic factors in ependymoma.

An ependymoma is an uncommon glial tumor, which arises from different parts of the neuroaxis. Considerable variation in presentation and survival in tumors in different locations after an optimum treatment indicates inherent molecular and genetic differences in tumorigenesis between them. A number of genetic aberrations have been identified to distinctly characterize different subgroups of ependymomas that include a posterior fossa tumor, a supratentorial tumor, and a pediatric tumor. These different groups have substantial genetic alterations, and also distinct demography, clinical characteristics, and prognosis. This article is intended to review the diverse molecular and genetic aberrations that may be helpful in prognostication and prediction of survival in patients suffering from an ependymoma.

Altered fractionation radiotherapy in head and neck squamous cell carcinoma.

INTRODUCTION: Fractionation plays a pivotal role in determining the effectiveness of radiation and follows the principle of 4 "R" of radiobiology. The various altered fractionation schedules used are hyper-fractionation, accelerated fractionation, and hypo fractionation. METHODS: We reviewed the landmark articles published in the peer reviewed journals to summarize the beneficial role of altered fractionation in the treatment of head and neck carcinoma. RESULTS: Hyper-fractionation definitely gives very good overall survival benefit for locally advanced head and neck patient's equivalent to survival benefit to that of concurrent chemoradiotherapy. Adding concomitant chemotherapy to altered fractionation is a logical approach to improve survival in locally advanced head and neck cancer patients, but it may be at a cost of higher toxicity. Mild hypo fractionation may be beneficial in early laryngeal cancers and may help in achieving better local control. CONCLUSION: Altered fractionation is a very important treatment schema and requires the reinforcement of its use.

The Expression of Cyclin D1, VEGF, EZH2, and H3K27me3 in Atypical Teratoid/Rhabdoid Tumors of the CNS: A Possible Role in Targeted Therapy.

Atypical teratoid/rhabdoid tumor (AT/RT) is an uncommon malignancy with a dismal outcome, which responds poorly to multimodality therapies. Animal studies have revealed Cyclin D1 as a possible therapeutic target. The addition of vascular endothelial growth factor (VEGF) inhibitors to chemotherapeutic regimens has shown promising results in pediatric central nervous system tumors. Enhancer of Zeste homolog 2 (EZH2) overexpression has been implicated in various cancers, including medulloblastomas. H3K27me3 is a new marker for pediatric high-grade gliomas. However, their role in AT/RT has not been evaluated sufficiently. We retrieved cases of AT/RT, and reviewed their clinical data and histopathologic features. Immunohistochemistry for Cyclin D1, VEGF, EZH2, and H3K27me3 was performed. Follow-up was noted when available. Fourteen cases of AT/RT were identified (mean age, 3.4 y; range, 10 mo to 8 y). Cyclin D1 immunopositivity was noted in all cases [labeling index (LI): 5% to 98%; mean, 41.3%]. VEGF positivity was seen in 83.3% of the cases. All cases showed EZH2 overexpression (mean LI, 74.3%; range, 32% to 96%). Reduction of H3K27me3 expression was noted in 63% of the cases, with no correlation with EZH2 LI. Two patients died of postoperative complications. Of the rest, follow-up was available for 7 (range, 7 to 120 wk): 1 achieved clinical remission, whereas 6 developed progressive disease, including 3 deaths. Varying degrees of immunoreactivity to Cyclin D1, VEGF, and EZH2 were noted in the majority of the AT/RTs, and detection of these markers may be of value in the development of novel therapeutic agents and in determining which patients can benefit from them. AT/RTs show reduction in H3K27me3 expression, independent of EZH2 expression, indicating that their interaction requires further evaluation.

Integrating Molecular Subclassification of Medulloblastomas into Routine Clinical Practice: A Simplified Approach.

Medulloblastoma (MB) is composed of four molecular subgroups viz. WNT, SHH, groups 3 and 4, identified using various high-throughput methods. Translation of this molecular data into pathologist-friendly techniques that would be applicable in laboratories all over the world is a major challenge. Ninety-two MBs were analyzed using a panel of 10 IHC markers, real-time PCR for mRNA and miRNA expression, and FISH for MYC amplification. ß-catenin, GAB1 and YAP1 were the only IHC markers of utility in classification of MBs into three subgroups viz. WNT (9.8%), SHH (45.6%) and non-WNT/SHH (44.6%). mRNA expression could further classify some non-WNT/SHH tumors into groups 3 and 4. This, however, was dependent on integrity of RNA extracted from FFPE tissue. MYC amplification was seen in 20% of non-WNT/SHH cases and was associated with the worst prognosis. For routine diagnostic practice, we recommend classification of MBs into three subgroups: WNT, SHH and non-WNT/SHH, with supplementation by prognostic markers like MYC for non-WNT/SHH tumors. Using this panel, we propose a new three-tier risk stratification system for MBs. Molecular subgrouping with this limited panel is rapid, economical, works well on FFPE tissue and is reliable as it correlates significantly with clinicopathological parameters and patient survival.

Radiation Induced Cystitis and Proctitis - Prediction, Assessment and Management.

