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Drug repurposing for cancer therapy is currently a hot topic of research. Theoretically, in contrast to the known hurdles of developing new molecular entities, the approach of repurposing has several advantages. Mostly, it is said that it is faster, safer, easier, and cheaper. In the real world, however, there are only three repurposed drugs so far, that are listed in widely recognized cancer guidelines, but a large number of them are being studied. Among the many barriers to repurposing cancer drugs, economical-driven are the most important that difficult the clinical development of them. In this review, we provide an overview of the current status of drug repurposing for cancer therapy and the barriers that need to be overcome to realize the benefit of this approach. It means to have repositioned drugs for cancer therapy accepted as standard therapy for cancer indications at low cost.

Introduction: Beyond early stages of cervical cancer (1A1, IA2, IB1, IIA1,), locally advanced disease (IB2, IIA2, IIA2, IIB, IIIA, IIIB, IIIC, IVA) and advanced (metastatic, recurrent or pe...

It is estimated that up to 10% of gastric carcinomas show familial aggregation. In contrast, around 1-3 % (approximately 33,000 yearly) are genuinely hereditary. Hereditary diffuse gastric cancer (HDGC) is a rare malignancy characterized by autosomal dominant inheritance of pathological variants of the CDH1 and CTNNA1 genes encoding the adhesion molecules E-cadherin and α-catenin, respectively. The multifocal nature of the disease and the difficulty of visualizing precursor lesions by endoscopy underscore the need to be aware of this malignancy as surgical prevention can be fully protective. Here, we provide an overview of the main epidemiological, clinical, genetic, and pathological features of HDGC, as well as updated guidelines for its diagnosis, genetic testing, counseling, surveillance, and management. We conclude that HDGC is a rare, highly penetrant disease that is difficult to diagnose and manage, so it is necessary to correctly identify it to offer patients and their families’ adequate management following the recommendations of the IGCL. A critical point is identifying a mutation in HDGC families to determine whether unaffected relatives are at risk for cancer.

Background Novel prognostic factors in patients with diffuse large B-cell lymphoma (DLBCL) are required in the era of Rituximab. Objective The objective of the study was to study the prognostic impact of exon-16 enhancer-of-zeste homolog-2 (EZH2) mutations in patients with DLBCL. Methods In a cohort of patients with DLBCL treated between 2015 and 2017, we analyzed the presence of EZH2 mutations and their association with clinical response (CR), relapse, progression-free survival (PFS), and overall survival (OS). Results A total of 198 patients were included; of them, 30 (15.2%) had mutations at codon 641, in exon 16 of EZH2. Response was achieved in 151 patients (76.3%), and 43 (21.7%) relapsed or progressed during follow-up. EZH2 mutations were associated with relapse/progression (risk ratio [RR] 1.18; 95% confidence interval [CI] 0.98-1.42; p = 0.031), while a trend for not achieving a complete response was observed (RR: 0.876; 95%CI 0.74-1.038; p = 0.071). Of note, Tyr641His and Tyr641Ser EZH2 mutations were associated with shorter PFS (hazard ratio 3.234; 95% CI 1.149-9.1; p = 0.026). Conclusion The presence of EZH2 mutations was negatively associated with relapse/progression and showed a trend for lack of complete response. Further studies are needed to define better the prognostic significance of these mutations in Mexican-Mestizo DLBCL patients.

Background: Diffuse large B-cell lymphoma (DLBCL) is the most frequent non-Hodgkin lymphoma worldwide. The current standard of care is chemoimmunotherapy with an R-CHOP regimen. We aim to review the role of this regimen after two decades of being the standard of care. Methods: A comprehensive literature review of DLBCL, including the epidemiology, trials defining R-CHOP as the standard of care, as well as dose intensification and dose reduction schemes. Additionally, we briefly review the development of rituximab biosimilars and the addition of targeted drugs to R-CHOP in clinical trials. Discussion: R-CHOP cures approximately 70% of DLBCL patients. Dose-dense regimens do not show a benefit in response and increase toxicity. Dose reduction, particularly in elderly patients or with comorbidities, may be a treatment option. DLBCL constitutes a group of diseases that activate different biological pathways. Matching specific treatments to a defined genetic alteration is under development. Rituximab biosimilars have become available to a broader population, particularly in developing countries, where access to treatment is limited because of economic resources. Conclusion: DLBCL landscape is heterogeneous. R-CHOP immunochemotherapy has been a standard of care for two decades and cures approximately 70% of cases. Molecular characterization of patients is evolving and may have critical therapeutic implications.

Cervical cancer (CC) is one of the most common gynecological tumors and an important health problem, especially in developing countries. The vast majority of patients in early stages are cured of the disease with surgical treatment and with concomitant chemoradiotherapy in locally advanced stages. However, in patients with recurrent, persistent, or metastatic cervical CC, the effectiveness of treatment is limited, except for the combination of chemotherapy based on platinum doublets plus bevacizumab, the treatment that has achieved the best results to date. Programmed cell death-1/PD ligand-1 (PD-1/PD-L1) inhibitors could be a novel and cutting-edge therapeutic option to improve clinical outcomes in this group of patients. Thus far, there are a few Phase I/II clinical trials that have assessed the usefulness of pembrolizumab and nivolumab in this group of patients; these include the KEYNOTE 028, KEYNOTE 158, and CHECKMATE 358 trials, in which clinical benefit has been proven with PD-1/PD-L1 inhibitors in recurrent, persistent, or metastatic CC, as second-line treatment. There are also some ongoing trials that could provide further evidence on the PD-1/PD-L1 pathway as a therapeutic target in CC. In this review, we will focus on the usefulness of these PD-1/PDL1 inhibitors in CC, as well as on trials that are still in the recruitment phase, to confirm their effectiveness in this clinical setting.

Background The increasing survival of patients with non-Hodgkin lymphoma has allowed the diagnosis of long-term com- plications, including late-onset hematological toxicity (LOHT), transitory cytopenias, or therapy-related myeloid neoplasm (t-MDS/t-AML). Objective The objective of the study was to determine the frequency and clinical evolution of LOHT in patients with lymphoproliferative malignancies. Materials and methods Two cohorts of patients B-cell lymphomas were reviewed. Patients who achieved full hematologic recovery at the end of treatment, and thereafter developed any degree of cytopenia were included in the study. Clinical and biochemical parameters were compared between patients with and without cytopenias with X2 test. Bi-and multivariate analyses were performed to evaluate factors associated with the development of late-onset cytopenias. Results Of 758 patients enrolled, 19 developed cytopenias (2.5%). Transitory cytopenia was documented in 6 cases, 3 developed ICUS, 8 t-MDS, and 2 t-AML. In patients with FL, only hemoglobin 6 nodal areas (p = 0.037) at diagnosis were factors statistically significant for the development of cytopenia. During cytopenias, 55% of patients died. Conclusions LOHT constitutes a cause of morbidity and mortality in 2.5% of lymphoma patients treated with different therapy regimens.

Cervical cancer is the fourth most common cancer in women with 85% of the mortality burden occurring in less-developed regions of the world. The Cervix Cancer Research Network (CCRN) was founded by the Gynecologic Cancer InterGroup (GCIG) with a mission to improve outcomes in cervix cancer by increasing access to high-quality clinical trials worldwide, with particular attention to less-developed, underrepresented sites. The CCRN held its second international educational symposium in Mexico City with ninety participants from fifteen Latin America countries in January 2017. The purpose of this symposium was to advance knowledge in cervix cancer therapy, promote recruitment to CCRN clinical trials, and to identify relevant future CCRN clinical trial concepts that could improve global care standards for women with cervical cancer., Highlights • Cervix cancer is the fourth most common cancer in women worldwide with up to an 18-fold disparity in mortality rates. • The Cervix Cancer Research Network (CCRN) aims to increase access to clinical trials in order to improve outcomes for women. • The 2nd CCRN international symposium was held in Mexico City including 90 participants from 15 Latin American countries. • CCRN clinical trials were discussed, including new trials proposed of hypofractionation and HPV targeted therapy.

