Region of interest (ROI) selection using vision transformer for automatic analysis using whole slide images.

Selecting regions of interest (ROI) is a common step in medical image analysis across all imaging modalities. An ROI is a subset of an image appropriate for the intended analysis and identified manually by experts. In modern pathology, the analysis involves processing multidimensional and high resolution whole slide image (WSI) tiles automatically with an overwhelming quantity of structural and functional information. Despite recent improvements in computing capacity, analyzing such a plethora of data is challenging but vital to accurate analysis. Automatic ROI detection can significantly reduce the number of pixels to be processed, speed the analysis, improve accuracy and reduce dependency on pathologists. In this paper, we present an ROI detection method for WSI and demonstrated it for human epidermal growth factor receptor 2 (HER2) grading for breast cancer patients. Existing HER2 grading relies on manual ROI selection, which is tedious, time-consuming and suffers from inter-observer and intra-observer variability. This study found that the HER2 grade changes with ROI selection. We proposed an ROI detection method using Vision Transformer and investigated the role of image magnification for ROI detection. This method yielded an accuracy of 99% using 20 × WSI and 97% using 10 × WSI for the ROI detection. In the demonstration, the proposed method increased the diagnostic agreement to 99.3% with the clinical scores and reduced the time to 15 seconds for automated HER2 grading.

CONCORDANCE: A real-world evidence study to evaluate the concordance of detecting epidermal growth factor receptor (EGFR) mutation by circulating tumor DNA* versus tissue biopsy in patients with metastatic non-small cell lung cancer.

Background: Molecular tissue testing in non-small cell lung cancer (NSCLC) is done for the assessment of epidermal growth factor receptor (EGFR) mutation. EGFR mutation status is the basis for deciding the targeted treatment option for patients with metastatic NSCLC. The nonavailability of tissue samples and contraindications for biopsy pose a significant challenge. Hence, circulating tumor DNA (ctDNA) by liquid biopsy can be a viable alternative for NSCLC patients. Methods: This study was conducted at 15 sites across India. EGFR mutation testing from plasma was done as part of the study at the central laboratory by the next-generation sequencing (NGS) method, and EGFR mutation test results from tissue samples (done as part of routine practice) were recorded for all the patients. Results: Out of the total patients enrolled (N = 245), the majority (64.5%, n = 158) were men. The median age of patients was 58.0 (range: 26-84) years. The concordance between plasma and tissue testing was found to be 82.9% (95% confidence interval [CI]: 77.55, 87.45). The sensitivity and specificity of NGS were 68.4% (95% CI: 56.92, 78.37) and 90.1% [95% CI: 84.36, 94.21), respectively. Plasma testing detected 1.2% (n = 3) and tissue sample testing detected 2.4% (n = 6) positive status of exon 20 T790M EGFR mutation. Out of the total number of patients enrolled, 25 were tissue positive and plasma negative, while 16 were plasma positive and tissue negative. Conclusions: "> This real-world study in Indian patients suggests that plasma testing for EGFR mutation analysis is a viable diagnostic option in newly diagnosed advanced/metastatic NSCLC patients. The noninvasive plasma procedure in patients without available/evaluable tumor sample may enable more patients to receive appropriate targeted therapies by providing clinicians with valuable insights into the patient's tumor mutation status. ClinicalTrials.gov Identifier: NCT03562819.

Expert survey on management of prostate cancer in India: Real-world insights into practice patterns.

To gain insights on the diverse practice patterns and treatment pathways for prostate cancer (PC) in India, the Urological Cancer Foundation convened the first Indian survey to discuss all aspects of PC, with the objective of guiding clinicians on optimizing management in PC. A modified Delphi method was used, wherein a multidisciplinary panel of oncologists treating PC across India developed a questionnaire related to screening, diagnosis and management of early, locally advanced and metastatic PC and participated in a web-based survey (WBS) (n = 62). An expert committee meeting (CM) (n = 48, subset from WBS) reviewed the ambiguous questions for better comprehension and reanalyzed the evidence to establish a revote for specific questions. The threshold for strong agreement and agreement was ≥90% and ≥75% agreement, respectively. Sixty-two questions were answered in the WBS; in the CM 31 questions were revoted and 4 questions were added. The panelists selected answers based on their best opinion and closest to their practice strategy, not considering financial constraints and access challenges. Of the 66 questions, strong agreement was reached for 17 questions and agreement was achieved for 22 questions. There were heterogeneous responses for 27 questions indicative of variegated management approaches. This is one of the first Indian survey, documenting the diverse clinical practice patterns in the management of PC in India. It aims to provide guidance in the face of technological advances, resource constraints and sparse high-level evidence.

