D. K. Vijaykumar

Sequential release of epigallocatechin gallate and paclitaxel from PLGA-casein core/shell nanoparticles sensitizes drug-resistant breast cancer cells

UNLABELLED Nanomedicines consisting of combinations of cytotoxic drugs and molecular targeted therapeutics which inhibit specific downstream signals are evolving as a novel paradigm for breast cancer therapy. This research addresses one such combination of Paclitaxel (Ptx), having several adversities related to the activation of NF-κB pathway, with Epigallocatechin gallate (EGCG), a multiple signaling inhibitor, encapsulated within a targeted core/shell PLGA-Casein nanoparticle. The sequential release of EGCG followed by Ptx from this core/shell nanocarrier sensitized Ptx resistant MDA-MB-231 cells to Ptx, induced their apoptosis, inhibited NF-κB activation and downregulated the key genes associated with angiogenesis, tumor metastasis and survival. More importantly, Ptx-induced expression of P-glycoprotein was repressed by the nanocombination both at the protein and gene levels. This combination also offered significant cytotoxic response on breast cancer primary cells, indicating its translational value. FROM THE CLINICAL EDITOR Breast cancer is the most common cancer in women worldwide. As well as surgery, chemotherapy plays a major role in the treatment of breast cancer. The authors investigated in this article the combination use of a chemotherapeutic agent, Paclitaxel (Ptx), and an inhibitor of NF-?B pathway, packaged in a targeted nano-based delivery platform. The positive results provided a new pathway for future clinical use of combination chemotherapy in breast cancer.

Neuroendocrine tumor of vulva: a case report and review of literature.

Neuroendocrine tumor (Merkel cell carcinoma-MCC) of the vulva is a very rare entity with less than 15 cases reported in the English literature. It is known for its aggressive behaviour and propensity for early dissemination. The actual cell of origin and etiology of this disease is controversial. In absence of any definite guidelines for management (due to its rarity), extrapolation of data from extra-vulvar MCC seems logical. We present a case of vulvar neuroendocrine tumor who presented at a locally advanced stage.

Correlation of clinico-pathologic and radiologic parameters of response to neoadjuvant chemotherapy in breast cancer

CONTEXT As of today, there is no validated standard method to assess clinical response of breast cancer to neo- adjuvant chemotherapy (NACT). Some centers use clinical dimensions while others use radiological measurements to evaluate response according to RECIST criteria. AIMS The aim was to correlate and compare the clinical, radiological, and pathological parameters for assessing the tumor response in patients of breast cancer receiving NACT. SETTINGS AND DESIGN Single institution, prospective nonrandomized study conducted over a 2-year period. MATERIALS AND METHODS Patients with diagnosed breast cancer were assessed for response to NACT prior to surgery using clinical and radiological techniques. This was correlated with pathological reponse which was assessed by measuring gross dimensions and Miller-Payne grading of response to chemotherapy. STATISTICAL ANALYSIS USED Spearmans rho nonparametric. RESULTS Fifty two patients completed the evaluation (out of 313 cases of ca breast treated during the same period) with a median age of 52.5 years. We noted a 26.9% clinical complete response (CR) and 19.2% had pathological CR. Clinical evaluation had a sensitivity and specificity of 73.5% and 88.5% respectively compared to 14.2% and 100% respectively for radiological assessment. CONCLUSIONS Clinical assessment of response to NACT shows a higher sensitivity compared to radiological assessment. However the overall low sensitivity and specificity rates of clinical assessment mandate a search for a better method of evaluation.

Evolution of surgery in advanced epithelial ovarian cancer in a dedicated gynaecologic oncology unit-seven year audit from a tertiary care centre in a developing country.

Aims To audit our performance as a dedicated gynaecologic oncology unit and to analyse how it has evolved over the years. To retrospectively evaluate the outcome of advanced ovarian cancer treated with neoadjuvant chemotherapy (NACT) followed by interval surgery versus upfront surgery. Methods and results One hundred and ninety-eight patients with advanced epithelial ovarian cancer (EOC) who were treated from 2004 to 2010 were analysed. Eighty-two patients (41.4%) underwent primary surgery and 116 (58.6%) received NACT. Overall, an optimal debulking rate of 81% was achieved with 70% for primary surgery and 88% following NACT. The optimal cytoreduction rate has improved from 55% in 2004 to 97% in 2010. In primary surgery, the optimal debulking rate increased from 42.8% in 2004 to 93% in 2010, whereas in NACT group the optimal cytoreduction rate increased from 60% to 100% by 2010. On the basis of the surgical complexity scoring system it was found that surgeries with intermediate complexity score had progressively increased over the years. There was a mean follow-up of 21 months ranging from 6 to 70 months. The progression-free survival and overall survival (OS) in patients undergoing primary surgery were 23 and 40 months, respectively, while it was 22 and 40 months in patients who received NACT. However, patients who had suboptimal debulking, irrespective of primary treatment, had significantly worse OS (26 versus 47 months) compared with those who had optimal debulking. Conclusions As a dedicated gynaecologic oncology unit there has been an increase in the optimal cytoreduction rates. The number of complex surgeries, as denoted by the category of intermediate complexity score, has increased. Patients with advanced EOC treated with NACT followed by interval debulking have comparable survival to the patients undergoing primary surgery. Optimal cytoreduction irrespective of primary modality of treatment gives better survival.

