Ocular Oncology - ebook

AUTHORS

Dariusz Adamek, MD, DSc, Professor

Chair of Pathomophology, Department of Neuropathology, Faculty of Medicine, Jagiellonian University Medical College, Kraków, Poland

Department of Pathomorphology, University Hospital, Krakow, Poland

Jinfeng Cao

Department of Ophthalmology, LUMC, Leiden, The Netherlands

Department of Ophthalmology, The Second Hospital of Jilin University, Changchun, China

Sarah E. Coupland, MBBS, PhD, FRCPath, Professor

Royal Liverpool University Hospital, Liverpool, UK

George Holt Chair of Academic Pathology, University of Liverpool, Liverpool, UK

Bertil Damato, MD, PhD, FRCOphth

Nuffield Department of Clinical Neurosciences, Medical Sciences Division, University of Oxford, UK

Martyna Elas, PhD, DSc

Department of Biophysics, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland

Bita Esmaeli, MD, FACS

Orbital Oncology and Ophthalmic Plastic Surgery, Department of Plastic Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

Joshua Ford, MD

Orbital Oncology and Ophthalmic Plastic Surgery, Department of Plastic Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

Martine J. Jager, MD, Professor

Department of Ophthalmology, LUMC, Leiden, The Netherlands

Barbara Jakubowska

Department of Ophthalmology and Ocular Oncology, University Hospital, Krakow, Poland

Chair of Ophthalmology, Faculty of Medicine, Jagiellonian University Medical College, Krakow, Poland

Department of Ophthalmology and Ocular Oncology, University Hospital, Krakow, Poland

Jakub Khzouz, MBBS

Department of Pathology and Laboratory Medicine, King Hussein Cancer Center, Amman, Jordan

Joanna Kobylarz, MD

Department of Ophthalmology and Ocular Oncology, University Hospital, Krakow, Poland

Agnieszka Kubicka-Trząska, MD, DSc

Chair of Ophthalmology, Faculty of Medicine, Jagiellonian University Medical College, Krakow, Poland

Department of Ophthalmology and Ocular Oncology, University Hospital, Krakow, Poland

Jolanta Orłowska-Heitzman

Chair of Pathomophology, Faculty of Medicine, Jagiellonian University Medical College, Krakow, Poland

Bożena Romanowska-Dixon, MD, DSc, Professor

Chair of Ophthalmology, Faculty of Medicine, Jagiellonian University Medical College, Krakow, Poland

Department of Ophthalmology and Ocular Oncology, University Hospital, Krakow, Poland

Beata Sas-Korczyńska, MD, DSc, Professor

Institute of Medical Sciences, Medical College of Rzeszow University, Rzeszow, Poland

Department of Ophthalmology and Ocular Oncology, Jagiellonian University Collegium Medicum, Krakow, Poland

Carol L. Shields, MD, Professor

Ocular Oncology Service, Wills Eye Hospital, Thomas Jefferson University, Philadelphia, Pennsylvania, USA

Jacek Składzień, MD, DSc, Professor

Department of Otolaryngology, Faculty of Medicine, Jagiellonian University Medical College, Krakow, Poland

Department of Otolaryngology, University Hospital, Krakow, Poland

Christina Stathopoulos, MD

Pediatric Ocular Oncology Service, Jules-Gonin Eye Hospital, Lausanne, SwitzerlandPREFACE

Dear Readers and Colleagues

The book that you hold in your hands presents the most common problems in ophthalmological oncology. Authors of this publication specialize in various fields, and have dedicated most of their professional lives to oncological patients. They have extensive knowledge and experience which they are kind enough to share.

The book is based on materials collected over many year of professional activity. It offers a review of oncological diseases, and discusses diagnostic and therapeutic methods currently applied by all centers which specialize in ocular and orbital tumors. It also discusses the immunological, genetic and pathomorphological aspects of ocular neoplasms as well as looks into the complex interdependencies between genetic, chromosomal and immunological disorders that predispose patients to the development of cancer. Additionally, it analyses disease risk factors and patient survival rates.