Prevalence of BRCA1 and BRCA2 Mutations Among Patients With Ovarian, Primary Peritoneal, and Fallopian Tube Cancer in India: A Multicenter Cross-Sectional Study.

PURPOSE: There are deficient data on prevalence of germline mutations in breast cancer susceptibility genes 1 and 2 (BRCA1/BRCA2) in Indian patients with ovarian cancer who are not selected by clinical features. METHODS: This prospective, cross-sectional, noninterventional study in nine Indian centers included patients with newly diagnosed or relapsed epithelial ovarian, primary peritoneal, or fallopian tube cancer. The primary objective was to assess the prevalence of BRCA1/BRCA2 mutations, and the secondary objective was to correlate BRCA1/BRCA2 status with clinicopathologic characteristics. Mutation testing was performed by a standard next-generation sequencing assay. RESULTS: Between March 2018 and December 2018, 239 patients with a median age of 53.0 (range, 23.0-86.0 years) years were included, of whom 203 (84.9%) had newly diagnosed disease, 36 (15.1%) had family history of ovarian or breast cancer, and 159 (66.5%) had serous subtype of epithelial ovarian cancer. Germline pathogenic or likely pathogenic mutations in BRCA1 and BRCA2 were detected in 37 (15.5%; 95% CI, 11.1 to 20.7) and 14 (5.9%; 95% CI, 3.2 to 9.6) patients, respectively, whereas variants of uncertain significance in these genes were seen in four (1.7%; 95% CI, 0.5 to 4.2) and six (2.5%; 95% CI, 0.9 to 5.4) patients, respectively. The prevalence of pathogenic or likely pathogenic BRCA mutations in patients with serous versus nonserous tumors, with versus without relevant family history, and ≤ 50 years versus > 50 years, were 40 of 159 (25.2%; 95% CI, 18.6 to 32.6) versus 11 of 80 (13.8%; 95% CI, 7.1 to 23.3; P = .0636), 20 of 36 (55.6%; 95% CI, 38.1 to 72.1) versus 41 of 203 (20.2%; 95% CI, 14.9 to 26.4; P < .0001), and 20 of 90 (22.2%; 95% CI, 14.1 to 32.2) versus 31 of 149 (20.8%; 95% CI, 14.6 to 28.2; P = .7956), respectively. CONCLUSION: There is a high prevalence of pathogenic or likely pathogenic germline BRCA mutations in Indian patients with ovarian cancer.

Bevacizumab based chemotherapy is a promising option in metastatic gallbladder adenocarcinoma.

Gallbladder cancer (GBC) is one of the most frequently observed cancers in India that is usually diagnosed at an advanced stage. Although surgery remains the only curative option, the majority of GBCs are unresectable. Palliative chemotherapy with gemcitabine and cisplatin is the recommended treatment in such cases. The current study reports a case of a 47-year-old female who exhibited GBC that had metastasized to the liver and peritoneum. She was administered palliative chemotherapy with gemcitabine and cisplatin, but due to disease progression the regimen was changed and an aggressive treatment initiated with gemcitabine and oxaliplatin with additional biosimilar bevacizumab (modified Gemox-B regimen). The patient completed six chemotherapy cycles with partial response and received bevacizumab (7.5 mg/kg 3-weekly) based maintenance treatment for an additional 6 cycles, after which she demonstrated disease progression, thus having a progression free survival of ~11 months. The patient is currently receiving palliative chemotherapy with capecitabine.

Biomarkers in Non-Small Cell Lung Cancers: Indian Consensus Guidelines for Molecular Testing.

