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Respons radiasi kanker serviks diduga dapat ditingkatkan dengan pemilihan waktu radiasi tetap yang berpola sirkadian karena dianggap sesuai dengan fase radiosensitif G₂-M sel kanker. Daur sirkadian dan melatonin dianggap berperan dalam radiosensitivitas. Dihipotesiskan respons radiasi pagi hari maupun efek samping radiasi pagi hari akan lebih baik dibanding sore hari.

Penelitian ini merupakan uji klinis dengan perolehan subjek secara berurutan. Alokasi pilihan waktu radiasi pada pagi (06.00–08.00) dan sore (16.00–18.00) hari dengan randomisasi blok tiap enam subjek terpisah antara stadium II dan III. Data diperoleh menggunakan metode open label. Pengukuran data klinis seperti ukuran tumor, respons klinis, dan efek samping dilakukan oleh dua dokter independen yang terlatih. Dilakukan pengukuran kadar melatonin dan fase G₂-M siklus sel di institusi resmi. Respons baik dan buruk ditetapkan berdasarkan kriteria WHO sedangkan efek samping ada atau tidak, ditetapkan berdasarkan kiriteria RTOG.

Penyinaran di waktu pagi menunjukkan respons klinis lebih baik dibandingkan sore (p 0,025; 95% IK:1,27–33,08; adj OR: 6,48) untuk respons pascaradiasi maupun 2–4 minggu pascaradiasi (p 0,048; 95% IK 1,02–47,81; adj OR 6,98). Kadar Hb awal dan ukuran klinis tumor berpengaruh secara bermakna terhadap respons baik pascaradiasi maupun respons baik 2–4 minggu pascaradiasi. Dalam hal efek samping, pilihan waktu radiasi tidak menunjukkan hasil yang bermakna, namun kadar melatonin praradiasi berpengaruh, khususnya efek samping kulit (p 0,006; 95% IK 1,66–18,99; adj OR 5,62). Variabel yang bermakna memengaruhi efek samping terapi pada gastrointestinal adalah overall treatment time (p 0,031; 95% IK 1,19–39,93; adj OR 6,89), sedangkan untuk genitourinaria adalah PA diferensiasi (p 0,015; 95% IK 1,51–46,37; adj OR 8,36), penurunan berat badan (p 0,025; 95% IK 1,22–18,30; adj OR 4,72), dan nyeri sebelum radiasi (p 0,017; 95% IK 1,31–15,32; adj OR 4,47).

Simpulan: Respons radiasi kanker serviks uteri yang diradiasi pagi hari lebih baik daripada yang diradiasi sore hari, namun efek samping radiasi pagi hari tidak berbeda bermakna dibandingkan sore hari. Belum dapat dipastikan pengaruh besarnya proporsi fase G₂-M terhadap respons klinis radiasi. Ada kecenderungan pengaruh kadar melatonin pagi hari terhadap respons klinis radiasi dan terbukti kadar melatonin berpengaruh pada efek samping kulit.

Kata kunci: kanker serviks, melatonin, radiosensitivitas, siklus sel, sirkadian

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The radiation response of cervical cancer can be enhanced by the choice of a fixed radiation time of circadian pattern because it is considered to be in accordance with the radiosensitive phase of G₂-M cancer cells. Circadian cycles and melatonin are thought to play a role in radiosensitivity. It is hypothesized that the response and side effects of morning radiation will be better than the afternoon.

This study was an RCT (randomized clinical trials) with consecutive sampling. Treatment allocation for radiation time in the morning (06.00–08.00) and afternoon (16.00–18.00) were determined by block randomization for every six subjects based on the stage (II and III). The data was obtained with an open label method. Measurement of clinical data such as tumor size, clinical response, and side effects were carried out by two-trained independent physicians. Measurement of melatonin levels and G₂-M phases of cell cycle were carried out in official institution. Good and poor responses were set based on WHO criteria while the side effects were determined based on the RTOG criteria.

Morning radiation showed a better post-radiation and 2–4 weeks post-radiation clinical response compared with afternoon (p 0.025; 95% CI:1.27–33.08; adj OR: 6.48 and p 0.048; 95%CI 1.02–47.81; adj OR 6.98, respectively). The initial Hb level and clinical size of the tumor had a significant effect on good response both post-radiation and 2-4 weeks post-radiation. In regards to the side effects, radiation time did not show significant results in causing side effects, but pre-radiation melatonin level did on skin (p 0.006; 95%CI 1.66–18.99; adj OR 5.62). The significant variable in influencing gastrointestinal side effects was overall treatment time (p 0.031; 95%CI 1.19–3.93; adj OR 6.89), whereas for genitourinaria were differentiation of histopathology (p 0.015; 95%CI 1.51–46.37; adj OR 8.36), weight loss (p 0.025; 95%CI 1.22–18.30; adj OR 4.72), and presence of pain pre-radiation (p 0.017; 95%CI 1.31–15.32; adj OR 4.47).

Conclusion: The radiation response of irradiated uterine cervical cancer is better in the morning than the afternoon. Nevertheless, the side effects of morning radiation do not differ significantly compared to the afternoon. The influence of the G₂-M phase proportion on the clinical response to radiation cannot be ascertained. The level of melatonin in the morning might affect the radiation response and affect the side effects on skin.

Keywords: cell cycle, cervical cancer, circadian, melatonin, radiosensitivity.

