Advanced Search
  • Users Online: 33
  • Print this page
  • Email this page


 
 
Table of Contents
CASE REPORT
Year : 2020  |  Volume : 1  |  Issue : 1  |  Page : 3-8

Impact of precision medicine in head and neck cancers: An illustrative case report

BM Joshna1, R Apoorva1, S Anand1, T Shalini1, K Akshay1, R Vishal1, N Ravi1, P Prasanth2
1 Department of Head and Neck Surgical Oncology, HCG Cancer Centre, Bengaluru, India
2 Department of Oncoplastics and Reconstructive Surgery, HCG Cancer Centre, Bengaluru, India

Date of Submission10-Mar-2020
Date of Decision17-Jun-2020
Date of Acceptance01-Jul-2020
Date of Web Publication22-Oct-2020

Correspondence Address:
Dr. K Akshay
Department of Head and Neck Surgical Oncology, HCG Cancer Centre, Bengaluru
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/WKMP-0197.298270

Rights and Permissions
How to cite this article:
Joshna B M, Apoorva R, Anand S, Shalini T, Akshay K, Vishal R, Ravi N, Prasanth P. Impact of precision medicine in head and neck cancers: An illustrative case report. J Precis Oncol 2020;1:3-8

How to cite this URL:
Joshna B M, Apoorva R, Anand S, Shalini T, Akshay K, Vishal R, Ravi N, Prasanth P. Impact of precision medicine in head and neck cancers: An illustrative case report. J Precis Oncol [serial online] 2020 [cited 2021 Oct 15];1:3-8. Available from: https://www.jprecisiononcology.com/text.asp?2020/1/1/3/298270




  Introduction Top


Precision medicine is an approach that takes into account genetic, biologic, metabolomic, proteomic and transcriptomic variability of every individual and creates specific treatment strategies. In this illustrative case of oropharyngeal cancer, critical variations in his genetic and immune makeup enabled us tailor the therapy to ensure optimal outcomes.


  Case Top


In April 2018, a 50-year-old Caucasian gentleman, a non-smoker and non-alcoholic, presented with difficulty in swallowing with restricted mouth opening for one month. He had a malignant ulcero-proliferative growth in the right tonsillar region along with a metastatic level II node [Figure 1].
Figure 1: Patient profile with an enlarged level II node

Click here to view


The whole body PET-CT showed a metabolically active lesion limited to the right tonsillar fossa and extending to the retromolar trigone area (SUVmax of 13.1) and a metabolically active right Level II-III lymph node (SUVmax of 1.7) [Figure 2]. The p16 immunohistochemistry was reported negative and the disease was staged cT4aN3bM0.1*,2*
Figure 2: PET CT images showing primary tumour and node after NACT

Click here to view






The Multi-Disciplinary Clinic (MDC) considered the HPV negative status, possible aggressive behavior in the absence of risk factors and suggested using two cycles of Neoadjuvant chemotherapy (Paclitaxel + Cisplatin + Cisplatin + Cetuximab).3*,4*,5*





a 2 Drug regimen (PF) in preventing the transformation into action potentials NACT.

After completion of NACT an interval PET CT was done. There was evidence of progressive disease {Mandibular erosion} (PERCIST Criteria).6*



In the MDC a decision on Radical Surgery with reconstruction followed by adjuvant therapy was suggested with curative-intent. Considering his professional commitments, the patient requested a non-obvious scar. A team consisting of Head and Neck Surgical Oncologist, Robotic Surgeons and Reconstructive Surgeon performed a minimally invasive retroauricular approach with Right Segmental Mandibulectomy with (TORS) transoral robotic surgery a robotic Right neck dissection and the defect was reconstructed with a Free Fibular Flap Osteo-cutaneous flap [Figure 2]. The primary tumour was reported as poorly differentiated squamous cell carcinoma (PDSCC) with a depth of invasion of 1.5 cm, with the erosion of underlying mandible without lymphovascular emboli or perineural invasion and the neck dissection specimen showing a metastatic neck node measuring 2.2 cm x 1.8 cm with minor ENE. The pathological staging was ypT4N2a.2*