An accurate diagnosis and a sufficiently early treatment is crucial in terms of prognosis (both health and survival outcomes) in primary ophthalmological neoplasms and metastatic tumors alike.

We point out the significance of different complementary imaging techniques in ophthalmological diagnostics, which make it possible to offer correct diagnosis. We also pay special attention to morphological features revealed in individual studies, juxtaposing them with the clinical findings. We make use of color photographs, red-free photography and autofluorescence, ultrasound tests (10 MHz US, 35–50 MHz US), SS-OCT, A-OCT, and in selected conditions also fluorescein and indocyanine angiography. Moreover, we present interesting cases with the differential diagnostics involved. All of the figures included in the publication come from the authors’ resources.

We do hope that our experience backed by the available literature will be useful in your daily clinical practice.

Bożena Romanowska-Dixon, MD, DSc, ProfessorFOREWORD

The University Eye Clinic of Krakow was one of the first ophtalmological institutions in Europe to use circumscribed irradiation with radioactive applicators for the treatment of intraocular tumors. Successful results obtained in Poland after the treatment of uveal melanomas with Cobalt 60 plaques had a positive contribution for the global acceptance by the international ophtalmological community of the conservative management of intraocular tumors.

Since 1968, the University Eye Clinic of Krakow is a national and European reference Center in ocular oncology. This allowed a cumulation of large experience and enlargement of therapeutic armamentarium including recently the creation of a facility for proton beam irradiation of uveal melanomas.

The present textbook on ocular oncology, edited by professor Romanowska-Dixon, on the occasion of the 50^(th) Anniversary of brachytherapy in Krakow, reflects major clinical experience which was progressively cumulated in her department.

This perfectly illustrated volume summarizes a complete overview of benign and malignant ocular tumors. The diagnostic modalities as well as the therapeutic options are clearly described.

This textbook, edited in English and Polish, has a high didactic value and will become soon a major theoretical support for the management of intraocular tumors.

Professor Leonidas Zografos

Honorary Professor at the Faculty of Biology and Medicine of the University of Lausanne, SwitzerlandRECOMMENDATION

Contemporary oncology advanced considerably in the recent years due to new insights from tumor immunology, tumor-host interactions and significant breakthroughs in cancer detection and treatment. Accurate diagnosis based on the proper diagnostic process, and then choosing the appropriate treatment is crucial for therapeutic success. Taking this into consideration, ocular oncology is one of the most demanding areas of ophthalmology.

‘Ocular Oncology’ reflects the wide-scope range expertise, based on the many years of work of the Authors. The book reviews the eye neoplasms, as well as recent diagnostic and therapeutic modalities used in world-renowned centers of ophthalmic oncology.

The present compendium is a comprehensive summary of all ocular oncology aspects, including the description of eye tumors and their epidemiological, morphological, immunohistochemical, genetic and immune characteristics. Tumor treatment methods are widely described, including malignant tumor biology. The reader will also find history of ocular oncology in Poland. The book outlines the standard care for tumors of the eyelid, conjunctiva, uvea, retina as well as intraocular lymphoma and orbital tumors. The principles of radiation therapy for ocular and orbital tumors are also discussed. The preparation of the material for histopathological evaluation and experimental models of uveal melanoma metastases, and metastases to the eye are presented.

It is worth pointing out that all the Authors are eminent and internationally recognized specialists in ophthalmic oncology, who shared their experience with the readers. What is more, they all come from prominent ophthalmology centers, with large clinical material. The aim of the book is to provide ophthalmologists and specialists in other branches of medical science with the latest updates in ocular oncology. The book is clearly written with rich graphics, photographs and figures.

It is an honor for me to recommend this remarkable publication. I would like to congratulate all the Authors for creating this book, which will serve both the ophthalmologists and their patients. Special thanks should be directed to Professor Bożena Romanowska-Dixon, whose endless commitment and enthusiasm for ocular oncology came to fruition in this book. I firmly believe that the Authors’ experience together with recent literature review will prove useful in your everyday practice.