Objective To describe the ultrasound, histopathological and genetic characteristics of uveal melanoma in a Mexican-Mestizo population. Material and methods A total of 39 enucleated eyes with a histopathological diagnosis of uveal melanoma were assessed by describing the clinical findings, and ultrasound, histopathological and genetic features. Results A high correlation was observed between tumor height measurement using ultrasound and histopathology. In our cases, tumor size and reflectivity were higher compared with those reported in the literature. The preliminary data on the molecular assessment of the tumors show the presence of an unreported polymorphism (T>C IVS5+34) and one sample with GNAQ mutation (A>C CAA>CCA Gln 209 Pro). Conclusion Ultrasound is a reliable method to identify the size of the tumor. Furthermore, knowledge of the molecular mechanisms promises new perspectives for the development of new targeted therapeutics. Fortunately this leads to progress in the treatment of patients with metastatic disease or prevents it in those at high risk.

Objectives To evaluate the activity and safety of hydralazine and valproate (Transkrip) in cutaneous T-cell lymphoma (CTCL). Methods Previously untreated and progressive/refractory CTCL patients received hydralazine at 83 mg or 182 mg/day for slow and rapid acetylators respectively plus magnesium valproate at a total dose of 30 mg/Kg t.i.d daily in continuous 28-day cycles in this phase II study. The primary objective was overall response rate (ORR) measured by the modified severity weighted assessment tool (m-SWAT), secondary end-points were time to response (TTR), time to progression (TTP), duration of response (DOR), progression-free survival (PFS), overall survival (OS) and safety. Results Fourteen patients were enrolled (7 untreated and 7 pretreated). ORR was 71% with 50% complete and 21% partial. Two had stable disease and two progressed. At a median follow-up of 36 months (5-52), median TTR was 2 months (1-4); median DOR was 28 months (5-45); median PFS 36 and not reached for OS. There were no differences in median TTR, DOR, and PFS between treated and pretreated patients. Pruritus relieve was complete in 13 out of 14 patients. No grade 3 or 4 toxicities were observed. Conclusion The combination of hydralazine and valproate is safe, very well tolerated and effective in CTCL.

The treatment of some early-stage and most locally advanced disease cervical cancer patients consists of concurrent chemoradiation, while almost all with advanced disease require palliative chemotherapy.This review is aimed to analyze the safety issues emerging from trials of chemoradiation for early-stage high-risk disease and locally advanced stages, as well as safety issues of trials of palliative chemotherapy for advanced disease. Safety issues on fertility preservation are also discussed.Cisplatin chemoradiation produces higher toxicity as compared to radiation alone, yet it is well-tolerated. Further advances would require (i) the development of more effective and tolerated combination chemoradiation regimens, (ii) demonstration of the efficacy and tolerability of adjuvant chemotherapy after cisplatin chemoradiation, and (iii) incorporation of targeted therapies into radiosensitizing regimens. A major problem continues to be the population of patients with advanced disease. The recent incorporation of bevacizumab into chemotherapy regimens represents a step forward; however, toxicity as well as economic issues may impede its wide acceptance worldwide. Preserving fertility in young women with cervical cancer is an issue that must be fully addressed. In this setting, neoadjuvant chemotherapy seems to increase fertlity rate without compromising oncological outcomes.

Cancer patients are particularly susceptible to undernourishment so associated weight loss is frequent. Approximately 15% of patients lose >10% of their usual body weight, 40-80% become undernourished, and about 20% die as a result. Well-nourished patients have a higher survival rate when compared with patients at risk of undernourishment (19.9 vs. 3.7 months); hence, nutritional intervention is pivotal. Undernourishment negatively influences the patient's prognosis, and its prevalence depends on the tumor type and location, disease stage, treatment, and the applied nutritional evaluation tool. During abdominopelvic radiotherapy, up to 90% of patients experience symptoms of varying severity; weight loss during radiotherapy is an early indicator of nutritional deterioration, and he the use of radiation is associated with a higher likelihood of undernourishment. In patients with gynecological malignancies, 12.5-54% are malnourished before receiving oncological treatment, worsening after treatment in 35.8-82% of cases. There is also deterioration of the nutritional status in patients with colorectal cancer once pelvic radiotherapy is initiated, whereby 50% of cases are malnourished at the beginning of treatment, and 66.7% are so when it ends. Although there are notable differences in the impact of radiotherapy on weight according to the radiated region, 88% patients receiving abdominal radiotherapy were found to lose weight compared to 38% of patients whose treatment was limited to the pelvis.

Nimotuzumab is a humanized IgG1 monoclonal antibody against the EGFR extracellular domain that has been evaluated in solid tumors as a single agent or in combination with chemotherapy and radiation. Cervical cancer patients who are refractory or progressive to first-line chemotherapy have a dismal prognosis, and no second- or third-line chemotherapy is considered standard. This pilot trial aimed to evaluate the efficacy and safety of nimotuzumab in 17 patients with pre-treated advanced refractory or progressive cervical cancer. Nimotuzumab was administered weekly at 200 mg/m(2) as single agent for 4 weeks (induction phase), then concurrent with 6 21-day cycles of gemcitabine (800 mg/m(2)) or cisplatin (50 mg/m(2)) for 18 weeks (concurrent phase) and then once every 2 weeks (maintenance phase). Nimotuzumab could be continued beyond disease progression. Seventeen patients were accrued and evaluated for safety and efficacy. The median number of nimotuzumab applications was 20 (5-96). The median number of chemotherapy cycles administered was 6 (1-6). No toxicity occurred during induction and maintenance phases (single agent nimotuzumab). In the concurrent phase, grade 3 toxicity events observed were leucopenia, anemia and diarrhea in 11.7%, 5.8% and 11.7% respectively. No complete or partial responses were observed. The stable disease (SD) rate was 35%. The median PFS and OS rates were 163 days (95% CI, 104 to 222), and 299 days (95% IC, 177 to 421) respectively. Nimotuzumab is well tolerated and may have a role in the treatment of advanced cervical cancer.

Worldwide, most cervical cancer (CC) patients require the use of drug therapy either adjuvant, concurrent with radiation or palliative.This review briefly discusses the current achievements in treating CC with an emphasis in emerging agents.Concurrent cisplatin with radiation and lately, gemcitabine-cisplatin chemoradiation has resulted in small but significant improvements in the treatment of locally advanced and high-risk early-stage patients. So far, only antiangiogenic therapy with bevacizumab added to cisplatin chemoradiation has demonstrated safety and encouraging results in a Phase II study. In advanced disease, cisplatin doublets yield median survival rates not exceeding 14 months. The first Phase III study of bevacizumab, added to standard chemotherapy cisplatin- or non-cisplatin-containing doublet, has shown significant increase in both overall survival and progression-free survival. Further studies are needed before bevacizumab plus chemotherapy can be considered the standard of care for advanced disease. The characterization of the mutational landscape of CC and developments of novel targeted therapies may result in more effective and individualized treatments for CC. The potential efficacy of knocking down the key alterations in CC, E6 and E7 human papilloma virus oncoproteins must not be overlooked.