Novel molecular targets and promising targeted therapies have reshaped diagnostics in patients with advanced non-small cell lung cancer (NSCLC). Despite this progress, the implementation of molecular screening to identify predictive biomarkers in Indian clinical and pathology settings has been challenging due to operational and logistical constraints. This consensus guideline brings together medical oncologists, molecular pathologists and pathologists from India to provide a quick and competent reference for biomarker testing in NSCLC. The guideline summarizes the importance of targetable mutations in NSCLC such as epidermal growth factor receptor (EGFR), rearrangements in anaplastic lymphoma kinase and receptor tyrosine kinase encoded by ROS-1 gene, overexpression of programmed cell death ligand-1 and resistant EGFR mutations. It reaffirms recommendations from international working groups, discusses vulnerable pre-analytical procedures and provides a balanced review on the pros and cons of different diagnostic tests (immunohistochemistry, fluorescence in situ hybridization, polymerase chain reaction-based testing and next-generation sequencing). The document also provides an algorithm to aid diagnostic decision-making and a checklist to assess the quality of testing laboratories that will help the medical oncologists make an informed choice. Overall, these recommendations are based on evidence and clinical experience and will aid policymakers, oncologists, health care practitioners and pathologists who strive to implement molecular strategies and make informed decisions for improved care in NSCLC in India.Funding: AstraZeneca Pharma India Limited.

Learning the Macroscopic Flow Model of Short Fiber Suspensions from Fine-Scale Simulated Data.

Fiber-fiber interaction plays an important role in the evolution of fiber orientation in semi-concentrated suspensions. Flow induced orientation in short-fiber reinforced composites determines the anisotropic properties of manufactured parts and consequently their performances. In the case of dilute suspensions, the orientation evolution can be accurately described by using the Jeffery model; however, as soon as the fiber concentration increases, fiber-fiber interactions cannot be ignored anymore and the final orientation state strongly depends on the modeling of those interactions. First modeling frameworks described these interactions from a diffusion mechanism; however, it was necessary to consider richer descriptions (anisotropic diffusion, etc.) to address experimental observations. Even if different proposals were considered, none of them seem general and accurate enough. In this paper we do not address a new proposal of a fiber interaction model, but a data-driven methodology able to enrich existing models from data, that in our case comes from a direct numerical simulation of well resolved microscopic physics.

A Prospective, Randomized, Multiple-Dose, Multi-Center, Comparative Clinical Study to Evaluate the Efficacy, Safety, Immunogenicity of a biosimilar Bevacizumab (Test product, Hetero) and Reference Medicinal Product (Bevacizumab, Roche) in Patients of Metastatic Colorectal Cancer.

OBJECTIVE: :To compare efficacy and safety of a biosimilar, Bevacizumab (Hetero) vs reference medicinal product (Bevacizumab, Roche) as first line therapy in patients with metastatic colorectal cancer (mCRC) in combination with chemotherapy. METHODS: Patients of aged 18 to 65 with histologically pre-confirmed mCRC and treatment naïve with unresectable metastatic disease or distant metastases were enrolled and randomized to receive either Hetero-Bevacizumab or RMPBevacizumab along with chemotherapy (XELOX or FOLFOX-4) regimen over a period of 24 weeks (up to 8 cycles of Hetero-Bevacizumab/RMP-Bevacizumab+ XELOX regimen (each cycle of 3 weeks) or up to 12 cycles of Hetero-Bevacizumab/ RMP-Bevacizumab + FOLFOX-4 regimen (each cycle of 2 weeks). Bevacizumab was administered at 7.5 mg/kg as an IV infusion over 60-90 minutes on Day 1 of each treatment cycle. The efficacy endpoints were the overall response rate (CR+PR) and disease control rate (DCR) according to RECIST 1.1. The safety endpoints included assessments of treatment emergent adverse events and immunogenicity. RESULTS: 160 patients were screened; 111 patients were randomized in the study. No statistical significant difference in overall response rate between both the treatment groups (HB-MAB vs. RB-MAB: 35.56 % vs. 20%, P=0.28 at Week 6; 37.50 % vs. 30.77 %, P=0.73 at Week 12). Similar trend was observed for disease control rate (HB-MAB vs. RB-MAB: 100% vs. 96%, P=0.36 at Week 6; 95.83 vs. 100%, P=1.00 at Week 12). CONCLUSIONS: Herero's Bevacizumab was found to be comparable to reference medical product, Bevacizumab in terms of efficacy and tolerability for the Indian patients with metastatic colorectal cancer.