Surgical treatment pattern and outcomes in epithelial ovarian cancer patients from a cancer institute in Kerala, India.

Objective To evaluate the treatment and survival pattern of patients with advanced epithelial ovarian cancer. Methods and results Retrospective study of all advanced epithelial ovarian cancer patients treated in the department of gynaecologic oncology from an academic centre, in a four year period from 1 January 2008–31 December 2011. Selection criteria All patients with advanced epithelial ovarian cancer (stage III and IV) who underwent surgery from 2008–2011and had a follow-up of at least three months after completion of treatment were included. The decision on whether primary surgery or neoadjuvant chemotherapy (NACT) in advanced ovarian cancer was based on age, performance status, clinical and imaging findings. Results A total of 178 cases of epithelial ovarian cancer were operated on during this four year period. Among them 28 patients were recurrent cases, 22 had early stages of ovarian cancer, and the rest 128 had stage III and IV ovarian cancer. In these 128 patients, 50(39.1%) underwent primary surgery and 78(60.9%) had NACT followed by surgery. In the primary surgery group 36(72.0%) patients had optimal debulking while in the NACT group 59(75.6%) patient had optimal debulking. With a median follow-up of 34 months, the median overall survival (OS) and progression free survival (PFS) was 53 and 49 months respectively. Patients who underwent primary surgery had better median PFS than patients who had NACT (56 months versus 39 months, p = 0.002). In stage III C the difference median PFS was significant for those treated with primary surgery when compared with NACT (55 months versus 39 months, p = 0.012). In patients who had optimal debulking to no residual disease (n = 90), primary surgery gave a significant improved PFS (59 months versus 38 months, p = 0.001) when compared with NACT. In univariate analysis, NACT was associated with increased risk of death (HR: 0.350; CI: 0.177–0.693). Conclusion In advanced epithelial ovarian cancer, primary surgery seems to have a definite survival advantage over NACT in patients who can be optimally debulked to no residual disease.

A prospective comparison of perioperative morbidity in advanced epithelial ovarian cancer: Primary versus interval cytoreduction - experience from India.

Objectives: The objective was to compare perioperative morbidity and mortality of patients with advanced epithelial ovarian cancer (EOC) treated with either of the two treatment approaches; neoadjuvant chemotherapy (NACT) followed by interval debulking versus upfront surgery. Design: Prospective comparative observational study. Participants: In total, 51 patients were included in the study. All patients with diagnosed advanced EOC (International Federation of Gynecology and Obstetrics IIIC and IV) presenting for the 1st time were included in the study. Interventions: Patients were either operated upfront (n = 19) if deemed operable or were subjected to NACT followed by interval debulking (n = 32). Primary and Secondary Outcomes: Intra- and postoperative morbidity and mortality were the primary outcome measures. Results: Patients with interval cytoreduction were noted to have significantly lesser operative time, blood loss, and extent of surgery. Their discharge time was also significantly earlier. However, they did not differ from the other group vis. a vis. postoperative complications or mortality. Conclusions: Neoadjuvant chemotherapy although has a positive impact on various intraoperative adverse events, fails to show any impact on immediate postoperative negative outcomes.

Long-term drug delivery using implantable electrospun woven polymeric Nanotextiles

A woven nanotextile implant was developed and optimized for long-term continuous drug delivery for potential oncological applications. Electrospun polydioxanone (PDS) nanoyarns, which are twisted bundles of PDS nanofibres, were loaded with paclitaxel (PTX) and woven into nanotextiles of different packing densities. A mechanistic modeling of in vitro drug release proved that a combination of diffusion and matrix degradation controlled the slow PTX-release from a nanoyarn, emphasizing the role of nanostructure in modulating release kinetics. Woven nanotextiles, through variations in its packing density and thereby architecture, demonstrated tuneable PTX-release. In vivo PTX-release, pharmacokinetics and biodistribution were evaluated in healthy BALB/c mice by suturing the nanotextile to peritoneal wall. The slow and metronomic PTX-release for 60 days from the loosely woven implant was extremely effective in enhancing its residence in peritoneum, in contrast to intraperitoneal injections. Such an implantable matrix offers a novel platform for therapy of solid tumors over prolonged durations.