Cervical cancer is the third most commonly diagnosed cancer worldwide and the fourth leading cause of cancer death in women. Major advances but still insufficient achievements in the treatment of locally advanced and high-risk early stage patients have occurred in the last decade with the incorporation of concurrent cisplatin with radiation and, lately, gemcitabine added to cisplatin chemoradiation. Despite a number of clinical studies incorporating molecular-targeted therapy as radiosensitizers being in progress, so far, only antiangiogenic therapy with bevacizumab added to cisplatin chemoradiation has demonstrated safety and shown encouraging results in a Phase II study. In advanced disease, cisplatin doublets do not have a great impact on the natural history of the disease with median survival rates not exceeding 13 months. The first Phase III study of bevacizumab, added to cisplatin or a non-cisplatin-containing doublet, showed significant increase in both overall survival and progression-free survival. Further studies are needed before bevacizumab plus chemotherapy can be considered the standard of care for advanced disease. Characterization of the mutational landscape of cervical cancer has already been initiated, indicating that, for now, few of these targetable alterations match with available agents. Progress in both the mutational landscape knowledge and developments of novel targeted therapies may result in more effective and individualized treatments for cervical cancer. The potential efficacy of knocking down the key alterations in cervical cancer – E6 and E7 human papillomavirus oncoproteins – must not be overlooked.

Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. The majority of the patients are Caucasian (97.8%) and aged 50–80 years. Choroidal melanoma is the predominant type (86.3%). The clinical presentation may range from no symptoms over various types of visual disturbances to visual loss. Examination includes slit-lamp biomicroscopy, indirect ophthalmoscopy and diagnostic testing, such as B-scan ultrasonography. A number of patients with posterior UM are treated with plaque radiation therapy or enucleation. At present, targeted therapy includes inhibitors of the mitogen-activated protein kinase/mitogen-activated protein kinase kinase signaling pathway. UM disseminates hematogenously, with a high propensity for metastasis to the liver, which the most common site (93% of the cases). While UM is uncommon, a significant proportion of affected patients succumb to this disease and new treatment options to improve patient survival are required.

Purpose To provide evidence-based, resource-stratified global recommendations to clinicians and policymakers on the management and palliative care of women diagnosed with invasive cervical cancer. Methods ASCO convened a multidisciplinary, multinational panel of cancer control, medical and radiation oncology, health economic, obstetric and gynecologic, and palliative care experts to produce recommendations reflecting resource-tiered settings. A systematic review of literature from 1966 to 2015 failed to yield sufficiently strong quality evidence to support basic- and limited-resource setting recommendations; a formal consensus-based process was used to develop recommendations. A modified ADAPTE process was also used to adapt recommendations from existing guidelines. Results Five existing sets of guidelines were identified and reviewed, and adapted recommendations form the evidence base. Eight systematic reviews, along with cost-effectiveness analyses, provided indirect evidence to inform the consensus process, which resulted in agreement of 75% or greater. Recommendations Clinicians and planners should strive to provide access to the most effective evidence-based antitumor and palliative care interventions. If a woman cannot access these within her own or neighboring country or region, she may need to be treated with lower-tier modalities, depending on capacity and resources for surgery, chemotherapy, radiation therapy, and supportive and palliative care. For women with early-stage cervical cancer in basic settings, cone biopsy or extrafascial hysterectomy may be performed. Fertility-sparing procedures or modified radical or radical hysterectomy may be additional options in nonbasic settings. Combinations of surgery, chemotherapy, and radiation therapy (including brachytherapy) should be used for women with stage IB to IVA disease, depending on available resources. Pain control is a vital component of palliative care. Additional information is available at www.asco.org/rs-cervical-cancer-treatment-guideline and www.asco.org/guidelineswiki . It is the view of ASCO that health care providers and health care system decision makers should be guided by the recommendations for the highest stratum of resources available. The guideline is intended to complement but not replace local guidelines.

The hypomethylating agents azacytidine and decitabine are unaffordable for many patients with MDS. The combination of the DNA methyltransferase inhibitor hydralazine and the histone deacetylase inhibitor valproate has shown preliminary efficacy in MDS. The aim of this study is to evaluate the clinical efficacy and safety of hydralazine/valproate in a case series of MDS patients treated in a compassionate manner. Hydralazine was dosed according to the acetylation genotype of patients (slow acetylators 83 mg daily; fast acetylators 182 mg daily), and valproate was dosed at 30 mg/kg/day. Both drugs were given daily until disease progression. Response and toxicity were evaluated with the International Working Group criteria and CTCAE, version 4, respectively. Survival parameters were estimated with the Kaplan-Meier method. From 2009 to 2012, 14 patients were treated. The median age ± SD was 55.2 ± 19.52 (range 23–87) years. According to the IPSS, cases were graded as intermediate-1 (n = 8/14; 57.2%) or intermediate-2 (n = 6/14; 42.8%). Responses were as follows: five (35.7%) complete response, one (7.1%) partial response, and two (14.28%) became transfusion independent. The mean duration of response ± SD was 60 ± 35.28 months (range 5–94). Three patients progressed to AML. At a median follow-up of 57 months (range 1–106), the median OS was 27 months. At that point, five patients remained on the treatment, one with partial response and four with complete response. The median OS was not reached in the eight patients who saw a clinical benefit from the treatment, in comparison to an OS of 7 months in the six patients who had no treatment. The combination of hydralazine and valproate is safe and effective in MDS, and its further testing is highly desirable.

To evaluate whether a country's Human Development Index (HDI) can help explain the differences in the country's breast cancer and gynecological cancer incidence and mortality rates in the Pan-American region.Ecological analysis.Pan-American region countries with publicly available data both in GLOBOCAN 2012 and the United Nations Development Report 2012 were included (n = 28). Incidence and mortality rates age-standardized per 100,000 were natural log-transformed for breast cancer, ovarian cancer, corpus uteri cancer, and cervical cancer. The mortality-to-incidence ratio (MIR) was calculated for each site. Pearson's correlation test and a simple linear regression were performed.The HDI showed a positive correlation with breast cancer and ovarian cancer incidence and mortality rates, respectively, and a negative correlation with cervical cancer incidence and mortality rates. The HDI and corpus uteri cancer showed no association. MIR and the HDI showed a negative correlation for all tumor types except ovarian cancer. An increment in 1 HDI unit leads to changes in cancer rates: in breast cancer incidence β = 4.03 (95% confidence interval [CI] 2.61; 5.45) P 0.001, breast cancer mortality β = 1.76 (95% CI 0.32; 3.21) P = 0.019, and breast cancer-MIR β = -0.705 (95% CI 0.704; 0.706) P 0.001; in cervical cancer incidence β = -3.28 (95% CI -4.78; -1.78) P 0.001, cervical cancer mortality β = -4.63 (95% CI -6.10; -3.17) P 0.001, and cervical cancer-MIR β = -1.35 (95% CI -1.83; -0.87) P 0.001; in ovarian cancer incidence β = 3.26 (95% CI 1.78; 4.75) P 0.001, ovarian cancer mortality β = 1.82 (95% CI 0.44; 3.20) P = 0.012, and ovarian cancer-MIR β = 5.10 (95% CI 3.22; 6.97) P 0.001; in corpus uteri cancer incidence β = 2.37 (95% CI -0.33; 5.06) P = 0.83, corpus uteri cancer mortality β = 0.68 (95% CI -2.68; 2.82) P = 0.96, and corpus uteri cancer-MIR β = -2.30 (95% CI -3.19; -1.40) P 0.001.A country's HDI should be considered to understand disparities in breast cancer and gynecological cancer in the Pan-American region.

