OBJECTIVE: "Multi-targeting" drugs can prove fruitful to combat drug-resistance of multifactorial disease-cervical cancer. This study envisioned to reveal if Thuja homeopathic mother tincture (MT) and its bioactive component could combat human papillomavirus (HPV)-16-infected SiHa cervical cancer cells since it is globally acclaimed for HPV-mediated warts. METHODS: Thuja MT was studied for its antiproliferative and antimigratory properties in SiHa cells followed by microscopic determination of reactive oxygen species (ROS) generation by 2',7'-dichlorodihydrofluorescein diacetate (DCFDA) staining and loss in mitochondrial membrane potential (MtMP) by rhodamine 123 (Rh123) staining. Apoptosis and autophagy inductions were studied by acridine orange/ethidium bromide (AO/EB) staining and immunoblot analyses of marker proteins. The bioactive component of Thuja MT detected by gas chromatography-mass spectrometry was studied for antiproliferative and antimigratory properties along with in silico prediction of its cellular targets by molecular docking and oral drug forming competency. RESULTS: Thuja MT showed significant antiproliferative and antimigratory potential in SiHa cells at a 50% inhibitory concentration (IC₅₀) of 17.3 µL/mL. An increase in DCFDA fluorescence and loss in Rh123 fluorescence prove that Thuja MT acted through the burst of ROS and loss in MtMP respectively. AO/EB-stained cells under the microscope and immunoblot analyses supported Thuja-induced cellular demise via dual pathways-apoptosis and autophagy. Immunoblots showed cleavage of caspase-3 and poly(adenosine diphosphate-ribose) polymerase-1 (PARP-1) along with upregulation of Beclin-1, microtubule-associated protein 1 light chain 3B (LC3B)-II, and p62 proteins. Hence, the apoptotic cascade followed a caspase-3-dependent pathway supported by PARP-1 cleavage, while autophagic death was Beclin-1-dependent and mediated by accumulation of LC3BII and p62 proteins. Thujone, detected as the bioactive principle of Thuja MT, showed greater anti-proliferative and anti-migratory potential at an IC₅₀ of 77 µg/mL, along with excellent oral drug competency with the ability for gastrointestinal absorption and blood-brain-barrier permeation with nil toxicity. Molecular docking depicted thujone with the strongest affinity for mammalian target of rapamycin, phosphoinositide 3-kinase, and protein kinase B followed by B-cell lymphoma 2, murine double minute 2 and adenosine monophosphate-activated protein kinase, which might act as upstream triggers of apoptotic-autophagic crosstalk. CONCLUSION Robust "multi-targeting" anticancer potential of Thuja drug and thujone for HPV-infected cervical cancer ascertained its therapeutic efficacy for HPV infections.
Animals ; Apoptosis ; Autophagy ; Beclin-1/pharmacology* ; Bicyclic Monoterpenes ; Caspase 3 ; Cell Line, Tumor ; Female ; Humans ; Mammals/metabolism* ; Mice ; Molecular Docking Simulation ; Papillomavirus Infections/drug therapy* ; Phosphatidylinositol 3-Kinases ; Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use* ; Reactive Oxygen Species/metabolism* ; Thuja/metabolism* ; Uterine Cervical Neoplasms/pathology*

OBJECTIVE: We aimed to assess the efficacy of neoadjuvant chemotherapy followed by surgery (NACT+S), and compared the clinical outcome with that of concurrent chemoradiotherapy (CCRT) in patients with International Federation of Gynecology and Obstetrics (FIGO) IB-IIB cervical cancer. METHODS: We reviewed 85 patients with FIGO IB-IIB cervical cancer who received NACT+S between 1989 and 2012, and compared them to 358 control patients who received CCRT. The clinical application of NACT was classified based on the following possible therapeutic benefits: increasing resectability after NACT by reducing tumor size or negative conversion of node metastasis; downstaging adenocarcinoma regarded as relatively radioresistant; and preservation of fertility through limited surgery after NACT. RESULTS: Of 85 patients in the NACT+S group, the pathologic downstaging and complete response rates were 68.2% and 22.6%, respectively. Only two young patients underwent limited surgery for preservation of fertility. Patients of the NACT+S group were younger, less likely to have node metastasis, and demonstrated a higher proportion of FIGO IB cases than those of the CCRT group (p≤0.001). The 5-year locoregional control, progression-free survival, and overall survival rates in the NACT+S group were 89.7%, 75.6%, and 92.1%, respectively, which were not significantly different from the rates of 92.5%, 74%, and 84.9% observed in the CCRT group, respectively (p>0.05). CONCLUSION: NACT+S has no therapeutic advantages over CCRT, the standard treatment. Therefore, NACT+S should be considered only in selected patients through multidisciplinary discussion or clinical trial setting.
Adult ; Aged ; Aged, 80 and over ; *Chemoradiotherapy ; Chemotherapy, Adjuvant ; Female ; Humans ; *Hysterectomy ; Middle Aged ; *Neoadjuvant Therapy ; Neoplasm Staging ; Retrospective Studies ; Treatment Outcome ; Uterine Cervical Neoplasms/diagnosis/mortality/pathology/*therapy

OBJECTIVETo investigate the relationship between sensitivity to cisplatin (DDP) and the expression of HSP70 in cervical cancer cells in vitro.