Professor Ewa Mrukwa-Kominek, MD, PhD

Departament of Ophthalmology, Medical University of Silesia, Katowice, Poland; Prof. Gibinski's University Clinical Center of the Medical University of Silesia in KatowiceABBREVIATIONS

3D-CRT – three-dimensional conformal radiation therapy

5-FU – 5-fluorouracyl

ACS – American Cancer Society

AF – autofluorescence

AJCC – American Joint Committee on Cancer

angio-OCT – optical coherence tomography angiography

ARVO – Association for Research in Vision and Ophthalmology

BAP1 – BRCA1 associated protein-1

BCC – basal cell carcinoma

Bq – bekerel

BRAF – a human gene that encodes a protein called B-Raf

BRCA – human tumor suppressor genes, which when mutated may lead to hereditary breast-ovarian cancer

BT – brachytherapy

CHRPE – congenital hypertrophy of retinal pigment epithelium

CM – conjunctival melanoma

CNS – central nervous system

CNV – choroidal neovascularisation

CT – computed tomography

CTLA4 – cytotoxic T cell antigen 4

DNA – deoxyribonucleic acid

DRI-OCT – deep range imaging OCT

EBRT – external beam radiation therapy

EGFR – epidermal growth factor receptor

ERM – epiretinal membrane

FA – fluorescein angiography

FAP – familiar adenomatous polyposis

FAZ – foveal avascular zone

Gy – grej

Gy (RBE) – unit of radiation dose, that includes relative biological effectiveness of the applied radiation; may be used for example in proton beam radiation

HIV – human immunodeficiency virus

HPV – human papilloma virus

IAC – intraarterial chemiotherapy

ICGA – indocyanine green angiography

IGRT – image-guided radiotherapy

IMRT – intensity-modulated radiation therapy

LET – linear energy transfer

MBD4 – Methyl-CpG-binding domain protein 4

MCC – Merkel cell carcinoma

MLC – multileaf collimator

MMC – mitomycyn C

MMS – Mohs micrographic surgery

MRI – magnetic resonance imaging

NRAS – gene encoding protein N-ras (neuroblastoma RAS viral oncogene homolog)

OARs – organs at risk

PAM – primary acquired melanosis

PBS – pencil beam scanning

PCPTCL – primary cutaneous peripheral T-cell lymphoma

PD-1 – programmed death receptor 1

PD-L1 – programmed death ligand 1

PDT – photodynamic therapy

PPV – pars plana vitrectomy

PSP – passive scattering protons

PT – proton beam radiotherapy

PVRL – primary vitreoretinal lymphoma

QUANTEC – quantative analysis of normal tissue effects in the clinic

RBE – relative biological effectiveness

RION – radiation-induced optic neuropathy

RON – radiation optic neuropathy

RPE – retinal pigment epithelium

RR – radiation retinopathy

SCC – squamous cell carcinoma

SebC – sebaceous carcinoma

SHH – sonic hedgehog

SLN – sentinel lymph node

SLNB – sentinel lymph node biopsy

SRS – stereotactic radiosurgery

SRT – stereotactic radiotherapy

S-OCT – spectral OCT

SS-OCT – swept source OCT

TCA – triamcinolon

TD – tolerance dose

TFSOM-UHHD – To Find Small Ocular Melanoma Using Helpful Hints Daily

T-NHL – T-cell non-Hodgkin lymphoma

TNM – Tumor Node Metastasis

TNMH – tumor, node, metastasis, heritable trait – retinoblastoma classification system according to American Joint Committee on Cancer Staging

TTT – transpupillary thermotherapy

UBM – ultrabiomicroscopy

UICC – Union for International Cancer Control

USG – ultrasonography

VEGF – vascular endothelial growth factor1. HISTORY OF OCULAR TUMOR RADIOTHERAPY IN KRAKOW - BOŻENA ROMANOWSKA-DIXON , BARBARA JAKUBOWSKA

In October 1850, the Ophthalmology Department was established as a part of the Medical Faculty of the Jagiellonian University in Krakow. The professors of the newly created Ophthalmology Department and heads of the Ophthalmology Clinic of the Jagiellonian University were as follows: Antoni Sławikowski (1851–1870), Lucjan Rydel (1870–1895), Wiktor Bolesław Wicherkiewicz (1895–1915), Jan Lauber, Kazimierz Wincenty Majewski (1939 i 1945), Jan Lauber (1940–1944), Marian Wilczek (1945–1967), Helena Żygulska-Mach (1967–1996), Maria Starzycka (1996–2004), Bożena Romanowska-Dixon (since 2004 to the present time).