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"Latar Belakang: Kanker serviks merupakan salah satu penyebab kematian tertinggi dari seluruh kasus keganasan di Indonesia. Salah satu penyebab tingginya angka kematian adalah pasien baru mulai mencari pengobatan pada stadium lanjut. Radioterapi tunggal dapat digunakan sebagai tatalaksana kanker serviks stadium lanjut pada pasien yang tidak dapat mentoleransi efek samping kemoterapi. Tetapi, pasien dengan kanker serviks menunjukkan respon yang beragam terhadap radioterapi.Tujuan: Penelitian ini bertujuan untuk menilai hubungan antara densitas CD8+ TILs pada kanker< serviks dengan respon terhadap radioterapi.Metode: Penelitian ini merupakan penelitian kasus kontrol. Kelompok respon radiasi komplet sebagai kasus dan kelompok populasi respon radiasi tidak komplet sebagai kelompok kontrol. Populasi penelitian adalah pasien yang telah didiagnosis sebagai karsinoma sel skuamosa serviks di Departemen Patologi Anatomik FKUI/RSCM dari tanggal 1 Januari 2016 hingga 31 Desember 2021, menerima radioterapi definitif di Departemen Onkologi Radiasi RSCM, dan memiliki data respon radioterapi yang lengkap. Pengambilan sampel dilakukan secara konsekutif. Data dianalisis secara statistik untuk menilai faktor-faktor yang mempengaruhi respon radiasi.Hasil: Didapatkan 40 kasus KSS serviks stadium IIIB yang terdiri atas 20 kasus dengan respon radiasi komplet dan 20 kasus dengan respon radiasi tidak komplet. Median densitas CD8+ iTILs pada kelompok yang mengalami respon komplet lebih tinggi dibandingkan dengan kelompok yang tidak mengalami respon komplet (1099 sel/mm2 vs 920,27 sel/mm2, p = 0,035) Nilai titik potong yang direkomendasikan untuk memprediksi respon terhadap radioterapi adalah 959,32 sel/mm2. Tidak ditemukan hubungan yang bermakna secara statistik antara ukuran tumor, derajat diferensiasi, dan keratinisasi terhadap respon terhadap radioterapi.Kesimpulan: Densitas CD8+ iTILs yang lebih tinggi berhubungan dengan respon terhadap radioterapi pada pasien KSS serviks stadium IIIB.

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Background: Cervical cancer is one of the leading causes of death related to malignancies. One of the contributing factor toward this high mortality rate is that patients are usually diagnosed at an already advanced stage. Radiotherapy can be used as a treatment for advanced cervical patients who cannot tolerate the side effects of chemotherapy. However, patients with cervical cancer show mixed responses to radiotherapy.

Objectives: This study aims to assess the association between CD8+ TILs density in advanced stage cervical cancer and its response to radiotherapy.

Methods: This is a case-control study. The study population were patients diagnosed with stage IIIB uterine cervix squamous cell carcinoma at the Department of Anatomical Pathology Faculty of Medicine University of Indonesia (FMUI)/Cipto Mangunkusumo Hospital (CMH) from January 1st, 2016 up to December 31st, 2021, who received definitive radiotherapy at the Department of Radiation Oncology FMUI/CMH, and had complete radiotherapy response data. Patients with complete response are classified as the response group and those with incomplete response are classified as the control group. Sampling is done consecutively. The data were statistically analyzed to assess the factors influencing radiation response.

Results: Forty cases of stage IIIB uterine cervix squamous cell carcinoma were selected, consisting of 20 cases with complete radiation response and 20 cases with incomplete response. The median CD8+ iTILs density in the complete response group was higher than in the incomplete response group (1099 cells/mm2vs 920,27 cells/mm2, p: 0,035). The recommended cut-off point for predicting radiotherapy response was 959,32 cells/mm2. No statistically significant relationship was found between tumor size, degree of differentiation, and keratinization on response to radiotherapy.

Conclusion: Higher CD8+ iTILs density was associated with better response to radiotherapy in stage IIIB uterine cervix squamous cell carcinoma."

"Latar Belakang : Pasien kanker serviks di Indonesia terbanyak dalam stadium lanjut. Terapi standarnya adalah radiasi. Respons terapi radiasi tidak selalu komplet. MnSOD merupakan garda terdepan melawan radikal bebas yang dihasilkan radiasi. Aktifitas MnSOD dipikirkan dapat digunakan sebagai prediktor respons terapi radiasi. Diperkirakan semakin tinggi aktifitas MnSOD akan semakin buruk respons radiasinya. Tujuan : Menilai aktifitas MnSOD pada biopsi KSS serviks stadium IIIB sebagai prediktor keberhasilan terapi radiasi. Metode : Penelitian potong lintang komparatif ini dilakukan di Divisi Onkologi Ginekologi, Departemen Obstetri dan Ginekologi FKUI, RSCM Jakarta dan Departemen Biokimia dan Biologi Molekuler FKUI. Dilakukan penelusuran data base penelitian sebelumnya untuk mengindentifikasi sampel respons positif dan negatif, dilanjutkan pemeriksaan aktifitas MnSOD dengan sprektrofotometri metode McCord dan Fridovich menggunakan kit RanSOD . Data komparatif yang didapat kemudian di analisis. Hasil : Didapatkan 76 sampel yang memenuhi kriteria inklusi terdiri dari respons positif 47 61,8 negatif 29 38,2 . Dilakukan kategorisasi aktifitas MnSOD dengan titik potong pada nilai 13,126 U/mL. Dengan uji chi-square didapat hubungan bermakna secara statistik antara aktifitas MnSOD pada pasien kanker stadium IIIB dengan respons terapi radiasi. Nilai RR sebesar 1,849 1.075-3.178, IK 95 . Kesintasan dengan analisis bivariat memakai metode Kaplan-Meier: pasien dengan aktifitas MnSOD cutoff < 13,126 U/mL memiliki tingkat kesintasan 1 tahun yang lebih baik 63 dibandingkan dengan pasien kanker serviks IIIB dengan nilai aktifitas MnSOD ge; 14 . Risiko kematian dengan pengujian bivariat metode regresi cox: pasien dengan aktifitas MnSOD cutoff 13,126 U/mL memiliki risiko kematian 1,055 kali IK 95 : 1,003-1,110 dibanding pasien dengan aktifitas MnSOD dibawah nilai cutoff. Dari analisis multivariat terlihat aktifitas MnSOD semakin kuat sebagai prediktor respons terapi radiasi. Kesimpulan : Aktifitas MnSOD tinggi pada jaringan KSS serviks stadium IIIB menghasilkan respons negatif dari terapi radiasi.