Purpose: This study aimed to determine the patterns of follow-up visits for cervix cancer in a national cancer center in Mexico. Materials and Methods: The National Cancer Institute of Mexico is cancer center with 119 beds that mostly cares for an underserved and socially disadvantaged population. The medical records of cases of cervical cancer that had at least one year of clinical follow-up after being in complete response at the end of primary treatment were analyzed. We recorded the numbers of total and yearly follow-up visits and these were compared with the number of follow-up visits recommended by the National Comprehensive Cancer Network 2013, version 2 for cervical cancer. Results: Between March and June 2007, the medical records of 96 consecutive patients were reviewed. Twenty (21%) of these met inclusion criteria and were selected. In the first year the median number of visits was 11 (4-20). In the ensuing years, 2 nd , 3 rd , 4 th and 5 th , the number of analyzed patients remaining in follow-up decreased to 17, 14, 13 and 9 respectively. There were 462 follow-up visits to primary treating services (Gynecology Oncology, Radiation Oncology and Medical Oncology) as compared to 220 suggested by the NCCN guidelines (X 2 test p

DNA methylation (DNMTi) and histone deacetylase inhibitors (HDACi) are in development for cancer therapy. So far, four epigenetic drugs are approved for myelodysplastic syndrome (MDS) and cutaneous T-cell lymphoma (CTCL). The combination of hydralazine-valproate (TRANSKRIP(™)) is being repositioned as an oral DNMT and HDAC inhibitor.Brief discussion on the current status of epigenetic drugs and studies published on the preclinical and clinical development of the hydralazine-valproate combination.Drug repositioning is a strategy for prompt and cost-efficient drug discovery. There is evidence that combining DNMTi with HDACi would be more efficacious than administering each agent on its own. Hydralazine-valproate is safe when used alone or in combination with chemotherapy or chemoradiation. The fact that both drugs are orally administered is another advantage over current epigenetic drugs. This combination is promising but larger studies are needed. Among these, the randomized Phase III trials in advanced and in locally advanced cervical cancer combined with chemotherapy and cisplatin-radiation respectively, would eventually confirm its efficacy. Studies on MDS and CTCL would also eventually prove the efficacy of hydralazine valproate so that in the coming years hydralazine-valproate could have a role in cancer epigenetic therapy.

Background The aim of the present study was to demonstrate that radical hysterectomy (RH) leads to improved survival outcomes in FIGO stage IB2–IIB cervical cancer when compared with standard brachytherapy (BCT) after identical external beam chemoradiation (EBRT-CT). Patients and methods EBRT-CT treatment consisted of six courses of cisplatin at 40 mg/m2 and gemcitabine at 125 mg/m2 per week concurrent with 50.4 Gy of radiation. In the BCT arm, EBRT-CT was followed by BCT to reach a point A dose of 85 Gy, whereas in the experimental arm, a type III RH with bilateral pelvic lymph node dissection and para-aortic lymph node sampling (RH) was carried out within 4–6 weeks after EBRT-CT. Results Between May 2004 and June 2009, 211 patients were enrolled (BCT, 100 and RH, 111). At a median follow-up time of 36 months (3–80), progression-free survival (PFS) and overall survival (OS) rates were similar in both the arms. PFS rates were 74.8% and 71.7% in the BCT and RH arms [HR 0.6516 (95% confidence interval (CI) 0.3504–1.2116)], P = 0.186. OS rates were 76.3% in the BCT versus 74.5% in the surgical arm [HR 0.6981 (95% CI 0.3106–1.3439)], P = 0.236. No differences were observed in the pattern of local and systemic failures. Conclusions This study failed to demonstrate that RH after EBRT-CT is superior to standard BCT.

Kast, Richard E. et al., To improve prognosis in recurrent glioblastoma we developed a treatment protocol based on a combination of drugs not traditionally thought of as cytotoxic chemotherapy agents but that have a robust history of being well-tolerated and are already marketed and used for other non-cancer indications. Focus was on adding drugs which met these criteria: a) were pharmacologically well characterized, b) had low likelihood of adding to patient side effect burden, c) had evidence for interfering with a recognized, well-characterized growth promoting element of glioblastoma, and d) were coordinated, as an ensemble had reasonable likelihood of concerted activity against key biological features of glioblastoma growth. We found nine drugs meeting these criteria and propose adding them to continuous low dose temozolomide, a currently accepted treatment for relapsed glioblastoma, in patients with recurrent disease after primary treatment with the Stupp Protocol. The nine adjuvant drug regimen, Coordinated Undermining of Survival Paths, CUSP9, then are aprepitant, artesunate, auranofin, captopril, copper gluconate, disulfiram, ketoconazole, nelfinavir, sertraline, to be added to continuous low dose temozolomide. We discuss each drug in turn and the specific rationale for use- how each drug is expected to retard glioblastoma growth and undermine glioblastoma’s compensatory mechanisms engaged during temozolomide treatment. The risks of pharmacological interactions and why we believe this drug mix will increase both quality of life and overall survival are reviewed.

The epigenetic drugs hydralazine and valproate were administered in a compassionate manner to 8 patients with chronic myeloid leukemia (CML) refractory to imatinib. Two patients had a complete hematologic response (25%),1 major cytogenetic response, 1 complete cytogenetic response (25% any cytogenetic response), and 3 (37.5%)stable disease. No grade 3 or 4 toxicity was observed. These results show the ability of epigenetic therapy to revert imatinib resistance.Epigenetic alterations participate in the development of acquired resistance to imatinib, hence, the DNA methylation, and histone deacetylase inhibitors hydralazine and valproate, respectively, has the potential to overcome it.A series of 8 patients with chronic myeloid leukemia (CML) refractory to imatinib mesylate with no access to second-generation tyrosine kinase inhibitors were treated with hydralazine and valproate in a compassionate manner. Clinical efficacy and safety of these drugs added to imatinib mesylate were evaluated.Two patients were in the blast phase, 5 were in the accelerated phase, and 1 was in the chronic phase. All the patients continued with the same dose of imatinib that they had been receiving at the time of development of resistance, with a median dose of 600 mg daily (range, 400-800 mg). The median time from diagnosis of CML to the start of hydralazine and valproate was 53.6 months (range, 19-84 months). Two (25%) patients had a complete hematologic response, one (12.5%) had an major cytogenetic response, and one (12.5%) had a complete cytogenetic response. Three (37.5%) patients had stable disease, and only one (12.5%) patient failed to respond. At a median follow-up time of 18 months (range, 3-18 months), the median survival had not been reached, and the projected overall survival was 63%. All the patients had mild neurologic toxicity, including distal tremor and somnolence. No grade 3 or 4 toxicity was observed.Our results suggest that the epigenetic drugs hydralazine and valproate revert the resistance to imatinib in patients with CML.

There is a shortage of therapeutical agents for invasive cervical cancer in late stages of development; however, a number of promising molecules are currently in early phases of development.This review briefly discusses the current achievements in treating cervical cancer with an emphasis in emerging agents based on a literature search on pubmed and related sites for cervical cancer information. This is not a systematic review.In advanced disease, modest survival gains have been achieved with cisplatin doublets. Contrariwise, chemoradiation has increased survival rates in locally advanced disease, but there is still room for improvement. Anti-vascular endothelial growth factor and anti-epidermal growth factor receptor monoclonal antibodies are promising molecules that are at present in late-phase development, but a high number of miscellaneous agents are in early development. Strong experimental bases support that the 'Achilles' heel' of cervical cancer are the HPV-E6/E7 oncogenes. Unfortunately, agents aimed at targeting these cervical cancer-driven players are found in very early development; hence, major research efforts must be focused on developing technological strategies for their effective targeting using nucleic acid-based vehicles for safe and effective delivery to cancer cells as well as accelerating the search for small-molecule inhibitors of E6/E7 themselves or their interacting cellular proteins.

Recent peer-reviewed publications on the treatment of early, locally advanced and advanced cervical cancer patients are reviewed to gain insight into the main research done in the field.In early-stage patients where cure is offered to most patients, research focuses on more conservative or less morbid approaches to increase quality of life and reduce the treatment-related sexual dysfunction. No major advances have occurred for treating locally advanced disease since the introduction of concurrent chemoradiation, but efforts are directed to increase efficacy while reducing toxicity with the use of combination chemoradiation and modern radiation technologies. Molecular-targeted therapy and identification of targetable gene alterations as well as immunotherapy are actively pursued in patients with advanced disease.Although global statistics indicate a trend for decreased age-standardized incidence rates, social and economical factors impede the uptake of therapeutic advances achieved as many patients have no access even to basic resources for treating cancer. The adherence to quality indicators in delivery of optimized standard concurrent chemoradiation and adherence to guidelines in cervical cancer surgery must not be underestimated. Major efforts are needed in both the scientific and social aspects of cervical cancer treatment to reduce mortality.