1898 saw the opening of a new building of the Ophthalmology Clinic, which was then modernized at the beginning of the 21st century.

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Figure 1.1. Heads of the Ophthalmology Department and Clinic of the Jagiellonian University: a – Antoni Sławikowski; b – Lucjan Rydel; c – Wiktor Bolesław Wicherkiewicz; d – Kazimierz Wincenty Majewski; e – Marian Wilczek; f – Helena Żygulska-Mach; g – Maria Starzycka; h – Bożena Romanowska-Dixon.

In the 1960s, ophthalmic oncology made significant progress all over the globe. The Clinic in Krakow was no exception in this respect. With Professor Marian Wilczek as Head, the Clinic introduced new diagnostic methods, techniques of conjunctival and eyelid tumor management, as well as reconstructive surgery.

At the beginning of the 1960s, the Clinic purchased the Meyer-Schwickerath xenon arc lamp which was used, amongst other things, for photocoagulation therapy in retinal detachment as well as treatment of other vascular disorders of the retina, primarily diabetic retinopathy, and intraocular neoplasms in adults (melanoma) and children (retinoblastoma).

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Figure 1.2. The building of the Clinic in the 19th century.

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Figure 1.3. Interior rooms of the Clinic in the 19th century.

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Figure 1.4. A team of doctors with Professor Marian Wilczek in the 1960s.

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Figure 1.5. Xenon arc lamp.

Thanks to the efforts of Professor Marian Wilczek, the Clinic made preparations for brachytherapy with cobalt (Co-60), and in 1967 several cobalt plaques (applicators) were purchased and then used for treating uveal melanoma patients. That happened in 1968, only after Professor Wilczek had passed away. The Krakow Ophthalmology Clinic was the second center worldwide, which introduced cobalt applicators (Co-60) for the treatment of intraocular neoplasms .

Professor Helena Żygulska-Mach started brachytherapy with cobalt applicators, which was initially used in the treatment of retinoblastoma and choroidal melanoma, and later expanded to other intraocular tumors. There were 3 types of plaques used, varying by size, namely with a 10 mm (CKA1), 15 mm (CKA2) and 20 mm (CKA3) diameter. They were periodically reactivated at the National Center for Nuclear Research in Świerk (Warsaw). Large melanomas and tumors located close to the optic disc were treated with brachytherapy with Co-60 in combination with xenon arc photocoagulation of the top of the tumor. Brachytherapy was also used after removal of conjunctival melanoma, and for irradiation of the orbit after enucleation in large melanomas with extraocular extension.

In addition, strontium applicators (Sr-90) were used to treat neoplasms on the surface of the eye. Patients from all over Poland have been (and still are) referred to the Clinic in Krakow. Reports from treatment have been published in national and international journals. The first publications of treatment outcomes at the Clinic appeared in 1972.

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Figure 1.6. An excerpt from an article on brachytherapy with cobalt, describing the technique of placing cobalt applicators with the use of marker fittings (shown in the picture), published in the Medical Journal of the Medical Academy in 1969.

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Figure 1.7. A drawing of a patient’s fundus with a choroidal melanoma. All hand drawings come from Ophthalmology Clinic documentation.

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Figure 1.8. Drawings of a patient’s fundus with a choroidal melanoma: a – prior to treatment; b – 8 months after brachytherapy with Co-60; c – almost 3 years after brachytherapy with Co-60.

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Figure 1.9. Drawings of a patient’s fundus with a choroidal melanoma: a – prior to treatment; b – 2 years after brachytherapy with Co-60.