METHODSCervical cancer Hela229 cells treated with different concentrations of DDP and the HSP70 inhibitor (PFT-µ) were examined for cell viability using MTT assay and colony forming ability. The cell apoptosis was analyzed by flow cytometry with propidium iodide staining and DAPI staining, and JC-1 staining was used to determine mitochondrial membrane potential. The expressions of HSP70, Bcl-2, Bax and caspase-3 were measured with Western blotting. A nude mouse model bearing Hela229 cell xenograft was used to evaluate the effect of DDP and PFT-µ on tumor growth.

RESULTSHela229 cells expressed a higher level of HSP70 than normal cervical cells. The combined use of PFT-µ significantly enhanced the inhibitory effect of DDP (P<0.01) and increased the cell apoptosis in Hela229 cells. JC-1 staining demonstrated that DDP combined with PFT-µ more obviously reduced mitochondrial membrane potential. DDP combined with PFT-µ more strongly lowered Bcl-2 expression and increased the expressions of casepase-3 and Bax than DDP alone. In the nude mouse model, PFT-µ significantly enhanced DDP sensitivity of Hela229 cell xenografts (P<0.01).

CONCLUSIONSInhibition of HSP70 expression can enhance the sensitivity of cervical cancer cell to DDP both in vivo and in vitro possibly by promoting cell apoptosis, suggesting the potential of HSP70 as a new target for gene therapy of cervical cancer.

Animals ; Antineoplastic Agents ; pharmacology ; Apoptosis ; Caspase 3 ; metabolism ; Cell Proliferation ; Cell Survival ; Cisplatin ; pharmacology ; Drug Resistance, Neoplasm ; Female ; HSP70 Heat-Shock Proteins ; antagonists & inhibitors ; HeLa Cells ; Humans ; Membrane Potential, Mitochondrial ; Mice ; Proto-Oncogene Proteins c-bcl-2 ; metabolism ; Sulfonamides ; pharmacology ; Uterine Cervical Neoplasms ; drug therapy ; pathology ; Xenograft Model Antitumor Assays ; bcl-2-Associated X Protein ; metabolism

OBJECTIVE: The aim of the study was to establish a predictive model of survival period after bone metastasis from cervical cancer. METHODS: A total of 54 patients with bone metastasis from cervical cancer were included in the study. Data at the time of bone metastasis diagnosis, which included presence of extraskeletal metastasis, performance status, history of any previous radiation or chemotherapy, the number of bone metastases, onset period, and treatment were collected. Survival data were analyzed using Kaplan-Meier method and Cox proportional hazards model. RESULTS: The median survival period after diagnosis of bone metastasis was 22 weeks (5 months). The 26- and 52-week survival rates after bone metastasis were 36.5% and 15.4%, respectively. Cox regression analysis showed that extraskeletal metastasis (hazard ratio [HR], 6.1; 95% CI, 2.2 to 16.6), performance status of 3 to 4 (HR, 7.8; 95% CI, 3.3 to 18.2), previous radiation or chemotherapy (HR, 3.3; 95% CI, 1.4 to 7.8), multiple bone metastases (HR, 1.9; 95% CI, 1.0 to 3.5), and a bone metastasis-free interval of <12 months (HR, 2.5; 95% CI, 1.2 to 5.3) were significantly and independently related to poor survival. A prognostic score was calculated by adding the number of each significant factor. The 26-week survival rates after diagnosis of bone metastasis were 70.1% in the group with a score ≤2, 46.7% in the group with a score of 3, and 12.5% in the group with a score ≥4 (p<0.001). CONCLUSION: This scoring system provided useful prognostic information on survival of patients with bone metastasis of cervical cancer.
Adult ; Aged ; Aged, 80 and over ; Bone Neoplasms/*mortality/*secondary/therapy ; Female ; Humans ; Kaplan-Meier Estimate ; Middle Aged ; Neoplasm Staging ; Proportional Hazards Models ; Survival Rate ; United States/epidemiology ; Uterine Cervical Neoplasms/*pathology/therapy