Cervical cancer is the third most prevalent cancer in females worldwide. When advanced, the disease requires primary radiation concurrent with chemotherapy. However, chemotherapy alone is the standard treatment for recurrent/persistent/metastatic disease.Areas covered in this review include the treatment of advanced cervical cancer with gemcitabine as radiosensitizer, either alone or in combination with cisplatin. The use of gemcitabine for recurrent/persistent/metastatic cervical cancer is also reviewed.Statistically significantly better survival rates are achieved with cisplatin doublets against cisplatin alone, in the management of recurrent/persistent/metastatic cervical cancer. The choice of the cisplatin doublet with paclitaxel, vinorelbine, gemcitabine and topotecan arms should be based on physician preference, pre-existing morbidity and patient-related factors. In advanced disease, a recently reported Phase III trial establishes the novel regimen of concurrent gemcitabine plus cisplatin and external radiation, followed by brachytherapy and two adjuvant 21-day cycles of gemcitabine plus cisplatin, as significantly improving survival outcomes when compared with the current standard of care. The increased acute toxicity of this regimen is clear; however, this should not deter its incorporation into clinical practice, in that the toxicity is predictable and manageable; nevertheless, the occurrence of late toxicity and survival at longer follow-up time are reasonable concerns in this regimen.

The reversing of epigenetic aberrations using the inhibitors of DNA methylation and histone deacetylases may have therapeutic value in cervical cancer. This is a randomized phase III, placebo-controlled study of hydralazine and valproate (HV) added to cisplatin topotecan in advanced cervical cancer. Patients received hydralazine at 182 mg for rapid, or 83 mg for slow acetylators, and valproate at 30 mg/kg, beginning a week before chemotherapy and continued until disease progression. Response, toxicity, and PFS were evaluated, and 36 patients (17 CT + HV and 19 CT + PLA) were included. The median number of cycles was 6. There were four PRs to CT + HV and one in CT + PLA. Stable disease in five (29%) and six (32%) patients, respectively, whereas eight (47%) and 12 (63%) showed progression (P = 0.27). At a median follow-up time of 7 months (1-22), the median PFS is 6 months for CT + PLA and 10 months for CT + HV (P = 0.0384, two tailed). Although preliminary, this study represents the first randomized clinical trial to demonstrate a significant advantage in progression-free survival for epigenetic therapy over one of the current standard combination chemotherapy in cervical cancer. Molecular correlates with response and survival from this trial are pending to analyze.

Cervical cancer continues to be a significant health burden worldwide. Globally, the majority of cancers are locally advanced at diagnosis; hence, radiation remains the most frequently used therapeutic modality. Currently, the value of adding cisplatin or cisplatin-based chemotherapy to radiation for the treatment of locally advanced cervical cancer is strongly supported by randomized studies and meta-analyses. Nevertheless, despite these significant achievements, therapeutic results are far from optimal; thus, novel therapies need to be investigated. A recent, randomized, phase III trial has shown for the first time that combination chemotherapy with cisplatin and gemcitabine concurrently with radiation improves parameters of survival over cisplatin alone and establishes a new standard for the management of locally advanced cervical cancer. On the other hand, advanced disease, presenting either as an International Federation of Gynecology and Obstetrics (FIGO) stage IVB or as persistent or recurrent to primary therapy without local curative options, remains a devastating group of diseases with no options other than palliative chemotherapy. Recent results from the GOG (Gynecologic and Oncologic Group)-204 study demonstrate that cisplatin-doublets with paclitaxel, vinorelbine, gemcitabine or topotecan only produce small improvements in survival, although with different toxicity patterns; hence, patient-related factors are important when choosing any one of these regimens. The role of targeted therapies both in locally advanced and advanced disease is promising, but still at an investigational stage.

Adenocarcinoma of the esophagogastric junction (EGJ) is rapidly increasing in the west. Our aim is to define the prognostic factors and treatment of EGJ carcinoma in Mexico, particularly the location after the Siewert's classification.A retrospective cohort of patients suffering from EGJ adenocarcinoma treated from 1987 to 2000. The Kaplan-Meier and the Cox's models were used to define prognostic factors.Two hundred and thirty-four patients were included, 90 females and 144 males. Surgical resection was possible in 68 cases only (29%). Significant prognostic factors were tumor node metastasis (TNM) stage [stages I-II: risk ratio (RR) is 1; stage III RR is 1.3, 95% confidence interval (CI) 0.75-2.4; stage IV RR, 2.04, 95% CI 1.1-3.7], gender (male RR = 1.47, 95% CI 1.05-2.05), metastatic lymph node ratio (no resection: RR = 1; ratio 0.2-1 RR=0.67, 95% CI 0.39-1.14; ratio 0-0.19 RR = 0.42, 95% CI 0.23-0.76) and seralbumin (3 mg/dL or less RR = 2.05 95% CI 1.3-3.2; 3.1-3.4 mg/dL RR = 1.9 95% CI 1.2-3.03; 3.5-3.8 mg/dL RR = 1.3 95% CI 0.8-1.9; 3.9 mg/dL or more: RR = 1) (model P = 0.0001).EGJ adenocarcinoma is a highly lethal neoplasia and the location after the Siewert' classification is not a prognostic factor. In Mexico, TNM clinical stage, serum albumin, gender, surgical resection and metastatic lymph node ratio are significant prognostic factors. Curative treatment is infrequent but radical resection is associated to longer survival. Consequently, the management must consider quality of life and surgical morbidity.

DNA methylation has become an attractive target for the treatment of cancer. DNA methyltransferase inhibitors have proven useful for the treatment of myelodysplastic syndrome and are being evaluated in gynecological neoplasias.We provide an overview of the current knowledge on DNA methylation and cancer and the role of DNA methylation in cervical, ovarian and endometrial carcinomas. The results of recent clinical trials with demethylating agents for cervical and ovarian cancer treatment are also discussed.There are few studies of DNA demethylating agents for cervical and ovarian cancer treatment; nevertheless, the results are promising. To accelerate these advances, there are at least two actions that can be simultaneously pursued. One is to greatly increase the number of small clinical exploratory trials with existing demethylating drugs and using methylome analyses to identify predictive factors for response and/or toxicity. The second is finding out epigenetic 'drivers' unique to gynecological cancers and their subtypes, and then proceed to clinical trials in a highly selected population of patients. It is expected that in the future, DNA demethylation could have a role in the treatment of gynecologic cancers.

Background. In Mexico and other developing countries, few reports of the survival of children with acute leukaemia exist.Objective. We aimed at comparing the disease-free survival of children with acute myeloid leukaemia who, in addition to being treated with the Latin American protocol of chemotherapy and an autologous transplant, either underwent early intensified chemotherapy or did not undergo such treatment.Procedure. This was a cohort study with a historical control group, forty patients, less than 16 years old. Group A (20 patients), diagnosed in the period 2005–2007, was treated with the Latin American protocol of chemotherapy with an autologous transplant plus early intensified chemotherapy: high doses of cytarabine and mitoxantrone. Group B (20 patients), diagnosed in the period 1999–2004, was treated as Group A, but without the early intensified chemotherapy.Results. Relapse-free survival for Group A was 90% whereas that for Group B it was 60% (P=0.041). Overall survival for Group A (18, 90%) was higher than that for Group B (60%). Complete remission continued for two years of follow-up.Conclusions. Relapse-free survival for paediatric patients treated with the Latin American protocol of chemotherapy with an autologous transplant plus early intensified chemotherapy was higher than that for those who did not receive early intensified chemotherapy.