A genetic analysis of the tumour showed PIK3 mutation5*.. He made an uneventful recovery went on to receive adjuvant radiotherapy therapy using IMRT technique to a dose of 66Gy/33 fractions with eight cycles of a weekly dose of Cetuximab. A post-therapy PET -CT scan three months later was reassuring with no residual disease [Figure 3].
Figure 3: PET CT image following CCRT

Click here to view




His Neutrophil Lymphocyte ratio (NLR) indicated a possible decline in immunity and hence he recieved cellular immunotherapy with activated T cells. The NLR improved from 4.78 to 2.51, suggestive of favourable response.7*



Five months later, he presented with pain and purulent discharge from the right cheek. He underwent a PET-CT, and it revealed a 6.6 x 2.9 x 4.8 cm metabolically active irregular lesion involving the right infratemporal fossa and extending to the parapharyngeal space, retropharyngeal space with a SUVmax of 19.6. A guided biopsy from the lesion was positive for squamous cell carcinoma.

The MDC suggested An option of salvage surgery with guarded prognosis followed by immunotherapy.8* was suggested to the patient. Considering the proximity of the lesion to critical vascular structures and cranial nerves, preoperative embolization of tumour feeders was done by our interventional radiology team. wide excision of the tumour with parotidectomy, segmental mandibulectomy, Partial pharyngectomy, ITF clearance with free fibula flap reconstruction. It was an R1 resection as the final histopathology showed PDSCC with the tissue around the Internal carotid artery and adjacent base of the skull, nasopharynx positive for malignancy. Ki 67 levels were low at 8 %, and PD L1 level was 50%. A tumour infiltrating lymphocytes (TILS) panel was done which showed CD3 levels of 68% and CD3 + CD 8 level of 11%. A cytokine panel was also done.



Based on these finding, he was advised immunotherapy with a PD-1 inhibitor, Nivolumab along with Methotrexate. He received 18 doses of Nivolumab.9* and 12 doses of Methotrexate at standard doses. A follow up PET-CT showed no evidence of loco-regional recurrence or distant failure. The patient has been on regular follow up and disease-free.




  Discussion Top


Accurate and reliable stratification of HNSCC for prediction of outcomes has been a challenge. The heterogeneity and lack of clonality of tumours is an essential factor that underscores the variable biologic behaviour. Identifying these changes and altering therapy is the fundament idea that drives the concept of precision medicine. Knowledge of genetic, epigenetic, proteomic, metabolomic, transcriptomics and other information could help prognosticate a patient better, foresee the disease course and select prompt and timely interventions.

In our case, the use of NACT at diagnosis was in accordance with standard guidelines (3). Use of NACT serves as a good predictor of radio response. The dissatisfying response on NACT, helped us consider surgery over the standard concurrent chemo-radiotherapy for oropharyngeal tumours (4). Presence of PIK3 mutation on genetic analysis and its associated resistance to Cisplatin in other cancers (5) helped us chose EGFR inhibitor Cetuximab over Cisplatin.

The immune system of cancer patients can be compromised through multiple means, including immune suppression by the tumour and by prior therapies. Therefore, a comprehensive means of assessing patient immunocompetence would seem helpful for determining whether patients are ready to benefit from immunotherapy, and perhaps even which immunotherapy might be most appropriate for them (6). Neutrophil lymphocyte ratio has emerged as a valuable yet straightforward biomarker to monitor immune response in cancers (7,8). In our case, NLR monitoring helped us gauge the immune response and include cellular immunotherapy to improve immune surveillance.

The role of image-guided surveillance has helped physicians detect recurrence early and initiate remedial strategies soon. The PET-CT has also shown sufficient credibility to reduce unwarranted surgical interventions (9). In our case, serial monitoring with PET-CT helped us identify the recurrence early and optimise treatment at various stages.

It was surprising to know that when a genetic analysis performed, when the patient recurred was different from what it was after the first curative-intent surgery. This highlights the genetic transitions that occur through the course of the disease. And the variation in our case is a sizeable example to consider the role of serial genetic testing at various stages of the disease.

When he recurred, our close surveillance aided us to salvage the recurrence. Though cytoreductive surgery has a finite role in HNSCC, we considered the option of an R1 resection followed by immune checkpoint inhibitors. Though the evidence for this practice is not compelling, it has been attempted earlier with reasonable success (10). In our case, the PDL1 levels and TILS panel substantiated the use of Nivolumab an immune checkpoint inhibitor.

