Robotic-assisted gynecologic surgery in an older population: A comparison study.

INTRODUCTION: Robotic-assisted surgery in select patients has been shown to result in less peri-operative morbidity. Few studies have explored the association of robotic-assisted gynecology oncology surgery complication rates and increasing age. Our objective was to evaluate the peri- and postoperative complication rates in patients age 65 years or above in minimally-invasive robotic gynecologic surgery. MATERIAL AND METHODS: We performed a retrospective review of data from 765 consecutive minimally-invasive robotic-assisted surgeries performed by high-volume gynecologic oncologists. The patients were divided into "younger" patients aged <65 years and "older" patients aged ≥65 years. The primary outcomes were intraoperative and postoperative complications. RESULTS: Of the 765 patients analyzed, 185 (24%) were ≥ 65. The intraoperative complication rate in patients <65 was 1.9% (11/580) versus 1.62% (3/185) in females ≥65 (p = 0.808). The postoperative complication rate in patients <65 was 15.5% (90/580) versus 22.7% (42/185) in females ≥65 (p = 0.328). We observed more post-operative complications with patients who had intraoperative complications compared to patients who developed post-operative complications without intraoperative complcations in our sample, but it was not statisticaly significant (OR = 2.78, p = 0.097). The average estimated blood loss was 137.5 ml (0-1000) for patients younger than 65 years and 134.81 ml (0-2200) in patients 65 years or older (p = 0.097). DISCUSSION: Robotic gynecologic oncology surgery is common. When performed by expert surgeons, complications are not associated with increasing age.

Anti-angiogenesis agents in metastatic or recurrent cervical cancer.

While the incidence of cervical cancer has declined significantly in the United States, it still remains a serious American health threat. When detected early, cervical cancer is generally curable. Early lesions are treated surgically, and locally advanced lesions are managed with concurrent cisplatin chemotherapy and pelvic radiation. Metastatic disease or recurrent lesions not amenable to radical local excision or regional radiation are treated with palliative chemotherapy. Current chemotherapeutic regimens are associated with significant side effects and only limited activity making the identification of active and tolerable novel targeted agents a high priority. Angiogenesis is central to cervical cancer development and progression. The dominant role of angiogenesis in cervical cancer seems to be directly related to HPV inhibition of p53 and stabilization of HIF-1 alpha, both of which increase VEGF. Bevacizumab binding and subsequent inactivation of VEGF seem to shrink cervical tumors and delay progression without appreciable toxicity, and are therefore being studied in a Gynecologic Oncology Group (GOG) phase III trial. Other intracellular tyrosine kinase inhibitors (TKIs) of angiogenesis such as pazopanib are also encouraging, especially in lieu of their oral administration. Further study of angiogenesis and its inhibition are ongoing.

Biologics in cervical cancer therapy.

Though cervical cancer incidence and prevalence have decreased in the United States, the disease remains a very important cause of morbidity and mortality worldwide. Current therapy for early-stage disease is surgical with adjuvant therapy being administered according to histopathologic findings. Pelvic radiation with concomitant platinum-based chemotherapy is used to treat locally advanced disease, whereas metastatic and recurrent lesions continue to be difficult to effectively treat and cure. Clinical trials in this latter scenario have suggested that clinical benefit may be associated with biologic therapies. This article focuses on the use of targeted therapies in cervical cancer, specifically evaluating antiangiogenesis and endothelial growth factor receptor-related treatments.

Safety and efficacy of salvage nano-particle albumin bound paclitaxel in recurrent cervical cancer: a feasibility study.

BACKGROUND: After platinum and taxane chemotherapy, with or without bevacizumab, active regimens for advanced or recurrent cervical cancer are lacking. Our objective was to review a single institution experience in treating recurrent, refractory cervical cancer with nano-particle albumin bound (NAB) paclitaxel with or without bevacizumab. METHODS: This retrospective case series was conducted in accordance with the regulations set forth by the Institutional Review Board at St. Joseph's Hospital and Medical center. The chemotherapy log at the outpatient infusion center at the University of Arizona Cancer Center was reviewed to identify all advanced cervical cancer patients treated with NAB-paclitaxel from November 2011 until February 2015. The following data points were extracted from patient charts: demographic information, number of cycles, progression free survival (PFS), overall survival (OS), dose reductions and dose-limiting toxicities. In addition the average number of treatment cycles and age at recurrence were calculated. RESULTS: A total of 12 subjects were identified as receiving treatment with NAB-paclitaxel. Mean age at time of recurrence was 47.2 years (36-55). Nine subjects had squamous cell histology and three subjects had adenocarcinoma histology. All subjects had failed treatment with platinum and taxane, or platinum and topotecan chemotherapy. Two subjects were lost to follow up. The Median number of cycles of NAB-paclitaxel was 6.5 (2-19). The total number of cycles of NAB-paclitaxel in the study population was 65. Seven subjects were treated in combination with bevacizumab. Of these, three subjects are still alive and one subject is currently receiving active treatment with NAB-paclitaxel. The median PFS and OS for all subjects that met mortality endpoint was 4.8 months and 8.9 months (n = 7), respectively. One subject discontinued NAB-paclitaxel secondary to peripheral neuropathy, and one subject developed a vesicovaginal fistula while obtaining combination NAB-paclitaxel and bevacizumab therapy. CONCLUSIONS: NAB-paclitaxel with or without bevacizumab is tolerable and potentially active in treating recurrent cervical cancer after failing platinum-taxane or topotecan chemotherapy. This small case series deserves confirmation through prospective clinical trials.