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Background: Most of the cervical cancer patients in Indonesia came with advanced stage. Therefore, the choice of treatment is radiotherapy. Although, radiotherapy does not always result in complete response. MnSOD is considered to be one the antioxidant enzyme which has the ability to work against free radicals. Its activity is expected to be acted as response predictor to radiotherapy treatment. It is hypothesized that high MNSOD activity tend to predict poor response of radiotherapy on advanced cervical cancer patients.

Objective : To investigate MnSOD activity on cervical SCC stage IIIB as a predictor of radiotherapy response.

Methods : It is a comparative cross sectional study conducted in the Gynecology Oncology Division, Obstetrics and Gynecology Department, Dr. Cipto Mangunkusumo Hospital Faculty of Medicine, University of Indonesia. Samples were collected from the tissue bank and research database. They were identified and divided into having positive or negative response to radiotherapy. In vitro experiment was conducted to measure the activity of MnSOD. Manganese superoxide dismutase was isolated using McCord and Fridovich method using RanSOD and the activity was analyzed using spectrophotometry. Data was then analyzed using SPSS.20 for comparative study.

Results : Seventy six samples were included in the study 47 61.8 with positive response and 29 38.2 with negative response on radiotherapy. Samples were then divided into having MnSOD activity of 13.126 U mL or 13.126 U mL. Univariate analysis chi square showed that there was statistically significant correlation between MnSOD activity and radiotherapy response in patients with cervical SCC stage IIIB RR 1.849 95 CI 1.075 3.178 . Survival analysis on the first year showed that patients with MnSOD activity 13.126 U mL had better survival than patients with MnSOD activity 13.126 U mL 63 vs 14 , Kaplan Meier study . Hazard ratio for overall survival was 1.055 95 CI 1.003 ndash 1.110 for patients with MnSOD activity of 13.126 U mL. Multivariate analysis showed that MnSOD activity was a strong predictor of radiotherapy response in this study.

Conclusion : This in vitro study showed that high activity of MnSOD was associated with poor response of radiotherapy for patients with cervical squamous carcinoma stage IIIB. "

"Latar balakang. Sekitar 75% kanker leher rahim datang ke rumah sakit dalam stadium lanjut. Terapi utama kanker serviks stadium lanjut adalah radioterapi. Kombinasi terapi radiasi dengan kemoterapi ternyata tidak menghasilkan respons terapi yang lebih baik, tetapi bahkan menimbulkan efek samping yang lebih berat dibandingkan terapi radiasi saja. Perubahan pola makan saat ini, diduga berpengaruh pada respons terapi. Rasio asupan Polyunsaturated Fatty Acids (PUFA) n-6 : n-3 sekitar 1-2 : 1 dapat melawan pertumbuhan kanker. Beberapa publikasi melaporkan bahwa PUFA n-3 (AL n-3) mempunyai efek pro-apoptosis, anti-inflamasi, anti-proliferatif dan anti-angiogenik. Penelitian ini bertujuan untuk mengetahui apakah suplementasi nutrisi tinggi PUFA bersamaan dengan terapi radiasi dapat meningkatkan respons tumor pada kanker serviks stadium lanjut. Metode. Penelitian ini merupakan Randomized Clinical Trial, double blind pada pasien kanker serviks stadium lanjut, jenis karsinoma sel skuama yang hanya mendapat terapi radiasi di Departemen Radioterapi, Rumah Sakit Cipto Mangunkusumo (RSCM), Jakarta. Subjek penelitian diambil secara konsekutif, melalui randomisasi dibagi dua kelompok, yaitu kelompok perlakuan dan kontrol. Selama radiasi subjek penelitian mendapat suplementasi nutrisi mengandung isokalori dan isoprotein dengan rasio AL n-6 : n-3 = 1,27 : 1 dan kontrol. Selama perlakuan dilakukan evaluasi setiap lima kali radiasi, meliputi BB dan efek samping radiasi akut. Parameter yang dinilai adalah respons klinis, respons histopatologis serta perubahan kadar PGE2 dan VEGF serum.Hasil. Sebanyak 31 subjek dari 45 subjek dapat menyelesaikan penelitian. Sebelum perlakuan, status sosio-demografi, pola asupan AL n-6 dan n-3, status gizi dan klinis tidak didapatkan perbedaan bermakna. Setelah perlakuan, didapatkan penurunan kadar PGE2 serum pada kelompok perlakuan, sedangkan kelompok kontrol mengalami kenaikan (p = 0,127). Penurunan kadar VEGF kelompok perlakuan lebih besar dibanding kontrol (p = 0,626). Respons klinis dan respons histopatologis kelompok perlakuan lebih baik dibanding kontrol, dengan kemaknaan masing-masing p = 0,172 dan p = 0,169. Secara statistik belum didapatkan perbedaan yang bermakna pada penurunan kadar PGE2 dan VEGF serum, respons klinis dan respons histopatologis, tetapi didapat kemaknaan klinis yang nyata pada kelompok perlakuan dibanding kontrol. Analisis statistik gabungan dari respons klinis, respons histopatologis, kadar PGE2 dan VEGF serum didapatkan respons tumor total yang bermakna (p = 0,048).Kesimpulan. Suplementasi nutrisi tinggi PUFA dengan rasio asam lemak n-6 : n- 3 = 1,27 : 1 pada kanker serviks stadium lanjut bersama terapi radiasi memberikan respons tumor total yang lebih baik.