Head and neck cancer treatment is intrinsically complex. Given the complexities of treatment, the rationale for the use of a Multi-disciplinary tumour board (MDT) to define individual optimal treatment strategies on a per-patient basis is apparent. MDT has played a critical role in improving outcomes. A multidisciplinary tumour board an MDT should include not the head and neck oncologist, radiation oncologist and medical oncologist, and radiologist but also a dietician, dentist, pain physician, and swallowing physician [11]. Our case is an excellent example of how a MDT can suggest precision strategies and its role cannot be overemphasised.

The case in the discussion is a valuable compendium of how targeted precision treatment can push horizons and achieve new benchmarks. The emerging paradigm of precision cancer medicine, in which the use novel treatment blueprints directly impacts patient treatment and clinical decision-making, has already had a substantial and direct impact on several aspects of cancer treatment. This is the future and its time to embrace it.

Precision Pearls

  1. Patients with HPV positive tumours have an improved overall and disease free survival. The beneficial effects of HPV infection is site specific. Patients with HPV-positive oropharyngeal tumours have a significantly lower risk of recurrence (1).Tobacco use increases the risk of death by 1% with each additional pack year irrespective of HPV positivity. Smoking negates any survival benefit gained in HPV positive tumours (2). In our case the patient did not have any risk habits like smoking, alcohol etc. Tumours in such patients are often aggressive as the mutational landscapes in them are different.
  2. HPV oropharyngeal cancer has emerged as a disease with good prognosis. Many prognostic staging systems incorporate HPV status as a stratification factor. The International Collaboration on Oropharyngeal cancer Network for Staging (ICON-S) paved way to develop a separate staging in the recent edition of AJCC staging(3). The demographics, comorbidities, risk factors, and carcinogenesis are different in HPV+ cancer (4). The best method for HPV detection remains controversial. Traditional PCR may be too sensitive and Quantitative PCR methods though allow precise measurement it cannot confirm tumour origin of the virus. These methods are challenging and not cost effective in clinical setting. In situ hybridization (ISH) for high- risk HPV is more practical in a clinical setting and is quite specific, allowing for direct visualization of virus in tumour cells. However, it is not completely sensitive. p16 is a surrogate marker for HPV positivity. p16 is a tumour suppressor protein and inhibits cyclin-dependent kinase 4A. A functional inactivation of the retinoblastoma protein (Rb) by HPV E7 protein leads to p16 overexpression (5)The recent 8th edition of AJCC has also incorporated extracapsular extension (ENE) into the staging system. The presence of ENE in HPV negative oropharyngeal malignancies clinically upstages the N staging to N3b. Similarly, in the pathological staging, presence of a single ipsilateral node less than 3cm with ENE is classified as 2a, else presence of pathological ENE in other instances is staged N3b (6,67).
  3. Despite decades of research The additive role of induction chemotherapy (ICT) in Head and neck cancers remains controversial. Newer evidence in the field have reignited interest in treating patients with locally advanced squamous cell carcinoma of the head and neck (LA SCCHN). Currently, for patients with operable disease the available options are concurrent chemoradiotherapy or sequential treatment with induction chemotherapy→ radiotherapy. Cisplatin, carboplatin and 5-FU (French regimen), or cetuximab (for cisplatin- unsuitable patients) have been tried as chemotherapeutic agent for concurrent chemo radiotherapy. The use of ICT followed by a radiotherapy or chemoradiotherapy as a routine treatment in patients with inoperable disease needs further exploration (8).