Myelodysplastic syndrome (MDS) is a heterogeneous clonal disorder characterized by deregulation of apoptosis, dysplastic features in hematopoietic precursors, peripheral blood cytopenias and an increased risk for transformation to acute leukemia. Roughly 20% of MDS are therapy related (t-MDS), and this is considered an independent adverse prognostic factor.This review based on a comprehensive literature search provides an overview on the main features of t-MDS, including its epidemiology, risk factors, molecular pathogenesis, prognostic classifications and therapy.Increasing evidence points out that the most important event in t-MDS is genetic alterations in hematopoietic stem precursor cells, however, ineffective hematopoiesis may also result from abnormalities in the bone marrow microenvironment. Thus, novel views onto the processes of t-MDS are needed such as the osteohematology concept. On the other hand, the number of people living with and beyond cancer is increasing worldwide; thus, most emphasis should be placed on preventing secondary malignancies such as t-MDS. From this review, it becomes clear that we are in urgent need not only to deepen our understanding of the leukemogenesis mechanisms induced by exposure to chemotherapy and radiation but also to translate this knowledge into clinical strategies aimed at risk reduction.

Our aim in this paper is to describe the results of treatment of acute lymphoblastic leukaemia (ALL) in Mexican children treated from 2006 to 2010 under the protocol from the Dana-Farber Cancer Institute (DFCI) 00-01. The children were younger than 16 years of age and had a diagnosis of ALL denovo. The patients were classified as standard risk if they were 1–9.9 years old and had a leucocyte count 9/L, precursor B cell immunophenotype, no mediastinal mass, CSF free of blasts, and a good response to prednisone. The rest of the patients were defined as high risk. Of a total of 302 children, 51.7% were at high risk. The global survival rate was 63.9%, and the event-free survival rate was 52.3% after an average follow-up of 3.9 years. The percentages of patients who died were 7% on induction and 14.2% in complete remission; death was associated mainly with infection (21.5%). The relapse rate was 26.2%. The main factor associated with the occurrence of an event was a leucocyte count >100 × 109/L. The poor outcomes were associated with toxic death during induction, complete remission, and relapse. These factors remain the main obstacles to the success of this treatment in our population.

The HER2 oncogene encodes a transmembrane protein partially homologous to epidermal growth factor receptor. This oncogene has been studied mainly in breast cancer where it has prognostic, predictive and therapeutic target value. The expression of HER2 in epithelial ovarian cancer has been less studied. HER2 expression can be determined through IHC, FISH, CISH and ELISA among other tests, with reported positivity frequencies of overexpression varying from 1.8% to 76%. In some studies HER2 overexpression has been associated with advanced stages, poorly differentiated tumors, resistance to chemotherapy and shortened survival. Although trastuzumab is able to produce a low response rate as a single agent in pretreated ovarian cancer patients with overexpression of HER2, its usefulness is limited due to the low frequency of strong expression. To date there is not enough bases for assessment and HER2-based therapies in epithelial ovarian cancer.

Ether à go-go (EAG) potassium channels display oncogenic properties. In normal tissues, EAG mRNA is almost exclusively expressed in brain, but it is expressed in several somatic cancer cell lines, including HeLa, from cervix. Antisense experiments against eag reduce cell proliferation in some cancer cell lines, and inhibition of EAG-mediated currents has been suggested to decrease cell proliferation in a melanoma cell line. Because of the potential clinical relevance of EAG, we investigated EAG mRNA expression in the following fresh samples from human uterine cervix: 5 primary cultures obtained from cancerous biopsies, 1 cancerous fresh tissue, and 12 biopsies of control normal tissue. All of the control cervical samples came from patients with negative pap smears. Reverse transcription-PCR and Southern-blot experiments revealed eag expression in 100% of the cancerous samples and in 33% of the normal biopsies. Immunochemistry experiments showed the presence of EAG channel protein in cells from the primary cultures and in cervical cancer biopsies sections from the same patients. In addition, we looked for EAG-mediated currents in the cultures from cervical cancer cells. Here we show for the first time EAG channel activity in human tumors. Patch-clamp recordings showed typical EAG-mediated currents modulated by magnesium and displaying a pronounced Cole-Moore shift. Because EAG expression and channel activity have been suggested to be important in cell proliferation, our findings strongly support the idea of considering EAG as a tumor marker as well as a potential membrane therapeutic target for cervical cancer.

The prognosis of cervical cancer patients with renal failure secondary to obstructive uropathy is poor. Our objective was to analyze our experience in the management with chemoradiation of untreated cervical cancer patients complicated by obstructive nephropathy and kidney dysfunction. Untreated patients with cervical cancer and renal failure as manifested by raised serum creatinine were treated with pelvic radiotherapy concurrently with weekly gemcitabine at 300 mg/m2. Response, toxicity and renal function pre- and post-therapy were evaluated. Eight FIGO stage IIIB and one IVB patients were treated. Pre-treatment serum creatinine ranged from 1.6 to 18.5 mg/100 ml (median 3.3, mean 6.8) and creatinine clearance varied from 4 to 57 mg/ml/min (median 17, mean 22.1). Four patients had a percutaneous nephrostomy placed and four patients had symptoms from kidney failure. All patient completed chemoradiation. Most patients had grade 3 leukopenia and neutropenia. Dermatitis, colitis and proctitis were common. All patients had improvement in creatinine clearance (pre-therapy 22.78, post-therapy 54.3 mg/ml/min) (p=0.0058) and all but one normalized serum creatinine. Eight (89%) of nine patients achieved complete response and one patient had persistence. At a median follow-up of 11 months (range 6-14), all patients are alive, one with pelvic and another with systemic disease. Ureteral obstruction causing any degree of renal insufficiency should not be a contraindication to receive chemoradiation to attempt cure. In this setting where cisplatin-based therapy is contraindicated, the use of gemcitabine may be considered.

Our aim was to evaluate the efficacy and safety of neoadjuvant chemotherapy followed by radical hysterectomy and adjuvant radiation concurrent with weekly cisplatin for locally advanced cervical carcinoma.Forty-three patients staged as IB2-IIIB were treated with three 21-day courses of carboplatin (area under the time-concentration curve 6 mg.min/ml) and paclitaxel at 175 mg/m(2) by 3-h infusion both on day 1 followed by radical type III hysterectomy and adjuvant radiation concurrent with 6-weekly doses of cisplatin at 40 mg/m(2). Response rate, resectability, toxicity and survival were evaluated.From December 2000 to June 2001, 43 patients were recruited. All were evaluated for response and toxicity to neoadjuvant chemotherapy. A total of 129 courses were administered. Clinical responses were seen in 41 patients (95%) [95% confidence interval (CI) 89.2% to 100%] with four (9%) complete and 37 (86%) partial. Forty-one patients underwent surgery (resectability 95%); pathologically complete or near-complete responses were seen in seven (17%) and eight (20%), respectively, positive surgical margins in five (12%), and positive pelvic lymph nodes in eight (20%). Twenty-six patients were scheduled for adjuvant chemoradiation. External radiation was delivered for 42.8 days (range 33-61), with a mean dose of 49.3 Gy (range 46-56), and a median of five cisplatin courses (two to six). The mean dose of brachytherapy was 32 Gy (range 25.5-35.6). Neoadjuvant therapy was well-tolerated with neutropenia grade 3 and 4 in 12% and 3% of the courses, respectively. Toxicity to adjuvant chemoradiation was mainly hematological and gastrointestinal, mostly grades 1/2. A total of 39 patients completed all scheduled treatment. At a median follow-up of 21 months (range 3-26), the projected overall survival in the intention-to-treat analysis was 79% (95% CI 62% to 88%).The triple modality of neoadjuvant chemotherapy followed by radical hysterectomy and adjuvant radiation concurrent with cisplatin is a highly active treatment for locally advanced cervical carcinoma with acceptable toxicity.