OBJECTIVE: This is a retrospective study aimed at clarifying the details of recurrence patterns and sites in patients with cervical cancer treated with definitive radiation therapy (RT). METHODS: Data were analyzed from consecutive patients, admitted to the University of Tokyo Hospital (Tokyo, Japan) between 2001 and 2013, who had received definitive RT, with or without chemotherapy, for International Federation of Gynecology and Obstetrics stages IB-IVA cervical cancer. RESULTS: One hundred and thirty-seven patients formed the patient cohort. The median follow-up period for surviving patients was 57.0 months. A complete response was achieved in 121 patients (88%). Of these, 36 (30%) developed a cancer recurrence during follow-up. The first sites of recurrence were located in intra-RT fields in nine, outside RT fields in 20, and both in seven patients. In the intra-RT field group, all patients showed a local recurrence, while no one experienced an isolated pelvic lymph node (PLN) recurrence. In the outside RT field group, the most frequent site of recurrence was lung (60%), and three-quarters of patients were free from intra-RT field recurrence until the last follow-up. Of the entire cohort, including 48 PLN-positive patients, only seven patients (5.1%) developed PLN persistence or recurrence, all in the common iliac, internal iliac, and/or obturator nodes, and all with another synchronous relapse. CONCLUSION: Local disease was a major type of intra-RT field recurrence, while PLN control was favorable even in initially PLN-positive patients. The predominance of outside RT field recurrence alone highlights issues concerning distant control, including the intensity enhancement of systematic therapy.
Adenocarcinoma/drug therapy/*radiotherapy/secondary ; Adult ; Aged ; Aged, 80 and over ; Antineoplastic Agents/therapeutic use ; Brachytherapy ; Carcinoma, Squamous Cell/drug therapy/*radiotherapy/secondary ; Chemoradiotherapy ; Disease-Free Survival ; Dose Fractionation ; Female ; Follow-Up Studies ; Humans ; Lung Neoplasms/*secondary ; Lymphatic Metastasis ; Middle Aged ; Neoplasm Recurrence, Local/*diagnosis ; Pelvis ; Retrospective Studies ; Survival Rate ; Uterine Cervical Neoplasms/drug therapy/pathology/*radiotherapy

Cervical cancer is one of the most common cancers in women worldwide. The outcome of patients with metastatic cervical cancer is poor. We reviewed the relevant literature concerning the treatment and diagnosis of metastatic cervical cancer. There are two types of metastasis related to different treatments and survival rates: hematogenous metastasis and lymphatic metastasis. Patients with hematogenous metastasis have a higher risk of death than those with lymphatic metastasis. In terms of diagnosis, fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) and PET-computed tomography are effective tools for the evaluation of distant metastasis. Concurrent chemoradiotherapy and subsequent chemotherapy are well-tolerated and efficient for lymphatic metastasis. As for lung metastasis, chemotherapy and/or surgery are valuable treatments for resistant, recurrent metastatic cervical cancer and chemoradiotherapy may be the optimal choice for stage IVB cervical cancer. Chemotherapy and bone irradiation are promising for bone metastasis. A better survival is achieved with multimodal therapy. Craniotomy or stereotactic radiosurgery is an optimal choice combined with radiotherapy for solitary brain metastases. Chemotherapy and palliative brain radiation may be considered for multiple brain metastases and other organ metastases.
Bone Neoplasms/secondary/therapy ; Brain Neoplasms/secondary/therapy ; Chemoradiotherapy ; Female ; Fluorodeoxyglucose F18 ; Humans ; Lung Neoplasms/secondary/therapy ; Lymphatic Metastasis ; Positron-Emission Tomography ; Uterine Cervical Neoplasms/diagnostic imaging/*pathology/therapy

Cervical cancer is one of the most common cancers in women worldwide. The outcome of patients with metastatic cervical cancer is poor. We reviewed the relevant literature concerning the treatment and diagnosis of metastatic cervical cancer. There are two types of metastasis related to different treatments and survival rates: hematogenous metastasis and lymphatic metastasis. Patients with hematogenous metastasis have a higher risk of death than those with lymphatic metastasis. In terms of diagnosis, fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) and PET-computed tomography are effective tools for the evaluation of distant metastasis. Concurrent chemoradiotherapy and subsequent chemotherapy are well-tolerated and efficient for lymphatic metastasis. As for lung metastasis, chemotherapy and/or surgery are valuable treatments for resistant, recurrent metastatic cervical cancer and chemoradiotherapy may be the optimal choice for stage IVB cervical cancer. Chemotherapy and bone irradiation are promising for bone metastasis. A better survival is achieved with multimodal therapy. Craniotomy or stereotactic radiosurgery is an optimal choice combined with radiotherapy for solitary brain metastases. Chemotherapy and palliative brain radiation may be considered for multiple brain metastases and other organ metastases.
Bone Neoplasms/secondary/therapy ; Brain Neoplasms/secondary/therapy ; Chemoradiotherapy ; Female ; Fluorodeoxyglucose F18 ; Humans ; Lung Neoplasms/secondary/therapy ; Lymphatic Metastasis ; Positron-Emission Tomography ; Uterine Cervical Neoplasms/diagnostic imaging/*pathology/therapy

