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Raman Theranostic Solutions for Low Cost Settings

16 Jan | By Biophotonics.World
Raman Theranostic Solutions for Low Cost Settings
By: C. Murali Krishna

Cancer is a leading cause of death accounting for around 8 million cases worldwide. It is predicted that by the end of the year 2020, over 10 million people would die globally each year because of cancer, with 70% deaths from the developing countries. The high mortality rate, mainly due to late detection and recurrences, is ascribed to limitations of conventional diagnostic methodologies. Screening and early detection are thus important tools for the overall management of cancer and to achieve decreased morbidity and higher disease-free survival rates. Currently practised diagnostic approaches involve invasive procedures and are prone to subjective errors; thus, it is crucial to develop sensitive, preferably non-invasive diagnostic methods. 

Theranostics encompass aspects of diagnosis and therapy. Optical spectroscopy methods such as laser-induced-fluorescence, FTIR, Raman and diffused reflectance are some of the most widely been pursued potential alternatives/adjuncts. Raman spectroscopy, named after discover Sir C.V. Raman, amongst them, is better suited due to attributes such as sensitivity to biochemical composition, objective, rapid, no external labeling/sample preparation, and most importantly in vivo/in situ on-line applications. In this context, this article is an bird-eye-view on fiber-optic based in vivo Raman and Raman microprobe studies pertaining to theranostic applications in oral and cervical cancers – major health burden in developing world. 

Oral cancers, a subtype of head and neck cancers, are cancers of the oral cavity. Lips, buccal mucosa, the upper and lower alveolar ridges with their attached gingiva, the retromolar trigone, the hard palate, the floor of the mouth, and the anterior two-thirds of the tongue majorly constitute the oral cavity. Oral cancers can arise from any of these sub-sites. Oral cancers form a significant health burden in developing countries where they account for over 30% of all cancers with 80, 000 new cases reported each year. Tobacco (both smoking and smokeless) and alcohol are major etiological factors. We have carried out extensive clinical trials of non-invasive (in vivo – on subjects) and minimally invasive (serum and exfoliated cells) Raman spectroscopy applications in oral cancer. Our in vivo Raman spectroscopy studies not only demonstrated stratification of healthy, habitué, premalignant and malignant conditions, but also delineation of malignancy associated changes (MAC)/cancer field effects (CFE), which are the earliest events in oral carcinogenesis. Further studies have also demonstrated feasibility of identifying subjects who are prone to recurrence/second tumors. Despite in vivo Raman being an non-invasive tool, requirement of on-site instrumentation and more stringent experimental conditions (regulated ambience and dark room) makes it less flexible and practical, especially in out-reach centers and screening camps. Therefore we have also successfully explored and demonstrated efficacy of serum Raman (Serum based Raman spectroscopy) and Raman exfoliative cytology (exfoliated cell specimen based Raman spectroscopy) in oral cancers. We could stratify healthy, habitué, premalignant and brain tumors (used as disease control) and malignant subjects using serum Raman. In addition, this approach is also shown to be useful in delineating recurrent and non-recurrent oral cancer subjects, after a curative surgery. Our Raman exfoliative cytology studies could also stratify healthy, habitués, premalignant and malignant subjects. A preliminary study suggests a correlation between Raman exfoliative cytology and recurrence.

Cervical cancer is the third most frequent cancer among women worldwide and commonest female cancer in developing countries, which contribute more than 80% to global cervical cancer burden. Papanicolau test (Pap test), exfoliated cervical-vaginal cytology, is the work horse of cervical cancer screening. Other conventional screening technologies are HPV testing, liquid based cytology, automated cervical screening tool and visual inspection of cervix after applying Lugol’s iodine (VILI) or acetic acid (VIA). In a typical clinical practice, an abnormal Pap smear is followed by colposcopic guided biopsies for confirmatory diagnosis. Therefore, conscious efforts are made for the development of minimally invasive and effective screening/diagnostic methodology that can probe the endogenous biomolecular properties of cells/tissue for early cancer detection. In this context,  Our in vivo Raman study demonstrated 98.5% classification efficiency in stratifying normal and control groups. Since composition of vagina and ecto-cervix are similar as they contain inner lining of squamous epithelial cells thus vagina can serve as good internal control. Hence this study also explored utility of vagina as an internal control by exploiting spectral misclassification between the control groups (spectra of normal cervix, vagina of normal subjects and vaginal sites of tumor subjects) and spectral classification between tumor and control groups. This approach could be helpful to circumvent inter-patient variability due to menopausal status, hormonal status; age, parity. This approach useful, especially, in screening camps where colposcopy may not be available. Sensitivity and specificity of two in vivo modalities, diffuse reflectance spectroscopy (DRS) and Raman spectroscopy (RS), were also evaluated. Though DRS revealed slightly lower diagnostic accuracies, owing to its lower cost and portability, could be more suited for cervical cancer screening in low resource settings. While, RS based devices are ideal for screening patients with centralized facilities. Proof of concept for Raman based screening of cervical exfoliated cells has also been demonstrated. We have also demonstrated feasibility of stratifying subjects on based response to radiotherapy using biopsy collected after 2 fractions of radiation treatment. 