Cystitis and proctitis are defined as inflammation of bladder and rectum respectively. Haemorrhagic cystitis is the most severe clinical manifestation of radiation and chemical cystitis. Radiation proctitis and cystitis are major complications following radiotherapy. Prevention of radiation-induced haemorrhagic cystitis has been investigated using various oral agents with minimal benefit. Bladder irrigation remains the most frequently adopted modality followed by intra-vesical instillation of alum or formalin. In intractable cases, surgical intervention is required in the form of diversion ureterostomy or cystectomy. Proctitis is more common in even low dose ranges but is self-limiting and improves on treatment interruption. However, treatment of radiation proctitis is broadly non-invasive or invasive. Non-invasive treatment consists of non-steroid anti-inflammatory drugs (NSAIDs), anti-oxidants, sucralfate, short chain fatty acids and hyperbaric oxygen. Invasive treatment consists of ablative procedures like formalin application, endoscopic YAG laser coagulation or argon plasma coagulation and surgery as a last resort.

Breast cancer with inguinal node recurrence.

Surgery and irradiation for breast cancer may interfere with conventional pathways of spread, leading to bizarre patterns of dissemination through lymphatics or through hematogenous route. Lymphoscintigraphic studies may help identify nodal involvement. Other possible reasons could be occurrence of primary breast cancer in accessory breast tissue retained in the vulva following involution of milk line. We describe a case of triple negative breast cancer, who developed contralateral breast cancer during treatment. Three years later, she developed isolated inguinal nodal metastases, which responded to local radiotherapy and chemotherapy. However, the patient relapsed after 2 years and could not be salvaged thereafter.

Toxic epidermal necrolysis in a patient receiving concurrent phenytoin and whole brain and thoracic radiotherapy.

Toxic epidermal necrolysis (TEN) is a severe drug induced type IV hypersensitivity syndrome that can be caused by anticonvulsant drugs, especially the aromatic anticonvulsants such as phenytoin. Most patients with brain metastasis receive whole brain radiotherapy along with anti-edema measures and anticonvulsants either as prophylactic or for symptom control; phenytoin being the most commonly used drug. In a subset of patients, cranial irradiation may act as a precipitating factor along with anticonvulsants for the development of TEN. We report a 54-year-old patient with metastatic non-small cell lung cancer treated with palliative whole brain and mediastinal radiotherapy with concurrent phenytoin-developing TEN, which started within the radiation portals with subsequent generalization. Though a rare, but serious complication, avoidance of the use of phenytoin concurrent with radiotherapy, replacing phenytoin with newer anticonvulsants, early recognition, aggressive management and awareness of this possible complication has been implied upon in this report.

18F-Fluoride PET/CT for detection of bone metastasis in patients with renal cell carcinoma: a pilot study.

PURPOSE: The aim of this study was to evaluate the role of F-fluoride PET/computed tomography (CT) in the detection of bone metastasis in patients with renal cell carcinoma (RCC) and compare the results with fluorine-18 fluorodeoxyglucose (F-FDG) PET/CT and technetium-99m methylene diphosphonate bone scintigraphy (BS) when available. MATERIALS AND METHODS: The data of 36 patients (mean age: 52.5±14.1 years; male/female: 27/9) with RCC who prospectively underwent F-fluoride PET/CT were analyzed. PET/CT images were analyzed by two nuclear medicine physicians in consensus, visually and semiquantitatively [maximum standardized uptake value (SUVmax)]. Results of F-fluoride PET/CT were compared with those of F-FDG PET/CT (n=16) and BS (n=22). Histopathology or clinical or imaging follow-up (minimum 6 months) were used as the reference standard. RESULTS: Overall, F-fluoride PET/CT showed a sensitivity of 100%, specificity of 94.4%, positive predictive value of 94.7%, negative predictive value of 100%, and accuracy of 97.2%. It demonstrated a total of 134 skeletal lesions, of which 101 were characterized as metastasis and 33 as benign. Corresponding CT changes were seen for 129/134 lesions. The mean SUVmax of the lesions was 30.3±48.4. F-Fluoride PET/CT and F-FDG PET/CT showed similar accuracy for visualization of bone metastasis (93.7 vs. 100%; P=0.993). However, F-FDG PET/CT additionally demonstrated extraskeletal metastasis in 6/16 patients. No significant difference was seen between the accuracies of BS and F-fluoride PET/CT for visualization of bone metastasis (93.7 vs. 100%; P=0.115), but the former showed significantly more skeletal lesions (91 vs. 44; P<0.0001). In 4/22 patients (18%) with negative BS, F-fluoride PET/CT demonstrated skeletal metastasis. CONCLUSION: F-Fluoride PET/CT shows high diagnostic accuracy for the detection of bone metastasis in patients with RCC. It shows comparable results to F-FDG PET/CT and detects more skeletal lesions compared to BS.

Recurrent posterior reversible encephalopathy syndrome after chemotherapy in hematologic malignancy-posterior reversible encephalopathy syndrome can strike twice!!!