  4. In advanced oropharyngeal tumours, studies have reported better survival with induction chemotherapy using cisplatin and fluorouracil. This finding is consistent with the results of the landmark MACH-NC study (9).Three drug regimen (platinum based + taxanes + 5 FU) should be the preferred choice unless contraindicated. Practice of giving 2 drugs chemotherapy (taxane and platinum) should only considered only if patients are not fit for taxanes, platinum and 5-FU (TPF) regimen. If 2 drugs regimens have to be used for logistic issues, docetaxel seems to be a better agent than paclitaxel (10).
  5. Cetuximab remains one of the targeted therapy approved for the treatment of head and neck squamous cell carcinoma (HNSCC). The EGFR pathway plays a critical role in the tumourigenesis and disease progression. It has a plausible role in the resistance to radiotherapy (RT). While several anti-EGFR agents have been tested in HNSCC, cetuximab, an IgG1 monoclonal antibody remains the only drug with proven efficacy for the treatment of both locoregionally-advanced (LA) and recurrent/metastatic (R/M) disease. The addition of cetuximab to radiotherapy is an approved treatment option in LA-HNSCC patients who are considered unfit for standard of care chemoradiotherapy (CRT) with cisplatin (11). Available data also supports its use in patients refractory to platinum drugs. Promising results have been demonstrated when cetuximab is given in combination with cisplatin in chemotherapy naïve patients (12).
  6. (PERCIST) PET response criteria in solid tumors Criteria evolved from the (RECIST) Response evaluation criteria in solid tumors criteria and takes into account the metabolic activity in the target organ/ site. Several other grading systems are available to evaluate and categorize response to treatment. Following these guidelines helps standardize the responses for easy interpretation (13). Stable or progressive disease after NACT may warrant a change in treatment strategy. Unsatisfactory response to NACT could be a indicator of radio-resistance.
  7. A complex set of interactions exist between the tumour micro-environment and the immune system. It is acknowledged that T lymphocytes play an important role in the immune surveillance of cancer cells (14). It was previously shown that the presence of CD8+ cytotoxic T lymphocytes nests confers better survival outcomes. A relative lymphopoenic state in head and neck cancer suggests poor outcomes and prognosis. Cancer-associated inflammation leads to poor survival. Studies have shown a possible relationship between NLR and event free survival (15). The inexpensive and readily available nature of NLR allows it to be conveniently monitored overtime. Large shifts in NLR are more challenging to interpret and may reflect increased tumour burden. NLR is driven primarily by the decline in neutrophils and the common causes of decline in neutrophils can include decreased bone marrow activity, infection, and malnutrition, all of which have an impact on OS (16).
  8. About 50% of advanced stage patients relapse after nonsurgical treatment. The role of salvage surgery (SS) remains critical in such cases. Surgery is generally regarded as the best treatment option in patients with recurrent resectable SCCHN. Surgeons are increasingly confronting patients with failed non-surgical primary treatment. Wide local excision to achieve clear margins must be balanced with the morbidity of the procedure. Accurate patient selection is the game changer. It is essential to establish objective criteria to choose the best candidates for SS (17). Patients should be carefully selected and counselled. Patient motivation, age, type of previous treatment, resectability, and exclusion of distant recurrence must be taken into consideration before a salvage procedure. Following SS, identifying patients with postoperative prognostic factors predicting high risk of recurrence is essential as these patients could benefit from adjuvant treatment (18).
  9. Immunotherapy is based on functional restoration of the host immune system, helping to counteract various tumour evasion strategies. These approaches encompass tumour-specific antibodies, cancer vaccines, cytokines, adoptive T-cell transfer, and immune-modulating agents. In 2015, US Food and Drug Administration (FDA)- approved targeted therapy for SCCHN. Later, the results from two prospective trials employing check point inhibitors nivolumab and pembrolizumab heralded a new era of anticancer treatment.