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Background. Approximately 75% of uterine cervical cancer came to the hospital in an advanced stage. Primary therapy of advanced cervical cancer is radiotherapy. The combination of radiotherapy with chemotherapy did not give better outcomes, but even cause more severe side effects than radiotherapy. Changes in dietary intake at this time, are supposed to influence the response to therapy. The ratio of n-6 to n-3 polyunsaturated fatty acids (PUFA) about 1-2: 1 can fight cancer growth. Several publications stated that n-3 PUFA has pro- apoptotic effect, anti-inflammatory, anti-proliferative and anti-angiogenic. This study aimed to examine whether radiotherapy combined with daily nutritional supplements enriched PUFA enhance tumor response in advanced cervical cancer.

Method. This study was a double-blind Randomized Clinical Trial (RCT) in patients with advanced squamous cell cervical cancer, received radiation only as control group, and those who received nutritional supplementation containing isocaloric and isoprotein with ratio of n-6 : n-3 PUFA = 1.27: 1 as treatment group. This study was performed in the Department of Radiotherapy Dr. Cipto Mangunkusumo General Hospital (RSUPNCM), Jakarta. Evaluation was done every five times radiation, including Karnofsky Perfomance Scale, body weight and side effects of acute radiation. Parameters assessed were clinical and hematological response, histopathological response and changes in the levels of PGE2 and VEGF serum.

Results. A total of 31 subjects from 45 subjects participated the study completely. Prior to treatment, socio-demographic status, patterns of n-6 and n-3 PUFA, clinical and nutritional status were analyzed, no significant differences were noted. After treatment, a decrease in serum PGE2 levels in the treatment group was found, while in the control group increased (P = 0.127). VEGF in the treatment group declined higher than controls (P = 0.626). Treatment group showed significant better clinical response and histopathological responses compared to the control group (p = 0.172 and p = 0.169). No significant differences were found in the reduction of PGE2 and VEGF serum levels, clinical response and histopathological response, although from clinical standpoint there is a better significant response in the treatment group than the control. The combined statistical analysis of clinical response, histopathological response, PGE2 and VEGF serum levels obtained total tumor response (P = 0.048).

Conclusion. Nutritional supplementation enriched PUFA (ratio of n-6: n-3 PUFA = 1.27 : 1) in advanced cervical cancer receiving radiotherapy gives better total tumor response."

"Radiasi merupakan terapi pilihan untuk kanker serviks stadium III B, namun permasalahan timbul karena adanya sifat radioresisten. Sel punca kanker SPK merupakan salah satu faktor yang diduga berkontribusi terhadap hal tersebut. SOX2 dan OCT4 merupakan faktor transkripsi yang mengekspresikan sifat-sifat SPK, yaitu mengontrol sifat pluripoten, self-renewal, berperan pada karsinogenesis, metastasis, resistensi terhadap terapi dan rekurensi tumor. Faktor apoptosis, DNA repair dan telomerase merupakan mekanisme yang berkaitan dengan radioresisten. Penelitian ini bertujuan untuk mempelajari hubungan antara SOX2 dan OCT4 sebagai penanda SPK terhadap respons terapi radiasi, serta kaitannya dengan faktor apoptosis caspase-3 , DNA repair Chk1 dan telomerase hTERT .Penelitian ini merupakan case control, terhadap 48 kasus karsinoma sel skuamosa serviks stadium III B yang telah menjalani terapi radiasi/kemoradiasi di RS Cipto Mangunkusumo/FKUI. Kasus dibagi dalam 2 kelompok, yaitu hasil terapi komplet 27 kasus dan hasil terapi inkomplet 21 kasus . Kasus dengan respons awal terapi radiasi baik dilakukan pemeriksaan bulan Pap smear dan HPV pada bulan ke-6 atau sampai ke-12 setelah terapi. Ekspresi SOX2, OCT4, caspase-3, Chk1 dan hTERT diperiksa secara imunohistokimia dari blok parafin biopsi awal.Ekspresi kuat SOX2 dan OCT4 dengan H-score masing-masing lebih dari 96,6 dan 61,9 mempunyai hubungan bermakna dengan respons awal terapi radiasi maupun respons akhir terapi radiasi SOX2 p = 0,017, p = 0,004 dan OCT4 p < 0,001, p < 0,001 . Ditemukan hubungan bermakna antara ekspresi Chk1 dan hTERT dengan respons awal terapi radiasi Chk1 p = 0,006, hTERT p = 0,029 . Tidak ditemukan hubungan yang bermakna antara ekspresi caspase-3, Chk1, hTERT dengan ekspresi SOX2 dan OCT4. Uji multivariat menunjukkan bahwa SOX2 dan OCT4 yang paling memengaruhi respons terapi OR = 5,12, p = 0,040 dan OR = 17,03, p < 0,001, secara berurutan . Uji probabilitas menunjukkan kemungkinan respons akhir terapi radiasi inkomplet sebesar 87,91 bila ekspresi kedua penanda SPK kuat.Ekspresi kuat SOX2 dan OCT4 dapat memprediksi hasil terapi radiasi inkomplet pada karsinoma serviks stadium III B.