The combination of platinum and paclitaxel is the standard treatment of advanced ovarian carcinoma; however, recent studies have questioned the actual role of the combination as compared to either of the two agents alone. We report an open-label, two-center, phase II study of upfront paclitaxel for patients with histological diagnosis of stage III ovarian carcinoma. Treatment consisted of paclitaxel at 175 mg/m2 administered in a 3-h infusion every 21 days. Response was evaluated after the third course by either laparoscopy or exploratory laparotomy. Patients with stable or progressive disease discontinued treatment, whereas responding patients continued treatment until a maximum of six courses. Response, toxicity, time to progression (TTP) and survival were evaluated. From November 1993 to December 1995, 30 patients were accrued. All patients underwent primary cytoreduction; 17 (57%) and 13 (43%) patients had residual tumors2 and2 cm, respectively. Of 27 patients evaluable, objective responses were seen in 18 (66.4%) (95% CI 49.5-83.2)--12 complete (45%) and six partial (22%). Four patients had stable disease (15%) and five (18%) patients progressed. A total of 149 courses were administered to 30 patients, median 4 (range 1-6). Grade 3/4 neutropenia was seen in 13% of courses, peripheral neuropathy, myalgia and arthralgia were frequent, but transitory and relieved with analgesics. At a median follow-up time of 44.5 months (0-99) the TTP and median survival were 16.6 and 43.1 months, respectively. We conclude that single-agent paclitaxel is an effective and well-tolerated first-line treatment for advanced ovarian carcinoma.

It is known that cell-free DNA circulates in plasma/serum of patients with cancer and that part of this DNA circulates as nucleosomes that can be quantified by ELISA. We analyzed the effect of tumor and chemotherapy upon the levels of nucleosomes in vitro, in vivo and in cervical cancer patients. The levels of nucleosomes pre- and post-treatment were correlated with response in 11 patients receiving chemotherapy. Nucleosomes were determined in nude mice treated with or without cisplatin and carrying tumors generated with HeLa cells, and in the cell lysate and supernatant of HeLa cells exposed to cisplatin in culture. In addition, nucleosomes were determined at different time points in patients and in rats receiving chemotherapy. Nucleosomes were higher in patients that controls (1,760 vs. 601, p = 0.0001). After 24 hr of treatment with oxaliplatin and gemcitabine, the levels decreased in 6 patients of whom 5 had response. Nucleosome levels differed between mice xenografted and not xenografted (765 vs. 378, p = 0.001) and between xenografted treated with or without cisplatin (650 vs. 765, p = 0.010), but not in tumor-free animals treated and untreated with cisplatin (378 vs. 379, p = 0.99). In vitro, nucleosomes reached at peak 8 hr in cell lysates to decrease thereafter, whereas in supernatant, levels continued to increase up to 24 hr. Serial determination of nucleosomes in patients showed a rise within 6-12 hr and then a reduction to below the basal at 24 hr. In rats, nucleosomes had no major changes in those receiving oxaliplatin or the triple combination of cisplatin, gemcitabine and paclitaxel as compared to untreated controls. An overdose of this triple combination produced a transient elevation of almost 1,000 AU over the basal. Our results demonstrate that most of circulating nucleosomes originate from the tumor and that chemotherapy produces an early rise most likely due to tumor apoptosis and that nucleosomes are rapidly cleared from circulation. On the contrary, chemotherapy within the therapeutic range of doses has no effect on nucleosome levels in healthy mice and rats. This data suggests that the determination of circulating nucleosomes pre- and post-treatment could be a useful test to predict response to chemotherapy in cancer patients.

Induction chemotherapy followed by surgery, particularly with newer agents or combinations, remains to be explored in locally advanced cervical cancer. Gemcitabine cisplatin is a very active combination for this tumor, therefore we explored the activity of gemcitabine in combination with oxaliplatin. Ten untreated patients with histologic diagnosis of cervical carcinoma and staged as IB2 to IIIB were treated with 3 21-day courses of oxaliplatin 130 mg/m 2 day 1 and gemcitabine 1,250 mg/m 2 days I and 8 followed by locoregional treatment with either surgery or concomitant chemoradiation. Response and toxicity were evaluated at the end of chemotherapy. All patients were evaluable. The overall clinical response rate was 80%, being complete in 3 patients (30%) and partial in 5 (50%). Seven (70%) patients underwent surgery, and three (30%) had chemoradiation as definitive treatment. Hematologic toxicity was moderate, with leukopenia grades III-IV in 17 and 0%; granulocytopenia grades III-IV in 23 and 3%, respectively. Eight patients had grade I oropharyngeal toxicity. At a median follow-up of 11 months (range: 10-12), all patients are disease free. Gemcitabine oxaliplatin is a very active and well-tolerated combination for locally advanced cervical cancer.

Clinical and experimental data demonstrate that local cytokines are able to induce tumor regression and in some cases antitumor systemic immune response. IRX-2 is a cell-free mixture of cytokines obtained from unrelated donor lymphocytes with demonstrated ability to induce immune mediated regression of squamous cell carcinomas of head and neck. The objective of this study was to evaluate the antitumor activity and toxicity of IRX-2 in untreated early stage cervical cancer patients. Ten consecutive patients clinically staged IB1, IB2 and IIA were treated with a neoadjuvant immunotherapy regimen that consisted in a single IV dose of cyclophosphamide at 300 mg/m2 on day 1, oral indomethacin or ibuprofen and zinc sulfate were administered from days I to 21 and 10 regional perilymphatic injections of IRX-2 on days 3 to 14. All patients were scheduled for radical hysterectomy on day 21. The clinical and pathological responses, toxicity and survival were evaluated. Clinical response was seen in 50% of patients (three partial responses, two minor responses). Seven patients underwent surgery and pathological tumor reduction associated with tumor fragmentation was found in five cases. Histological studies demonstrated a rather heterogeneous cell type infiltrating pattern in the tumor which included lymphocytes, plasma cells, neutrophils, macrophages and eosinophils. Immunohistochemical analysis of the surgical specimens demonstrated an increase of tumor infiltrating CD8+ cells. The treatment was well tolerated except for mild pain and minor bleeding during injections and gastric intolerance to indomethacin. At 31 months of maximum follow-up (median 29), eight patients are disease-free. Our results suggest that the immunotherapy approach used induces tumor responses in cervical cancer patients. Further studies are needed to confirm these results as well as to elucidate the mechanisms underlying these effects.

Aplastic anemia (AA) is a hematological disease characterized by the deficient production of blood cells. The incidence of AA worldwide is low (1-5 new cases per 10(6) individuals per year). In contrast to other countries, no current reports exist on the incidence of this disorder in Mexico. In the present study, we have determined the incidence of AA in a defined subpopulation from Mexico City during the period 1996-2000. For the purpose of this study, we focused on the experience from a single medical institution: the Mexican Institute of Social Security (IMSS), which covers around 50% of Mexico's population. The incidence of AA was determined based on the actual number of patients diagnosed with this disease at the IMSS in Mexico City in a given year and the total number of individuals registered at the IMSS in Mexico City in the same year. Considering the IMSS population as a whole, the annual incidence of AA was 3.9 new cases per 10(6) individuals per year. In the pediatric population, the annual incidence was 4.2 new cases per 10(6) individuals per year, whereas in people 15-years-old and older the incidence was 3.8 new cases per 10(6) individuals per year. These incidences were higher than those reported in most studies from the USA, Europe and Israel. Compared to the incidence in Thailand, the incidence we observed in children was considerably higher, whereas the one in adults was similar to the one in that country. The results of the present study suggest that the incidence of AA in Mexico City is one of the highest worldwide, particularly in terms of the pediatric population; however, these results must be taken with caution since this study comprises only a subpopulation from Mexico City and not the entire population. Thus, further studies including a broader population, both in Mexico City and other urban and rural areas of this country, will be necessary in order to obtain better and more complete estimates of the actual incidence of AA in Mexico.