Exploratory biomarker analyses indicated that patients treated with Nivolumab had longer OS than standard therapy. And this benefit was regardless of tumour PD-1 ligand (PD-L1) expression or p16 status. In the non- randomised, multicohort phase Ib study KEYNOTE-012, treatment with pembrolizumab achieved comparable results. Most of the responding patients had a long-lasting response and this was reassuring.

Patients with high tumour expression of PD-L1 tend to have a better outcome. However, the durable benefit seen in others without high PD-L1 levels challenges its role as an independent.

The prognostic value of NLR at the initiation of Immune check-point inhibitors (ICI) could help monitor outcomes. The relationship between NLR and survival is not linear. Only a moderate decrease in NLR is associated with long OS. An excessive shift in NLR was associated with reduced OS (19).


  References Top


  1. Ragin, C.C.R. and Taioli, E. (2007), Survival of squamous cell carcinoma of the head and neck in relation to human papillomavirus infection: Review and meta-analysis. Int. J. Cancer, 121: 1813-1820. doi:10.1002/ijc.22851
  2. Ang KK, Harris J, Wheeler R, Weber R, Rosenthal DI, Nguyen-Tân PF, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med. 2010;363:24–35
  3. O'Sullivan B, Huang SH, Su J, et al. Development and validation of a staging system for HPV-related oropharyngeal cancer by the International Collaboration on Oropharyngeal cancer Network for Staging (ICON- S): a multicentre cohort study. Lancet Oncol. 2016;17(4):440-451. doi:10.1016/S1470-2045(15)00560-4
  4. Porceddu SV. A TNM classification for HPV+ oropharyngeal cancer. Lancet Oncol. 2016;17(4):403-404. doi:10.1016/S1470-2045(15)00611-7
  5. Lewis JS Jr, Thorstad WL, Chernock RD, et al. p16 positive oropharyngeal squamous cell carcinoma:an entity with a favorable prognosis regardless of tumour HPV status. Am J Surg Pathol. 2010;34(8):1088-1096. doi:10.1097/PAS.0b013e3181e84652
  6. Huang SH, O'Sullivan B. Overview of the 8th Edition TNM Classification for Head and Neck Cancer. Curr Treat Options Oncol. 2017;18(7):40. doi:10.1007/s11864-017-0484-y
  7. Hay A, Nixon IJ. Recent advances in the understanding and management of oropharyngeal cancer. F1000Res. 2018;7:F1000 Faculty Rev-1362. Published 2018 Aug 30. doi:10.12688/f1000research.14416.1
  8. Haddad RI, Posner M, Hitt R, et al. Induction chemotherapy in locally advanced squamous cell carcinoma of the head and neck: role, controversy, and future directions. Ann Oncol. 2018;29(5):1130-1140. doi:10.1093/annonc/mdy102
  9. Domenge, C., Hill, C., Lefebvre, J. et al. Randomized trial of neoadjuvant chemotherapy in oropharyngeal carcinoma. Br J Cancer 83, 1594–1598 (2000). https://doi.org/10.1054/bjoc.2000.1512
  10. Noronha V, Patil V, Joshi A, Muddu V, Bhattacharjee A, Juvekar S, Arya S, Chaturvedi P, Chaukar D, Pai P S, Dcruz A K, Prabhash K. Is taxane/platinum/5 fluorouracil superior to taxane/platinum alone and does docetaxel trump paclitaxel in induction therapy for locally advanced oral cavity cancers?. Indian J Cancer [serial online] 2015 [cited 2020 May 19];52:70-3. Available from: http://www.indianjcancer.com/text.asp?2015/52/1/70/175604
  11. Taberna M., Oliva M., Mesía R. Cetuximab-Containing Combinations in Locally Advanced and Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma. Frontiers in Oncology(2019). Retrieved from https://www.frontiersin.org/article/10.3389/fonc.2019.00383
  12. Merlano M, Occelli M. Review of cetuximab in the treatment of squamous cell carcinoma of the head and neck. Ther Clin Risk Manag. 2007;3(5):871-876.
  13. Wahl RL, Jacene H, Kasamon Y, Lodge MA. From RECIST to PERCIST: Evolving Considerations for PET response criteria in solid tumours. J Nucl Med. 2009;50 Suppl 1(Suppl 1):122S-50S. doi:10.2967/jnumed.108.057307
  14. Grivennikov SI, Greten FR, Karin M (2010) Immunity, inflam- mation, and cancer. Cell 140(6):883–899
  15. Tham T, Wotman M, Chung C, et al. Systemic immune response in squamous cell carcinoma of the head and neck: a comparative concordance index analysis. Eur Arch Otorhinolaryngol. 2019;276(10):2913-2922. doi:10.1007/s00405-019-05554-x
  16. Li M, Spakowicz D, Burkart J, et al. Change in neutrophil to lymphocyte ratio during immunotherapy treatment is a non-linear predictor of patient outcomes in advanced cancers. J Cancer Res Clin Oncol. 2019;145(10):2541- 2546. doi:10.1007/s00432-019-02982-4
  17. Hamoir M, Schmitz S, Suarez C, et al. The Current Role of Salvage Surgery in Recurrent Head and Neck Squamous Cell Carcinoma. Cancers (Basel). 2018;10(8):267. Published 2018 Aug 10. doi:10.3390/cancers10080267
  18. Matoscevic K, Graf N, Pezier TF, Huber GF. Success of salvage treatment: a critical appraisal of salvage rates for different subsites of HNSCC. Otolaryngol Head Neck Surg. 2014;151(3):454-461. doi:10.1177/0194599814535183
  19. Szturz P, Vermorken JB. Immunotherapy in head and neck cancer: aiming at EXTREME precision. BMC Med. 2017;15(1):110. Published 2017 Jun 2. doi:10.1186/s12916-017-0879-4