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Radiotherapy is the main choice of treatment for stage III B cervical cancer, but radioresistance becomes a difficult matter. Cancer stem cell is one of the factors suspected involving in radioresistant cancers. SOX2 and OCT4 are transcription factors which have pluripotent cell characteristics, and self renewal ability. They also involved in carcinogenesis, metastasis, tumor recurrent, and resistance toward therapy. Apoptotic, DNA repair, and telomerase factors are mechanisms that also contribute to radioresistance. This study aims to know the role of SOX2 and OCT4 as CSC markers, apoptotic factor caspase 3 , DNA repair Chk1 and telomerase hTERT toward radiotherapy.The design of this study was case control with 48 cases of stage III B cervical squamous cell carcinoma patients who had finished receiving radiation chemo radiation therapy at Cipto Mangunkusumo Hospital FMUI, Jakarta. They were classified in 2 groups based on the final response of treatment, which were complete and incomplete one. Pap smear and DNA HPV were performed in month 6 or until month 12 after therapy for good initial therapy. Immunohistochemistry was done to analyze SOX2, OCT4, caspase 3, Chk1 and hTERT expression from the paraffin block of initial biopsy.Strong expression of SOX2 and OCT4 with each H score was higher than 96.6, and 61.9 had significant association with both initial and final therapy response SOX2 p 0.017, p 0.004 and OCT4 p 0.001, p 0.001, repectively . There was significant association between expression of Chk1 and hTERT, and initial therapy response p 0.006 for Chk1, and p 0.029 for hTERT . No significant differences were found between caspase 3, Chk1, hTERT, and SOX2 and OCT4. Multivariate analysis showed SOX2 and OCT4 were the most influenced antibodies for radiotherapy response OR 5.12, p 0.040, and OR 17.03, p 0.001, respectively . The likelihood of incomplete final therapy response was 87.91 if the expression both of CSC markers were strong.Expression of SOX2, and OCT4 could predict the incomplete radiotherapy of stage III B cervical cancer cases. "

"ABSTRAKLatar Belakang: Kanker serviks stadium lanjut lokal (IIB-IIIB) masih menjadi beban kesehatan di Indonesia saat ini. Radiasi menjadi modalitas utama terapi pada stadium ini. Programmed Death-Ligand 1 (PD-L1) merupakan sebuah ligand yang diekspresikan pada sel tumor yang terkait dengan proses immune escape. Sampai saat ini belum diketahui karakteristik kadar PD-L1 pada karsinoma sel skuamosa (KSS) serviks stadium lanjut lokal serta pengaruh radiasi terhadap ekspresinya. Penelitian ini bertujuan untuk melihat karakteristik PD-L1 intratumoral pada kanker serviks stadium lanjut lokal serta pengaruh radiasi eksterna terhadap ekspresinya. Metode: Dilakukan pemeriksaan kadar PD-L1 pada sampel biopsi serviks dengan 2 metode, yaitu Enzyme Linked Immuno Sorbent Assay (ELISA) dan immunohistokimia (IHK). Pengambilan sampel dilakukan dua kali, yaitu preradiasi dan pascaradiasi eksterna. Dilakukan analisis statistik untuk mengetahui perbedaan kadar antara sebelum dan sesudah radiasi. Selain itu dilakukan analisis untuk melihat kesesuaian antara kadar yang ditunjukkan pada metode ELISA dengan metode IHK. Hasil: Didapatkan 29 sampel KSS serviks stadium lanjut lokal yang memenuhi kriteria inklusi dan eksklusi. Dari pemeriksaan IHK, didapatkan bahwa PD-L1 diekspresikan hampir pada seluruh subjek (96,5%). Didapatkan nilai median PD-L1 ELISA preradiasi 409,19 pg/mg protein (59,80-3011,30), pascaradiasi 444,40 pg/mg protein (27,24-3217,85). Tidak didapatkan perbedaan bermakna antara kedua kelompok tersebut (p = 0,804). Pada analisis receiver operating characteristics (ROC) didapatkan nilai ELISA >400 pg/mg protein bersifat prediktif menyebabkan terjadinya penurunan kadar ELISA pascaradiasi. Terdapat kesesuaian antara kadar PD-L1 metode ELISA dengan metode IHK, dimana nilai ELISA > 499 pg/mg protein cenderung menunjukkan nilai grade 3 pada pemeriksaan IHK. Kesimpulan: PD-L1 diekspresikan positif pada KSS serviks uteri stadium lanjut lokal. Tidak terlalu jelas efek radiasi dalam menyebabkan naik-turunnya ekspresi PD-L1. Pemeriksaan ELISA mempunyai potensi untuk dipertimbangkan mewakili hasil pemeriksaan IHK, namun perlu bukti yang lebih kuat berupa penelitian dengan jumlah sampel yang lebih banyak.