Purpose: Gemcitabine (2′,2′-difluorodeoxycytidine) is an antineoplastic agent with activity against a variety of solid tumors. To investigate its in vitro activity toward cervical cancer, we exposed six cervical cancer cell lines to gemcitabine. Methods: Combinational cytotoxic studies using viability tests and clonogenicity assays. Results: Gemcitabine was cytostatic and cytotoxic in some of the lines at peak plasma concentrations similar to those achieved in clinical trials. Gemcitabine was also found to effectively synergize with cisplatin and showed a radiosensitizing effect in these cells. The cytotoxicity observed in sensitive cell lines was due to apoptosis, as demonstrated by DNA fragmentation assays. Conclusions: We recommend performing additional in vitro experimentation so that these results can be confirmed to support clinical trials of gemcitabine in cervical cancer patients both as first-line therapy and with concomitant radiation.

La combinacion de carboplatino y paclitaxel se considera el tratamiento estandar en el carcinoma de ovario avanzado. Sin embargo, estas combinaciones proporcionan un control de la enfermedad a largo plazo solo en la mitad de las pacientes. El objetivo fue evaluar la supervivencia y la toxicidad de la combinacion de cisplatino y vinorelbina como tratamiento adyuvante en cancer epitelial de ovario. Se estudiaron 30 pacientes con cancer epitelial de ovario; de ellas, 26 recibieron quimioterapia adyuvante con 100 mg/m2 de cisplatino el primer dia y vinorelbina 25 mg/m2 en el primer y octavo dia por 6 ciclos y las 4 pacientes restantes recibieron 3 ciclos de quimioterapia primaria. Posteriormente se las trato con cirugia citorreductora y 3 ciclos mas de quimioterapia adyuvante con el mismo esquema. La toxicidad se evaluo con los criterios de la Organizacion Mundial de la Salud (OMS) y la supervivencia se estimo con el metodo de Kaplan Meier. La edad promedio fue de 45 anos (19 a 75 anos), la distribucion por estadios fue de estadio I en 10 pacientes, II en 1, III en 18 y IV en 1. Todas las pacientes con estadios I y II tuvieron citorreduccion optima, mientras que de aquellas con estadios III y IV, 11 tuvieron citorreduccion optima ( 2 cm) y 4 fueron llevadas a cirugia de intervalo debido a irresecabilidad en la exploracion inicial. Las pacientes sin citorreduccion primaria se lograron citorreducir despues de quimioterapia de induccion. Se observo neutropenia grado 3 o 4 en 18 pacientes (60%), neutropenia febril en 2, anemia grado 3 en 1; ninguna paciente presento trombocitopenia grado 3 o 4, nausea y vomito grado 3 y 4 en 13 y 1 paciente con toxicidad cardiaca. La supervivencia global fue del 60% a una mediana de seguimiento de 48 meses (rango: 4–58 m). Actualmente 16 pacientes se encuentran vivas sin actividad tumoral, 8 de ellas en estadios III y IV. Los resultados de este estudio piloto sugieren que la combinacion de vinorelbina y cisplatino es activa en cancer epitelial de ovario. Se requieren estudios aleatorizados para determinar el valor de esta combinacion en comparacion al tratamiento estandar, asi como para evaluar el papel de la vinorelbina es esquemas triples.

Neoadjuvant chemotherapy followed by surgery is a promising approach in locally advanced cervical carcinoma. The aim of this study was to evaluate the feasibility, technical aspects, and clinical results of surgery after induction chemotherapy in this patient population. Forty-one untreated cervical carcinoma patients staged as IB2 to IIIB received three 21-day courses of cisplatin 100mg/m2 on day 1 and gemcitabine 1000 mg/m2 on days 1 and 8 followed by surgery or concomitant chemoradiation. The response to chemotherapy, operability, surgical/pathological findings, disease-free period, and survival of the surgically treated patients were evaluated. All 41 patients were evaluated for toxicity and 40 were evaluated for response. The overall objective response rate was 95% (95% confidence interval 88%-100%), and was complete in three patients (7.5%) and partial in 35 (87.5%). Granulocytopenia grades 3/4 occurred in 13.8% and 3.4% of the courses, respectively, whereas nonhematological toxicity was mild. Twenty-three patients underwent type III radical hysterectomy. Mean duration of surgery was 3.8 h (range 2:30-5:20), median estimated blood loss was 670 ml and median hospital stay was 5.2 days. Intraoperative complications occurred in one case (venous injury). In all but one case the resection margins were negative. Four patients (17%) had positive nodes (one node each); six (26%) had complete pathologic response, three (13%) had microscopic; and 14 (60%) macroscopic residual disease. At 24 months of maximum follow-up (median 20), the disease-free and overall survival rates were 59% and 91%, respectively. Induction chemotherapy with cisplatin/gemcitabine produced a high response rate and did not increase the difficulty of surgery. Operating time, blood loss, intraoperative complications, and hospital stay were all within the range observed for type III hysterectomy in early stage patients. We therefore conclude that type III radical hysterectomy is feasible in locally advanced cervical cancer patients who respond to chemotherapy.

Duenas-Gonzalez A, Lara Medina FU, Solorza-Luna G, de la Garza-Salazar J, Sobrevilla-Calvo PJ. Adjucant high-dose chemotherapy supported by peripheral blood stem cell transplantation for high-risk cervical cancer. Cervical carcinoma is a common disease for which the prognosis has not been substantially improved with standard locoregional treatments. Three stage IB patients with untreated cervical carcinoma were treated with high-dose chemotherapy and refrigerated peripheral blood stem cell support using the ICE program (Ifosfamide 10 g/m2 plus mesna at 100% of the ifosfamide dose; Carboplatin at 1.5 g/m2 and Etoposide 2.1 g/m2). Patients received the treatment in an adjuvant setting after radical hysterectomy with pelvic lymph-node dissection and postoperative cisplatin-based standard-dose chemotherapy. All patients underwent postoperative radiotherapy. The treatment was well-tolerated, all patients had rapid hematologic recovery, and the most frequent complications were grade 3 mucositis and neutropenic fever. The three patients are disease-free at 58, 60, and 63 months of follow-up. Our results show that adjuvant high-dose chemotherapy could be effective to reduce the likelihood of relapse in high-risk patients. High-dose chemotherapy deserves a formal evaluation in high-risk cervical cancer.

Cervical cancer is the fourth leading cause of cancer death in females worldwide. Incorporation of chemotherapy to radiation in locally advanced disease and molecular targeted therapy for advanced disease has increased survival; nevertheless, there is room for further improvement.This review aims to discuss major recent advances in the treatment of invasive cervical cancer from randomized Phase III trials and ongoing late-stage developments.Combination chemotherapy concurrent with radiation plus adjuvant chemotherapy has demonstrated better survival rates as compared to standard cisplatin chemoradiation and ongoing Phase III trials would eventually confirm these findings. Gemcitabine and paclitaxel are the most evaluated agents added to cisplatin chemoradiation and in the adjuvant setting. Further survival gains combining classical cytotoxics will be limited by toxicity, hence, novel antitumor drugs; in particular angiogenesis inhibitors must be evaluated to increase the efficacy of current chemoradiation regimens. In advanced disease, modest survival gains were recently achieved with cisplatin doublets as compared to single agent cisplatin. Bevacizumab added to standard chemotherapy has for the first time demonstrated that targeted agents are valuable in the treatment of advanced cervical cancer. Ongoing Phase III trials for cervical cancer are limited reflecting the shortage of promising molecules and the need to increase research efforts for this disease.