Durable and self-hydrating tungsten carbide-based composite polymer electrolyte membrane fuel cells.

Proton conductivity of the polymer electrolyte membranes in fuel cells dictates their performance and requires sufficient water management. Here, we report a simple, scalable method to produce well-dispersed transition metal carbide nanoparticles. We demonstrate that these, when added as an additive to the proton exchange Nafion membrane, provide significant enhancement in power density and durability over 100 hours, surpassing both the baseline Nafion and platinum-containing recast Nafion membranes. Focused ion beam/scanning electron microscope tomography reveals the key membrane degradation mechanism. Density functional theory exposes that OH• and H• radicals adsorb more strongly from solution and reactions producing OH• are significantly more endergonic on tungsten carbide than on platinum. Consequently, tungsten carbide may be a promising catalyst in self-hydrating crossover gases while retarding desorption of and capturing free radicals formed at the cathode, resulting in enhanced membrane durability.The proton conductivity of polymer electrolyte membranes in fuel cells dictates their performance, but requires sufficient water management. Here, the authors report a simple method to produce well-dispersed transition metal carbide nanoparticles as additives to enhance the performance of Nafion membranes in fuel cells.

Indian Council of Medical Research Consensus Document for the Management of Non-Hodgkin's Lymphoma (High Grade).

This consensus document is based on the guidelines related to the management of Non Hodgkin's Lymphoma (High grade) in the Indian population as proposed by the core expert committee. Accurate diagnosis in hematolymphoid neoplasm requires a combination of detailed history,clinical examination, and various investigations including routine laboratory tests, good quality histology section (of tumor and also bone marrow aspirate/biopsy), immunostaining, cytogenetic and molecular studies and radiology investigations. The staging system used for adult high grade lymphomas is based on the Ann Arbor system and includes various parameters like clinical, haematology, biochemistry, serology and radiology. Response should be evaluated with radiological evaluation after 3-4 cycles and at the end of treatment based on criteria including and excluding PET. Treatment of high grade lymphomas is based on histologic subtype, extent of disease, and age of the patient. Autologous stem cell transplantation after high dose chemotherapy is effective in the treatment of relapsed NHL. Newer RT techniques like 3 dimensional conformal radiation therapy (3D-CRT) and intensity modulated radiation therapy (IMRT) can significantly reduce radiation doses to surrounding normal tissues in lymphoma patients. Patients should be followed up every 3 to 4 months for the first 2 years, followed by 6 monthly for the next 3 years and then annually.

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.

Efficacy, Safety and Immunogenecitystudy of Intravenous Infusion of Rituximab (Hetero) and Reference Medicinal Product (Rituximab, Roche) in Indian Patients of Follicular Lymphoma Preliminary report (HERILY).

OBJECTIVE: To compare the antitumor efficacy, safety, and pharmacodynamics (PD) characteristics of Hetero-Rituximab (test) with Reference Medicinal Product (Rituximab, Roche) in Non-Hodgkin's Lymphoma (NHL). PATIENTS AND METHODS: Total 40 Follicular Lymphoma (FL) patients were randomized to receive intravenous infusion of either test or reference product. Efficacy (best overall response [BOR] rate [primary end point]), safety, PD (CD19), and immunological assessments (secondary end points) were done at the end of cycle 3 and cycle 6. RESULTS: Out of 40 patients randomized, 17 were in test arm while 23 were in reference arm. At the end of 6 cycles, BOR (complete response [CR] and partial response [PR]) rate was 64.71% (n=11) in Hetero Rituximab compared to the 43.48% (n=10) in reference arm. The difference between test and reference proportions of best overall response rate at cycle 6, lies within the pre-specified limit for noninferiority. Anti-Rituximab antibodies were found to be negative at cycle 3 and cycle 6 for all FL patients. The FL patients who were treated with Hetero Rituximab, showed significant depletion in CD19+ cell which was comparable with Reference drug. Safety and Immunogenic potential of the test drug was comparable to the reference drug in the patients of FL. CONCLUSION: Best overall response rate at Cycle 3, Cycle 6 and end of the study lies within the pre-specified limit for non-inferiority which concludes that test product is therapeutically non-inferior to reference medicinal product.