Fiberoptic in vivo Raman spectroscope for  a) oral ;  b) cervical cancer applitions; c)  Raman microprobe for minimally invasive applications - serum Raman spectroscopy and Raman exfoliative cytology.

 Our Raman spectroscopy studies, also by many other groups across the globe, both non-invasive (on subjects) and minimally invasive (serum/exfoliated cells) clearly demonstrated utility of these technologies in cancer diagnosis and therapeutic monitoring. Despite advancements and large volume of studies, few further fine-tuning measures for more user friendly, transportability of data across different platforms, and further refinement of data acquisition (for minimally invasive methods) are to be implemented before routine clinical applications. 

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2.      Stoler M H, Schiffman M, 2001. Interobserver Reproducibility of Cervical Cytologic and Histologic Interpretations. JAMA, 285:1500-5.

3.      Kirita T, Omura K, 2015. Oral Cancer: Diagnosis and Therapy. Springer, Verlag.

4.      Singh S P, Deshmukh A, Chaturvedi P, Krishna C M, 2012.  In vivo Raman spectroscopic identification of premalignant lesions in oral buccal mucosa. J Biomed Opt, 17:105002.

5.      Singh S P, Sahu A, Deshmukh A, Chaturvedi P, Krishna C M, 2013. In vivo Raman spectroscopy of oral buccal mucosa: a study on malignancy associated changes (MAC)/cancer field effects (CFE). Analyst, 138(2013)4175-82.

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7.      Sahu A, Gera P, Pai V, Dubey A, Tyagi G, Waghmare M, Pagare S, Mahimkar M, Krishna C M, 2017. Raman exfoliative cytology for oral precancer diagnosis. J Biomed Opt, 22:115003.

8.      Malik A, Sahu A, Singh S P, Deshmukh A, Chaturvedi P, Nair D, Nair S, Murali Krishna C, 2017. In vivo Raman spectroscopy–assisted early identification of potential second primary/recurrences in oral cancers: An exploratory study. Head Neck, 39:2216-23.

9.      Sahu A, Nandakumar N, Sawant S, Krishna C M, 2015. Recurrence prediction in oral cancers: a serum Raman spectroscopy study. Analyst, 140:2294-301.

10.    Sahu A, Gera P, Malik A, Nair S, Chaturvedi P, Murali Krishna C, 2019. Raman exfoliative cytology for prognosis prediction in oral cancers: A proof of concept study. J Biophotonics, 201800334.

11.    Rubina S, Amita M, Bharat R, Krishna C M, 2013. Raman spectroscopic study on classification of cervical cell specimens. Vib Spectrosc, 68:115-21.

12.    Shaikh R S, Dora T K, Chopra S, Maheshwari A, Kedar D K, Bharat R, Krishna C M, 2014. In vivo Raman spectroscopy of human uterine cervix: exploring the utility of vagina as an internal control. J Biomed Opt, 19:087001

13.    Shaikh R, Prabitha V G, Dora T K, Chopra S, Maheshwari A, Deodhar K, Rekhi B, Sukumar N, Krishna C M, Subhash N, 2017. A comparative evaluation of diffuse reflectance and Raman spectroscopy in the detection of cervical cancer. J Biophotonics, 10:242-52. 

14.    Vidyasagar M S, Maheedhar K, Vadhiraja B M, Fernendes D J, Kartha V B, Krishna C M, 2008. Prediction of radiotherapy response in cervix cancer by Raman spectroscopy: A pilot study. Biopolymers, 89:530-7.

15.    Rubina S, Vidyasagar M S, Murali Krishna C, 2013. Raman spectroscopy in cervical cancers: An update.  J Innov Opt Health Sci, 6:1350014.


Author: C. Murali Krishna1,2 (1 Advanced Center for Treatment, Research & Education in Cancer, Kharghar, Navi Mumbai 410210 (India), 2 Homi Bhabha National Institute, Mumbai, (India) )

mchilakapati@actrec.gov.in

Area of application: Oncology

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