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ABSTRACTBackground: Locally advanced cervical cancer (IIB-IIIB) remains a health burden in Indonesia. Radiation is the main modality of therapy at this stage. PD-L1 is a ligand that is expressed in tumor cells associated with the immune escape process. Until now there is no clear characteristics of PD-L1 levels in locally advanced-stage cervical SCC and the effect of radiation on its expression. This study is aimed to look for the intratumoral PD-L1 characteristics in locally advanced cervical cancer and the effect of external radiation on its expression. Method: PD-L1 levels were examined on cervical biopsy samples using two methods, i.e. ELISA and IHC. Biopsy was carried out twice, preradiation and post-external radiation. Statistical analysis was performed to determine differences in levels between before and after radiation. In addition, an analysis was conducted to see the conformity between the levels indicated in the ELISA method and the IHC method. Results: Twenty nine samples of local advanced cervical SCC were obtained that met the inclusion and exclusion criteria. From the IHC examination, it was found that PD-L1 was expressed in almost all subjects (96.5%). The median PD-L1 concentration of ELISA PD-L1 preradiation was 409.19 pg / mg protein (59.80-3011.30), post-radiation 444.40 pg / mg protein (27.24-3217.85). No significant difference was found between the two groups (p = 0.804). In the ROC analysis it was found that ELISA values > 400 pg / mg protein were predictive to cause a decrease in postradiation ELISA levels. There is a conformality between the levels of PD-L1 ELISA method with the IHC method, where the ELISA value > 499 pg/mg of protein tends to show grade 3 values ​​on the IHC examination. Conclusion: PD-L1 was expressed positively in locally advanced cervical SCC. The effects of radiation in causing the ups and downs of the expression of PD-L1 is not very clear. ELISA examination has the potential to be considered as a representative to the results of the IHC examination, but stronger evidence is needed in the form of study with a larger number of samples."

"Tujuan. Penelitian ini bertujuan untuk mengetahui profil Treg (ditunjukkan oleh Foxp3), CD4, dan CD8 pada kanker serviks stadium lanjut lokal dan dampaknya terhadap progresivitas tumor dan respons radiasi. Metode. Setelah disetujui oleh komite penelitian, kami mengumpulkan data pasien kanker serviks stadium lanjut lokal yang menjalani radioterapi, di RSCM, Jakarta, pada Januari 2018 – Desember 2020. Subjek penelitian harus memiliki pencitraan pra dan paska radiasi dan spesimen blok parafin untuk memenuhi syarat dalam penelitian ini. Profil Foxp, CD4, dan CD8, akan dianalisis dengan imunohistokimia dengan penghitungan jumlah sel. Respons radiasi akan dianalisa dengan kriteria RECIST 1.1. Semua informasi klinis pasien yang diperlukan akan dikumpulkan dari rekam medis elektronik. Hasil. Kami menemukan bahwa sebagian besar pasien memiliki karsinoma sel skuamosa (93%), stadium IIIC (48%), dan menjalani radiasi saja (72%). Evaluasi RECIST menunjukkan 62% pasien memiliki respons lengkap, 28% respons parsial, dan 10% respons buruk (penyakit stabil dan progresif). Kami dapatkan median jumlah sel CD4 =29 (7 – 154), CD8 = 30 (6 – 227), dan Foxp3 = 36 (2 – 156). Tidak ada hubungan bermakna antara jumlah sel limfosit CD4, CD8, dan Foxp3 dengan volume tumor, dengan p = 0.858; p = 0.975, dan p = 0.723 masing masing. Tidak ada hubungan bermakna dengan dimensi terbesar tumor dengan p = 0.481, p = 0.480, dan p = 0.792 masing masing. Tidak ada pula hubungan bermakna antara jumlah sel limfosit CD4, CD8, dan Foxp3 dengan respons radiasi dengan p = 0.964, p = 0.296, dan p = 0.787 masing masing. Namun kami mendapatkan korelasi positif yang kuat dan bermakna pada jumlah sel tumor pada stroma, CD 4 - CD8 (r = 0.580, p=0.001); CD4 - Foxp3 (r = 0.699, p < 0.001), dan CD8 - Foxp3 (r = 0.652, p < 0.001). Kesimpulan. Sebagian besar pasien kanker stadium lanjut lokal yang menjalani radiasi memiliki respons lengkap. Tidak didapatkan hubungan bermakna antara jumlah sel limfosit CD4, CD8, dan Foxp3 dengan volume tumor, dimensi terbesar tumor, dan respons radiasi. Terdapat korelasi yang kuat dan signifikan antar sel imun (CD4-CD8, CD4-Foxp3, dan CD8-Foxp3) pada lingkungan stroma.

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Aims: This study aims to determine profile of Treg (shown by Foxp3), CD4, and CD8 in locally advanced cervical cancer and the impact to tumor progressivity and radiation response. Method. After been approved by the institution research committee, we collect data of locally advanced of cervical cancer patients who underwent radiotherapy, at RSCM, Jakarta, in January 2018 – December 2020. Studies subjects must have pre and post irradiation imaging and paraffin block specimen to be eligible in this study. Profile of Foxp, CD4, and CD8, will be analyzed by immunohistochemistry, by counting the number of cells, and radiation response will be analyzed by RECIST 1.1 criteria. All necessary patient’s clinical information will be collected from electronic medical record. Result. We found that most of the patients had squamous cell carcinoma (93%), stage IIIC (48%), and underwent radiation alone (72%). RECIST evaluation showed 62% of patients had a complete response, 28% a partial response, and 10% had a poor response (stable and progressive disease). We found median CD4 cell counts = 29 (7 – 154), CD8 = 30 (6 – 227), and Foxp3 = 36 (2 – 156). There was no significant relationship between the number of CD4, CD8, and Foxp3 lymphocytes with tumor volume, with p = 0.858; p = 0.975, and p = 0.723 respectively. There was no significant relationship with the dimensions of the largest tumor with p = 0.481, p = 0.480, and p = 0.792, respectively. There was no significant relationship between the number of CD4, CD8, and Foxp3 lymphocytes with radiation response with p = 0.964, p = 0.296, and p = 0.787, respectively. However, we found a strong and significant positive correlation in the number of tumor cells in the stroma, CD4 - CD8 (r = 0.580, p = 0.001); CD4 - Foxp3 (r = 0.699, p < 0.001), and CD8 - Foxp3 (r = 0.652, p < 0.001). Conclusion. Most locally advanced cancer patients who undergo radiation have a complete response. There are no significant relationships between the number of CD4, CD8, and Foxp3 lymphocytes with tumor volume, largest tumor dimensions, and radiation response. There is a strong and significant correlation between immune cells (CD4-CD8, CD4-Foxp3, and CD8-Foxp3) in the stromal environment."