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Figure 1.10. Drawings of a child’s fundus with retinoblastoma: a – prior to treatment; b – 1 year after brachytherapy with Co-60.

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Figure 1.11. A publication on radiotherapy with cobalt and a photograph of Co-60 applicators.

Use of brachytherapy to treat extraocular tumors has gradually gained proponents and currently this method relies on a number of different radioactive elements. Until recently, the Krakow Ophthalmology Clinic was the only center in Poland and one of the few centers in Europe to use brachytherapy for treatment of ocular tumors, and therefore has accumulated extensive clinical data. Brachytherapy was successful in salvaging the globe, often with a satisfactory visual acuity, without compromising the patients’ survival rates. The probability of 5- and 10-year survival was, respectively, 0.86 and 0.67. In order to maximize damage to the tumor, brachytherapy was used in combination with xenon arc photocoagulation in most cases. Photocoagulation was also used successfully as a stand-alone therapy for small tumors, achieving a 5-year survival rate of 0.98 for patients treated with the xenon arc lamp.

In 1995, four plaques containing a radioactive isotope of ruthenium (Ru-106) were acquired by the Clinic. In that year, the first pediatric and adult patients received brachytherapy with ruthenium. Ru-106 plaques need to be replaced once a year due to the element’s half-life and the applicator’s active time. We used Ru-106 plaques of different sizes (with diameters ranging from 10 to 25 mm) and shapes (round, with a notch for the cornea, and with a notch for the optic nerve). We usually hold 3 to 4 active ruthenium plaques, which are in regular use (with sterilization in each case). In 1997, three additional plaques containing a radioactive isotope of iodine (I-125) were purchased .

At that time, we discontinued the use of Co-60 plaques. As per the standard of care, Ru-106 plaques are used for tumors up to 5 mm thick, and iodine applicators for tumors with a greater thickness. We hold three types of iodine applicators: round (3 large ones with a 20 mm diameter and 1 small one with a 10 mm diameter) as well as one applicator with a notch for the optic nerve (20 mm in diameter). Iodine seeds in the applicators need to be replaced every 2–3 months due to the element’s half-life and the plaque’s active period. Until October 2018, radiotherapy with ruthenium was administered to 2,596 patients and with radioactive iodine to 1,951 patients. Most of them suffered from uveal melanoma while some had choroidal metastases and the treatment was also provided to children with retinoblastoma. Only in few cases, brachytherapy with ruthenium is used after removal of conjunctival melanoma.

Since 1995 we have used transpupillary thermotherapy (TTT) with a diode laser in addition to brachytherapy (in the so-called ‘sandwich therapy’), particularly in case of tumors located near the disc, as adjuvant therapy following brachytherapy, or as a stand-alone therapy in case of small tumors, metastatic choroidal tumors, retinoblastoma, choroidal hemangioma and other.

In 1990s, new surgical methods were introduced for treatment of conjunctival melanoma, iris melanoma and ciliary body melanoma, namely iridocyclectomy and iridocyclochoroidectomy. Since 2010, we have performed endoresection of choroidal melanoma after radiation by pars plana vitrectomy (PPV) to prevent development of the toxic tumor syndrome.

Small, symptomatic choroidal hemangiomas are treated using photodynamic therapy (PDT) while larger tumors are managed by transpupillary thermotherapy (TTT) or brachytherapy.

Patients treated with brachytherapy need to remain on dedicated hospital wards.

Patients who undergo brachytherapy with iodine need to wear eye shields to shield the radiation. Healthcare professionals providing brachytherapy and caring for patients wear protective clothing and carry ring and film badge dosimeters. Each year ca. 170 patients receive brachytherapy with I-125 applicators, roughly 200 with Ru-106 applicators.

The operating suite houses a radiological laboratory and 2 sterilizers – one using steam and the other using gas (to sterilize the applicators). The applicators are kept in a safe box, and the movement of radiation sources is closely monitored and recorded (in accordance with the recommendations and approval issued by the National Atomic Energy Agency). The wards for irradiated patients are in close proximity to the operating suite, separated from the regular wards.