Genomic heterogeneity and instability in colorectal cancer: spectral karyotyping, glutathione transferase-Ml and ras.

Genomic instability in cancer is frequently described as being either chromosomal instability or microsatellite instability, although when events within chromosomes are monitored, extensive intrachromosomal instability is also found. Spectral karyotyping was used to visualize how extensively genomic instability gives rise to intratumor genomic heterogeneity in sporadic colorectal carcinomas. Two factors were then examined which might relate to intrachromosomal instability in colorectal cancers: the presence of the glutathione transferase-Ml gene to detoxify potential carcinogens, and the presence of activated ras which has been associated with chromosomal instability when first expressed. Intrachromosomal genomic instability was previously determined by inter-(simple sequence repeat) PCR (inter-SSR PCR) and by fractional allelic loss rate for 348 markers. GSTM1 status was determined for each of 49 tumors through use of specific PCR, and 28 of the tumors showed the GSTM1 null genotype. A significant association was found between GSTMl-null status and elevated inter-(simple sequence repeat) PCR instability. In contrast, no association was found with fractional allelic loss rate. The first exons of the K-ras and H-ras oncogenes were sequenced in 72 colorectal cancers; 19 of the tumors had a mutation in codon 12 of the K-ras gene (24.5%), but no H-ras mutations were found. A weak correlation (p=0.10) was observed between mutant K-ras and inter-(simple sequence repeat) PCR genomic instability, and no association existed with fractional allelic loss rate.

Targeted therapy in ovarian cancer.

Ovarian cancer is the most common cause of mortality of tumors from gynecologic origin and is often diagnosed after patients have already progressed to advanced disease stage. The current standard of care for treatment of ovarian cancer includes cytoreductive surgery followed by adjuvant chemotherapy. Unfortunately, many patients will recur and ultimately die from their disease. Targeted therapies have been evaluated in ovarian cancer as a method to overcome resistant disease. Angiogenesis inhibitors have shown success in many tumor types and have also demonstrated promise in trials involving patients with ovarian cancer. PARP inhibitors may be potentially active agents in patients with BRCA-associated ovarian cancer. Trials that have evaluated combinations of targeted agents have often revealed untoward toxicities, thus tempering enthusiasm for this approach.

Cervical cancer therapy: current, future and anti-angiogensis targeted treatment.

While the incidence of cervical cancer has declined significantly in the USA, ethnic disparities remain in terms of increased mortality and morbidity. Furthermore, this disease continues to be a significant burden on developing countries, with cervical cancer currently ranked as the second most common cause of cancer-related morbidity and the third most common cause of mortality worldwide. Treatment of cervical cancer has typically been viewed as surgical with possible adjuvant therapy versus initial radiotherapy and platinum-based chemotherapy. Prognosis and therapy for patients with recurrent disease is dependent upon the site of recurrence and ability to pursue curative therapy. This article will review the management of cervical cancer, including studies that have evaluated the treatment of distant metastasis or recurrent disease, as well as discussing the importance of angiogenesis and the use of therapies targeted against this phenomenon.

Catalysis of strand annealing by replication protein A derives from its strand melting properties.

Eukaryotic DNA-binding protein replication protein A (RPA) has a strand melting property that assists polymerases and helicases in resolving DNA secondary structures. Curiously, previous results suggested that human RPA (hRPA) promotes undesirable recombination by facilitating annealing of flaps produced transiently during DNA replication; however, the mechanism was not understood. We designed a series of substrates, representing displaced DNA flaps generated during maturation of Okazaki fragments, to investigate the strand annealing properties of RPA. Until cleaved by FEN1 (flap endonuclease 1), such flaps can initiate homologous recombination. hRPA inhibited annealing of strands lacking secondary structure but promoted annealing of structured strands. Apparently, both processes primarily derive from the strand melting properties of hRPA. These properties slowed the spontaneous annealing of unstructured single strands, which occurred efficiently without hRPA. However, structured strands without hRPA displayed very slow spontaneous annealing because of stable intramolecular hydrogen bonding. hRPA appeared to transiently melt the single strands so that they could bind to form double strands. In this way, melting ironically promoted annealing. Time course measurements in the presence of hRPA suggest that structured single strands achieve an equilibrium with double strands, a consequence of RPA driving both annealing and melting. Promotion of annealing reached a maximum at a specific hRPA concentration, presumably when all structured single-stranded DNA was melted. Results suggest that displaced flaps with secondary structure formed during Okazaki fragment maturation can be melted by hRPA and subsequently annealed to a complementary ectopic DNA site, forming recombination intermediates that can lead to genomic instability.