"Latar belakang: Aldehyde dehydrogenase 1 (ALDH1) merupakan marker sel punca kanker serviks yang menunjukkan karakteristik radioresisten. Studi ini bertujuan untuk mengetahui hubungan ALDH1 terhadap respon radiasi karsinoma sel skuamosa serviks stadium IIIB.Metode: Sebanyak 58 sampel dari 360 pasien yang didiagnosis karsinoma sel skuamosa serviks stadium IIIB yang mendapat radiasi lengkap periode 2016 – 2021 di RSCM memenuhi kriteria eligibilitas subjek penelitian ini. Pemeriksaan MRI pra-radiasi dan pasca radiasi serta ekspresi ALDH dengan imunohistokimiawi (Santa Cruz®) dilakukan pada 58 sampel blok paraffin. Respon terapi dinilai pada 3 bulan setelah radiasi. Kami membandingkan respon terapi komplet yang dihasilkan pada ekspresi ALDH rendah dan ekspresi ALDH tinggi. Analisis dilakukan dengan software SPSS.Hasil: Nilai titik potong optimal skor ALDH terhadap respon radiasi adalah 166,05 pg/mL yang diperoleh dari analisis kurva ROC. Nilai AUC menunjukkan hasil 0.682 dengan sensitivitas 63,6% dan spesifisitas 64,0%. Skor ALDH ≥166,05 meningkatkan risiko hingga 3,1 kali untuk tidak tercapainya respon komplet (adj OR 3,127, IK 95% 1,034 – 9,456, p = 0,043). Ukuran tumor pre-radiasi (p = 0,593), derajat diferensiasi (p = 0,161), kelainan ginjal pre-radiasi (0,114), dan keratinisasi (p = 0,477) tidak berhubungan dengan respon radiasi.Kesimpulan: Ekspresi ALDH yang tinggi berhubungan dengan respon radiasi tidak komplet pada karsinoma sel skuamosa serviks stadium IIIB. Pasien dengan skor ALDH ≥ 166,05 meningkatkan risiko tidak tercapainya respon komplet hingga 3,1 kali lebih tinggi dibandingkan dengan subjek dengan skor ALDH < 166,05.

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Background: ALDH is cancer stem cell marker that has radioresistance characteristic. This study aims to determine the association between ALDH1 and the radiation response of stage IIIB cervical squamous cell carcinoma.

Methods: A total 58 of 360 patients diagnosed with stage IIIB cervical squamous cell carcinoma who received complete radiation during 2016-2021 at the RSCM met the eligibility criteria for this study. Pre- and post-irradiation MRI examinations and ALDH expression with immunohistochemistry (Santa Cruz®) were performed on 58 paraffin block samples. Therapy response was assessed at 3 months after radiation. We compared the complete response resulting in low and high ALDH expression. The analysis was carried out with SPSS software.

Results: The optimal ALDH score cut-off point on the radiation response was 166.05 pg/mL which was obtained from the analysis of the ROC curve. The AUC value was 0.682 with sensitivity and specificity, 63,6% and 64%, respectively. ALDH score ≥166.05 increased the risk by 2.7 times for not achieving the complete response (OR = 2,656, IK 95% 0,844 – 8,356, p = 0,095). Pre-radiation tumor size (p = 0.593), degree of differentiation (p = 0.161), renal abnormalities (p = 0.114), and keratinization (p = 0.477) were not associated with radiation response.

Conclusions: High ALDH expression was associated with incomplete radiation response in squamous cell carcinoma of cervix stage IIIB"

"Angka kematian kanker serviks masih tinggi karena banyak pasien datang berobat pada tahap lanjut. Respons terapi radiasi pada pasien kanker serviks stadium lanjut bervariasi walau dengan faktor klinikopatologi yang sama seperti stadium, massa tumor, jenis histopatologi, derajat diferensiasi, invasi limfovaskular, reaksi limfosit dan nekrosis. Oleh karena itu dipikirkan faktor prognosis lain seperti faktor apoptosis-survivin, telomerase dan sitokrom c. Penelitian ini bertujuan untuk mengetahui peran survivin, telomerase, dan sitokrom c sebagai prediktor respons terapi radiasi pada kanker serviks stadium lanjut khususnya stadium IIIB.Studi ini bersifat prospektif menggunakan metode nested case control. Pengambilan data dilakukan di Poliklinik Onkologi Departemen Obstetri dan Ginekologi RSCM serta Departemen Patologi Anatomi FKUI pada bulan Januari 2016 hingga Mei 2017. Pada subjek penelitian dilakukan wawancara, pemeriksaan histopatologi dan pemeriksaan biokimia secara ELISA untuk mengetahui kadar survivin, telomerase, sitokrom c, dan MRI pra-radiasi serta pasca-radiasi. Dari 90 subjek penelitian didapatkan rerata usia pasien 50 tahun, rerata massa tumor 6,7 cm dan sebagian besar berkeratin 84,4 , berdiferensiasi baik 81,1 , reaksi limfosit negatif 75,6 dan nekrosis 74,4 . Rerata faktor apoptosis-survivin, telomerase dan sitokrom c adalah 591,2 pg/mL, 5.223,2 pg/mL dan 191,3 ng/mL. Dari analisis bivariat didapatkan variabel yang berhubungan dengan respons terapi secara independen adalah massa tumor p = 0,1 , diferensiasi p = 0,17 , kadar survivin p = 0,01 , kadar telomerase p = 0,08 dan kadar sitokrom c p = 0,47. Hasil analisis multivariat didapatkan hubungan kadar survivin dan kadar telomerase dengan respons terapi radiasi p = 0,01 dan p = 0,07 . Tidak terdapat hubungan kadar sitokrom c dengan respons terapi radiasi p = 0,64 . Dengan model cox regresi survival didapatkan hazard ratio subjek dengan kadar survivin tinggi dan kadar telomerase tinggi terhadap respons terapi radiasi negatif adalah 4,20 dan 1,97.Simpulan: kadar survivin dan telomerase tinggi berhubungan dengan respons terapi radiasi negatif.