Clinicopathological Profile of Breast Cancer Patients at a Tertiary Care Hospital in Marathwada Region of Westen India.

BACKGROUND: Breast cancer is the most prevalent malignancy among women with wide differences in clinical profile from region to region. The present study aimed to describe the profile of breast cancer patients attending a tertiary care hospital in Marathwada region of Western India. MATERIALS AND METHODS: In this descriptive retrospective study, we reviewed records of pathologically diagnosed patients of breast cancer managed at our center from years 2009 to 2015. Data with respect to demographic status, detailed past, medical, familial and personal history, findings of clinical examination and histological features were obtained. Patients were staged according to the Tumor Node Metastasis (TNM) system. RESULTS: Among 260 cases, mean age of presentation was 52.6, with average age of menarche of 11.3 and menopause of 52.6 years. The majority of patients were from urban regions and were postmenopausal (64.3%). Main clinical features presentation were breast lumps. Most patients were in stage II and had infiltrating duct carcinomas. CONCLUSIONS: Most common risk factors for breast cancer observed are increasing age, low parity and obesity. Breast cancer was more prevalent among postmenopausal women presenting in stage II with infiltating duct carcinoma in our region of India.

C-Reactive Protein and Breast Cancer: New Insights from Old Molecule.

Recently an association between breast cancer and inflammation has emerged as the seventh hallmark of cancer. Chronic inflammation is a key contributor in the development and progression of carcinogenesis. Inflammatory pathways play an important role in the causation of breast cancer. C-reactive protein (CRP) an acute-phase reactant inflammatory protein is synthesized in hepatocytes in response to cytokines that are released from leucocytes within the tumor microenvironment. Several epidemiological studies appraised an association of CRP with breast cancer risk with inconsistent findings. Elevated levels at the time of diagnosis of breast cancer indicate aggressiveness of the tumor. CRP is also a well-established independent prognostic marker. Breast cancer survivors with the state of chronic inflammation are at risk of recurrence and metabolic disturbances. CRP lowering agents along with chemotherapeutic drugs will improve the survival of breast cancer patients. Also, it is a risk predictor for subsequent cardiotoxicity in patients receiving chemotherapy. The present review is aimed at elucidating the role of C-reactive protein, as an inflammatory risk marker and prognostic predictor of breast cancer. It also focuses on conflicting views on the role of CRP in breast cancer and its impact on therapeutic interventions.

Kodameae ohmeri - An Emerging Yeast: Two Cases and Literature Review.

Kodameae ohmeri is an emerging pathogen in various types of infections. Most infections are seen in patients with compromised immunity like cancer patients. Few cases of neonatal infections due to K. ohmeri have been reported earlier in premature neonates with fatal outcomes. We report two cases of fungemia; the first case was a patient with hematological malignancy, who complained of fever spikes and grew K. ohmeri in blood despite prophylactic voriconazole therapy. The second case was in a mature neonate, who developed respiratory distress and features of sepsis two days after birth, multiple blood cultures were positive for K. ohmeri. Both the patients responded well to Amphotericin B. Repeat blood cultures were sterile and patients were discharged. K. ohmeri is an unusual and emerging fungal pathogen of late an increasing number of cases of fungemia, funguria, endocarditis, peritonitis and wound infections due to the same are being reported. Some occur in immunocompromised patients and some inapparently immunocompetent patients, neonates with an inclination for preterm babies. We report two case of fungemia, one with lymphoma and the second in a neonate.

A phase II, single-arm, open-label, multicenter study to evaluate the efficacy and safety of P276-00, a cyclin-dependent kinase inhibitor, in patients with relapsed or refractory mantle cell lymphoma.