In 1988–1989, the Ophthalmology Clinic in Krakow joined the international Retinoblastoma International Clinical Study (RICS). The study was carried out in 14 countries all over the world, and our Clinic contributed the third largest clinical database.

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Figure 1.12. Ru-106 applicators.

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Figure 1.13. I-125 applicators.

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Figure 1.14. Proton therapy facility of the University Hospital in Krakow located at the Institute of Nuclear Physics of the Polish Academy of Sciences.

The Ophthalmology Clinic in Krakow also collaborates with the Genetic Outpatient Clinic of the Clinical Genetics Department and the Immunology Clinic of the Polish-American Children’s University Hospital in a study on families of children with retinoblastoma. The Clinic also studied genetic markers in various ocular disorders, including retinoblastoma, in collaboration with the Department of Forensic Medicine of the Jagiellonian University.

Following a rapid development in the area of ocular oncology, our Clinic was renamed as the Ophthalmology Department, Ophthalmology and Ocular Oncology Clinic of the Jagiellonian University Hospital.

In January 2011, we started treating patients with choroidal melanoma using a proton beam (proton therapy) in cooperation with the Institute of Nuclear Physics of the Polish Academy of Sciences (PAN) in Krakow.

The therapy is managed by a team of physicians (ophthalmologists, radiotherapists and an oncologist), medical physicists, radiology technicians and nursing staff from the Ophthalmology and Ocular Oncology Clinic of the Jagiellonian University in Krakow while the Institute of Nuclear Physics of PAN in Krakow contributes the proton beam. Every year around 50 patients receive proton therapy.

Everyday the outpatient cancer center of the Ophthalmology and Ocular Oncology Clinic sees between 30 and 40 patients referred from all regions of Poland as well as a few patients from abroad (Lithuania, Latvia, Ukraine and the UK). Our operations were enabled by collaboration with other institutions, including the Anatomical Pathology Department, Otorhinolaryngology Clinic and the Pathomorphology Department of the Jagiellonian University and, with respect to experimental research, the Faculty of Biochemistry, Biophysics and Biotechnology .

We have presented our research in diagnosing and treating ocular oncology patients at national and international scientific symposiums, and published papers in Polish and international scientific journals. Irradiation of tumors enabled us not only to salvage the eye and, frequently, retain a satisfactory visual acuity, but also improve patient survival rates. A review of brachytherapy treatment outcomes showed that secondary glaucoma proves to be the most destructive complication. Other complications included: radiation retinopathy, radiation neuropathy and vitreous hemorrhage. Secondary cataract was the most frequently reported complication.

We also engage in extensive international scientific cooperation. In 2016, the Ophthalmology Clinic of Krakow joined the UMCURE 2020 program (grant agreement 667787; https://www.umcure2020.org/en/). It is one of 4 centers in Europe involved in developing new therapies of uveal melanoma, with a particular focus on treating metastatic uveal melanoma.

References

1. Żygulska-Mach H., Maciejewski Z., Link E: Conservative treatment of choroidal melanomas. Combined use of cobalt plaques and photocoagulation. Intraocular Tumors. Fortschritte der Onkologie. Band 9 (red. P.K. Lommatzsch, F.C. Blodi). Akademie-Verlag, Berlin 1983: 417–423. 2. Romanowska B., Żygulska-Mach H., Księżyk M.: Survival rate of young patients with malignant choroidal melanoma after conservative treatment. Klinika Oczna 1998; 100(4): 211–216.3. Romanowska-Dixon B., Elas M., Swakoń J. et al.: Metastasis inhibition after proton beam, β- and γ-irradiation of melanoma growing in the hamster eye. Acta Biochimica Polonica 2013; 60(3): 307–311.4. Romanowska B., Kukiełczak J., Bryk B. et al.: New technique for implanting Bomirski melanoma into the anterior chamber of Syrian hamster eyes. Klinika Oczna 1995, 97(11–12): 324–327.