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Cervical cancer mortality rate is still high mostly due to patients seeking for help in advanced stage of the disease. Even with the same clinicopathologic features such as stage of the diseases, size of the tumor, histopathological types, level of differentiation, lymphocyte reaction and tumor necrosis, the radiotherapy outcomes still vary from patient to patient. Therefore, we thought another predictive factors like apoptosis inducing factors i.e. survivin, telomerase and cytochrome c as a new predictor of therapeutic resp onses on patients with stage IIIB squamous cell carcinoma of cervix.

This is a prospective study with nested case control method. Data collection was conducted in Oncology Polyclinic, Department of Obstetrics and Gynecology RSCM and Department of Pathological Anatomy of FKUI from January 2016 to May 2017. Subjects were interviewed, conducted histopathological and biochemical examination with ELISA to determine levels of survivin, telomerase, cytochrome c, and patients undergo pre and post radiation MR imaging.

There were 90 patients in this study with the mean of ages was 50 years, mean of tumor size was 6.7 cm and most subjects were keratinizing 84.4 , well differentiated 81.1 , negative lymphocyte reaction 75.6 and tumor necrosis 74.4 . The mean levels of apoptosis inducing factors survivin, telomerase and cytochrome c were 591.2 pg mL, 5,223.2 pg mL, and 191.3 ng mL.

Bivariate analysis showed the independent association between tumor size, level of differentiation, levels of survivin and telomerase p 0.1, p 0.17, p 0.01, p 0.08 . Multivariate analysis showed the correlation between levels of survivin and telomerase with radiation therapeutic response p 0.01 and p 0.07 and there was no association with level of cytochrome c p 0.64 With the survival cox regression models, the hazard ratio of subjects with high levels of survivin and telomerase on the negative radiation therapy responses were 4.20 and 1.97.Conclusion there were association between high levels of survivin and telomerase on the negative radiation therapy response. "

"Latar belakang: Kanker serviks merupakan kanker terbanyak ketiga diderita oleh perempuan dengan morbiditas dan mortalitas tinggi. Tatalaksana kanker serviks stadium lanjut dengan radiasi baik itu radiasi saja maupun kemoradiasi. Overall survival (OS)dan disease free survival (DFS) pada kanker serviks stadium lanjut dengan histologi karsinoma sel skuamosa (KSS) dan adenokarsinoma (AK) berbeda pada beberapa penelitian. Begitu juga dengan terjadinya kekambuhanTujuan: (1) Mengetahui OS pada jenis histologi KSS dan AK kanker serviks stadium lanjut (2) Mengetahui DFS kanker serviks stadium lanjutMetode: Penelitian ini menggunakan studi kohort retrospektif menggunakan data rekam medis pasien kanker serviks stadium IIB hingga IVA dengan histologi KSS dan AK pada tahun 2008 hingga 2013. Pengamatan dilakukan saat subjek pertama kali didiagnosis kanker ovarium hingga terjadi peristiwa hidup, meninggal, atau hilang dari pengamatan dalam waktu 120 bulan.Hasil: Dari 518 pasien yang memenuhi kriteria, 426 pasien dengan jenis histologi KSS, 92 pasien dengan jenis AK. Hasil dari uji log rank p value=0,07 menunjukkan tidak ada perbedaan bermakna OS KSS dan AK dengan probabilitas kumulatif 42% pada bulan ke 120 Uji chi square didapati perbedaan bermakna p=0,042 terjadinya relaps pada AK dan KSS sbesar 26,1% dan 16,4%.Kesimpulan: Tidak ada perbedaan bermakna antara karsinoma sel skuamosa dan adenokarsinoma secara overall survival pada kanker serviks stadium lanjut dan terdapat perbedaan bermakna disease free survival pada kedua jenis histologi tersebut.

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Background: Cervical cancer is the third most common cancer among women with high morbidity and mortality. Management of advanced stage cervical cancer with radiation be it radiation alone or chemoradiation. Overall survival (OS) and disease free survival (DFS) in advanced cervical cancer with histology of squamous cell carcinoma (KSS) and adenocarcinoma (AK) differ in several studies. Likewise with recurrence Objectives: (1) Knowing OS in the type of histology of SCC and AK in advanced cervical cancer (2) Knowing DFS in advanced cervical cancerMethod: This study used a retrospective cohort using data from medical records of stage IIB to IVA cervical cancer patients with histology of SCC and AK in 2008 to 2013. Observations were made when the subject was first diagnosed with ovarian cancer until a life event, death, or disappear from observation in time 120 monthsResults: Of the 518 patients who met the criteria, 426 patients with type of KSS histology, 92 patients with type AK. The results of the log rank test p value = 0.07 showed no significant difference in OS KSS and AK with a cumulative probability of 42% in the 120th month 16.4%.Conclusion: There was no significant difference OS between SCC and AC in advanced stage of cervical cancer and there were significant differences in disease free survival in the two types of histology"