INTRODUCTION: Overexpression of cyclin D1 is a hallmark feature of mantle cell lymphoma (MCL). Many of the oncogenic effects of cyclin D1 are mediated through cyclin-dependent kinases (CDKs). P276-00 is a potent small molecule inhibitor of CDK4-D1, CDK1-B, and CDK9-T, with promising activity in preclinical models. In phase I studies of P276-00 in patients with refractory solid neoplasms, it was well-tolerated with a mild trend toward single-agent efficacy. PATIENTS AND METHODS: A phase II study of P276-00 was conducted in patients with relapsed or refractory MCL at the recommended dose of 185 mg/m(2)/day from days 1 to 5 of a 21-day cycle. Thirteen patients were enrolled in the present study. RESULTS: Of the 13 patients, 11 experienced disease progression, 1 patient was withdrawn because of an adverse event (AE), and 1 patient died. Also, 11 patients (84.6%) experienced a treatment-emergent AE deemed related to P276-00. Of the 13 patients, 9 (69.2%) received ≥ 2 cycles of treatment, which was the predefined threshold to be evaluable for efficacy. Treatment was discontinued early in 2 patients because of AEs (1 of which was attributed to P276-00 administration) and in 2 patients because of disease progression. Finally, 2 patients experienced stable disease for an estimated median duration of 60.5 days (range, 58-63 days). The estimated median time to progression for the predefined efficacy population was 43 days (range, 38-58 days). CONCLUSION: Given the results observed in the present study, if evaluation of CDK inhibition in MCL continues, it should be considered earlier in the disease course or as a part of combination strategies for relapsed or refractory disease.

Saree cancer in Indian woman treated successfully with multimodality management.

Saree is a common, traditional garment of Indian women, wrapped around the waist is tightened by a thick cord and with one end draped over the shoulder. Tight knot in the same place, sweat, soiling and continuous use can cause pigmentation, scaling of the waist and even transform to malignancy. We present here a case of saree cancer successfully managed with multimodality therapy. A 50-year-old woman was referred to our hospital (India) for itching and non-healing ulcerative lesion on waistline. She was wearing saree continuously for 34 years with knot at the same place. Magnetic resonance images suggested ulcerative growth with lymph node metastasis. She then underwent wide local excision; histopathological examination confirmed it was a squamous cell carcinoma. She therefore received concomitant chemotherapy and radiotherapy. She is now (2 years after the completion of treatment) in remission state. Awareness of saree cancer among Indian is important to avoid malignant lesions at waistline. Multimodality management with surgery, chemotherapy and radiotherapy is ideal mean for good outcome.

An elderly woman with triple primary metachronous malignancy: A case report and review of literature.

INTRODUCTION: Prevalence of multiple primary malignancies is slowly increasing due to prolonged survival of cancer patients with advances in diagnostic and therapeutic modalities. The reasons may be environmental modifications, genetic predisposition or therapy induced. We describe a case of a 64-year-old woman with three different metachronous primary malignancies managed at our center since 4 years. PRESENTATION OF CASE: First primary diagnosed in our patient was adenocarcinoma of small intestine which is a rare gastrointestinal malignancy. For this she underwent surgical resection followed by chemotherapy. After 21 months she developed infiltrating duct carcinoma of breast which was managed with modified radical mastectomy and chemotherapy. Again after latent period of 10 months patient had papillary adenocarcinoma of ovary for which she was administered chemotherapy. During follow up tumor was found to be chemoresistant and again she underwent cytoreductive surgery followed by chemotherapy. DISCUSSION: In present case patient did not have significant risk factors for development of carcinoma of small intestine, breast and ovary. Our patient underwent surgical excision three times and received total 16 chemotherapy cycles of different regimens during management of all three primary malignancies. Development of second and higher order primary malignancy after successful management of previous one should be always kept in mind. CONCLUSION: Awareness, suspicion of multiple primary malignancy and aggressive diagnostic work up plays crucial role in their detection at earlier stage for better outcome. In addition choice of appropriate chemotherapeutic agents and their regimens remains the cornerstone while managing the patients with multiple primary malignancies.