 
  References Top

1.
Wahl RL, Jacene H, Kasamon Y, Lodge MA. From RECIST to PERCIST: Evolving Considerations for PET response criteria in solid tumours. J Nucl Med. 2009;50 Suppl 1(Suppl 1):122S-50S. doi:10.2967/jnumed.108.057307  Back to cited text no. 1
    
2.
Rao V, Subash A, Sinha P, Prasad R, Majumdar K, Puranik P. Modified facelift approach for posterior segmental mandibulectomy: a blend of oncology and cosmesis. Eur Arch Otorhinolaryngol. 2020;277(4):1205-1210. doi:10.1007/s00405-020-05793-3  Back to cited text no. 2
    
3.
NCCN Guidelines  Back to cited text no. 3
    
4.
Amini A, Karam SD. Concurrent chemotherapy in oropharyngeal cancer: Cisplatin wins. Oncotarget. 2019;10(6):624-625. Published 2019 Jan 18. doi:10.18632/oncotarget.26594  Back to cited text no. 4
    
5.
Arjumand W, Merry CD, Wang C, et al. Phosphatidyl inositol-3 kinase (PIK3CA) E545K mutation confers cisplatin resistance and a migratory phenotype in cervical cancer cells. Oncotarget. 2016;7(50):82424-82439. doi:10.18632/oncotarget.10955  Back to cited text no. 5
    
6.
Chang S, Kohrt H, Maecker HT. Monitoring the immune competence of cancer patients to predict outcome. Cancer Immunol Immunother. 2014;63(7):713-719. doi:10.1007/s00262-014-1521-3  Back to cited text no. 6
    
7.
Chen MF, Tsai MS, Chen WC, Chen PT. Predictive Value of the Pretreatment Neutrophil-to-Lymphocyte Ratio in Head and Neck Squamous Cell Carcinoma. J Clin Med. 2018;7(10):294. Published 2018 Sep 20. doi:10.3390/jcm7100294  Back to cited text no. 7
    
8.
Xu, C., Yuan, J., Du, W., Wu, J., Fang, Q., Zhang, X., & Li, H. (2020). Significance of the Neutrophil-to- Lymphocyte Ratio in p16-Negative Squamous Cell Carcinoma of Unknown Primary in Head and Neck. Frontiers in Oncology, 10, 39. https://doi.org/10.3389/fonc.2020.00039  Back to cited text no. 8
    
9.
Mehanna H, Wong WL, McConkey CC, et al. PET-CT Surveillance versus Neck Dissection in Advanced Head and Neck Cancer. N Engl J Med. 2016;374(15):1444-1454. doi:10.1056/NEJMoa1514493  Back to cited text no. 9
    
10.
Bryan RB, Gough MJ, Seung SK, et al. Cytoreductive surgery for head and neck squamous cell carcinoma in the new age of immunotherapy [published correction appears in Oral Oncol. 2017 Mar;66:e3]. Oral Oncol. 2016;61:166-176. doi:10.1016/j.oraloncology.2016.08.020  Back to cited text no. 10
    
11.
Lo Nigro C, Denaro N, Merlotti A, Merlano M. Head and neck cancer: improving outcomes with a multidisciplinary approach. Cancer Manag Res. 2017;9:363-371. Published 2017 Aug 18. doi:10.2147/CMAR.S115761  Back to cited text no. 11
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]



 
Top
 
  Search
 
    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
    Access Statistics
    Email Alert *
    Add to My List *
* Registration required (free)  

 
  In this article
Introduction
Case
Discussion
References
References
Article Figures

 Article Access Statistics
    Viewed1491    
    Printed102    
    Emailed0    
    PDF Downloaded147    
    Comments [Add]    

Recommend this journal

Online since 16th July 2019