Posterior reversible encephalopathy syndrome (PRES) is a neuro-radiological syndrome characterized by seizures, altered level of consciousness, visual disturbance, and hyperintense lesions on magnetic resonance imaging most commonly in the posterior regions. PRES is typically associated with a number of complex clinical conditions including: Preeclampsia/eclampsia, allogeneic bone marrow transplantation, solid organ transplantation, autoimmune diseases, and high-dose anti-neoplastic therapy. We herein describe a case of recurrent PRES in a 29-year-old lady of refractory anaplastic large-cell lymphoma who was on second-line chemotherapy with Ifosfamide-Carboplatin-etoposide regimen. We have also tried to illustrate the pathogenesis, radiological features, and management of PRES. Although reversible in most cases, PRES may be recurrent even in chemotherapy--induced cases and result in fatal outcomes despite appropriate intervention. This is the first--reported case of recurrent PRES with such a fatal outcome, as a complication of anti-neoplastic systemic therapy.

A patient-based dosimetric study of intracavitary and interstitial brachytherapy in advanced stage carcinoma of the cervix.

Intracavitary brachytherapy (ICBT) and interstitial brachytherapy (IB) techniques are commonly practiced for treating carcinoma of the cervix, either alone or in combination with external beam radiotherapy. Both these brachytherapy techniques have their own advantages and limitations in terms of tumor coverage and normal tissue sparing. Limited studies have been reported comparing the dosimetric features of these two techniques, especially from a single institution. We carried out a prospective clinical dosimetric comparison between ICBT and IB for patients treated at one center to bring out the inherent dosimetric features of these to two techniques. The study was carried out on 26 patients treated with ICBT and 55 with IB using CT-based planning. Of the 55 patients treated with IB, 27 included tandem source loading (IBT) and 28 without the tandem loading (IBWT). The high-dose volumes covered by 200% and 180% isodose surfaces were considerably larger in ICBT as compared to IB, whereas the treated volume was larger in IB as compared to ICBT. The bladder and rectal doses were the highest in ICBT and IBWT, respectively. The larger treated volume in IB as compared to ICBT was mainly because patients with larger tumor volumes were generally considered for IB. The results also indicated that in interstitial brachytherapy, better rectal sparing was achieved by including the tandem for treatment delivery.

Comparison of high-dose-rate intracavitary brachytherapy dosimetry with and without anesthesia in patients with cervical carcinoma.

This study compares the dosimetry of high-dose-rate intracavitary brachytherapy (HDR-ICBT) performed with and without general anesthesia/spinal anesthesia (GA/SA) in patients with cervical carcinoma. We retrospectively retrieved the records of 138 HDR-ICBT applicator insertions performed in 46 patients: 69 performed with GA/SA (anesthesia group known as AG) in 23 patients, and 69 performed without GA/SA (nonanesthesia group known as NAG) in 23 patients. The intracavitary brachytherapy (ICBT) application was done with central tandem and two vaginal ovoids. For each ICBT plan, a high-dose-rate (HDR) dose of 7 Gy was prescribed to point A. From each plan, the doses to Point B right (B(R)), Point B left (B(L)), bladder and rectal reference points (Bladder(ref) and Rectal(ref)) were recorded and compared in the two groups. Student's t-test was applied to find out the significance of difference. The two groups were comparable in terms of demography and clinical characteristics. Mean Point BL doses in AG and NAG were 1.89 Gy (27% of Point A dose) and 1.82 Gy (26% of Point A dose), respectively. Mean Point BR doses in AG and NAG were 1.91 Gy (27% of Point A dose) and 1.85 Gy (26% of point A), respectively (p-value 0.7). The mean dose to Bladder(ref) in AG and NAG was 5.03 Gy and 4.90 Gy, respectively (p-value 0.6). The mean dose to Rectal(ref) was significantly higher in AG than NAG (5.09 Gy vs. 4.49 Gy, p-value 0.01). Although based on conventional 2D dosimetry planning, our study has demonstrated that avoiding GA/SA does not result in inferior HDR-ICBT dosimetry.

Assessment of Her-2/neu status using immunocytochemistry and fluorescence in situ hybridization on fine-needle aspiration cytology smears: experience from a tertiary care centre in India.

Breast carcinoma shows amplification/overexpression of Her-2/neu in ∼20-30% of cases. The determination of Her-2/neu expression accurately is vital in clinical practice as it has significant predictive value and eligibility for anti Her-2/neu therapy. Amplification and overexpression of Her-2/neu gene is traditionally identified by fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) on tissue sections; only a few studies have evaluated feasibility of these techniques on cytological smears. One hundred cases of breast cancer with fine-needle aspiration cytology (FNAC) samples and corresponding surgically resected specimen were selected. Immunocytochemistry (ICC) and FISH for Her-2/neu was done on FNA smears, whereas IHC was performed on corresponding tissue sections. Diagnostic accuracy of ICC was 99% when compared with IHC. Comparison of FISH results with IHC showed 100% concordance. Unlike many centers in West, FNAC is still routinely performed in developing countries like India where vast majority of breast cancer cases present as palpable lumps. The high rates of accuracy of ICC and FISH for Her-2/neu detection can make FNAC a relevant first line of investigation as a cost effective model with a rapid turn-around time, providing complete information necessary for initial management of breast cancer patients.