Adenocarcinoma, Clear Cell ; diagnosis ; etiology ; therapy ; Cervix Uteri ; pathology ; Child ; Diethylstilbestrol ; Fatal Outcome ; Female ; Humans ; Magnetic Resonance Imaging ; Pregnancy ; Prenatal Exposure Delayed Effects ; Uterine Cervical Neoplasms ; diagnosis ; etiology ; therapy

OBJECTIVE: To evaluate the efficacy and tolerability of a neoadjuvant paclitaxel, ifosfamide, and cisplatin chemotherapy in patients with locally advanced cervical carcinoma. METHODS: Patients with histologically confirmed locally advanced cervical carcinoma, aged > or =18 years, were treated with intravenous ifosfamide 5,000 mg/m2 and mesna 5,000 mg/m2, on day 1; intravenous paclitaxel 175 mg/m2 and cisplatin 75 mg/m2, on day 2; every 3 weeks for three cycles. Following chemotherapy, operable patients underwent radical hysterectomy and pelvic lymphadenectomy, and, if necessary, adjuvant radiotherapy. RESULTS: One hundred fifty-two patients with median age 53 years (range, 24 to 79 years), FIGO stage IIB in 126 (89%), were treated with chemotherapy for median 3 cycles (range, 1 to 3). Treatment was delayed or withdrawn in 23 patients (15%). One hundred thirty-nine patients (91%) underwent surgery. Postchemotherapy pathological complete response rate was 18% (25 patients). Postoperative radiotherapy was administered in 100 patients (72%). The 5-year overall survival and progression-free survival were 87.3% (95% confidence interval [CI], 84.5 to 90.3) and 76.4% (95% CI, 73.5 to 79.5), respectively. CONCLUSION: Neoadjuvant paclitaxel, ifosfamide, and cisplatin chemotherapy was feasible and effective in the treatment of locally advanced cervical carcinoma patients with older age and more advanced disease stage than reported in previous studies. Hematological and renal toxicity could be carefully prevented.
Adult ; Aged ; Antineoplastic Combined Chemotherapy Protocols/*therapeutic use ; Carcinoma, Squamous Cell/*drug therapy/mortality/pathology ; Cisplatin/*administration & dosage/adverse effects ; Disease Progression ; Feasibility Studies ; Female ; Humans ; Ifosfamide/*administration & dosage/adverse effects ; Middle Aged ; Neoadjuvant Therapy ; Paclitaxel/*administration & dosage/adverse effects ; Retrospective Studies ; Treatment Outcome ; Uterine Cervical Neoplasms/*drug therapy/mortality/pathology ; Young Adult

OBJECTIVE: Concurrent chemoradiotherapy (CCRT) is the primary treatment for locally advanced cervical cancer. We studied prognostic factors for patients treated with CCRT. METHODS: We retrospectively reviewed records of 85 consecutive patients with cervical cancer who were treated with CCRT between 2002 and 2011, with external beam radiation therapy, intracavitary brachytherapy, and platinum-based chemotherapy. Survival data were analyzed with Kaplan-Meier methods and Cox proportional hazard models. RESULTS: Of the 85 patients, 69 patients (81%) had International Federation of Gynecology and Obstetrics (FIGO) stage III/IV disease; 25 patients (29%) had pelvic lymph node enlargement (based on magnetic resonance imaging), and 64 patients (75%) achieved clinical remission following treatment. Median maximum tumor diameter was 5.5 cm. The 3- and 5-year overall survival rates were 60.3% and 55.5%, respectively. Cox regression analysis showed tumor diameter >6 cm (hazard ratio [HR], 2.3; 95% confidence interval [CI], 1.2 to 4.6), pelvic lymph node enlargement (HR, 2.2; 95% CI, 1.1 to 4.5), and distant metastasis (HR, 10.0; 95% CI, 3.7 to 27.0) were significantly and independently related to poor outcomes. CONCLUSION: New treatment strategies should be considered for locally advanced cervical cancers with tumors >6 cm and radiologically enlarged pelvic lymph nodes.
Adult ; Aged ; Aged, 80 and over ; Brachytherapy/adverse effects/methods ; Chemoradiotherapy/adverse effects/*methods ; Female ; Humans ; Kaplan-Meier Estimate ; Lymphatic Metastasis ; Middle Aged ; Prognosis ; Proportional Hazards Models ; Retrospective Studies ; Treatment Outcome ; Uterine Cervical Neoplasms/diagnosis/pathology/*therapy