Low-dose fractionated radiation and chemotherapy prior to definitive chemoradiation in locally advanced carcinoma of the uterine cervix: Results of a prospective phase II clinical trial.

BACKGROUND: We investigated the feasibility of neoadjuvant low-dose radiation and chemotherapy with paclitaxel and carboplatin (LDCRT) before radical chemoradiation (CRT) and assessed the feasibility, efficacy, and response rate to such a regimen. METHODS: This is a single-arm phase II trial of 24 patients, with locally advanced squamous cell carcinoma of the cervix (stage IIB-IIIB). Patients received low-dose fractionated radiotherapy, carboplatin (AUC×5) and paclitaxel (175 mg/m(2)), three weekly for two cycles followed by CRT. The primary end point was overall and disease-free survival. RESULTS: Mean age of the patients at diagnosis was 50 years; Radiological complete or partial response rate was 40% and 60%, respectively, post-LDCRT. The median follow-up was 30 months (24-36 months). Both overall and progression-free survivals at 2.5 years were 84%. Grade 3/4 toxicities were 24% hematological toxicity during LDCRT and 46% during CRT (hematological: 42%, non-hematological: 4%). CONCLUSION: A good response rate is achieved by low-dose radiation and chemotherapy with carboplatin and paclitaxel followed by radical CRT. This treatment regimen is feasible and effective as evidenced by the acceptable toxicity and 84% local control at 2.5 years.

Accuracy of relocation, evaluation of geometric uncertainties and clinical target volume (CTV) to planning target volume (PTV) margin in fractionated stereotactic radiotherapy for intracranial tumors using relocatable Gill-Thomas-Cosman (GTC) frame.

The present study is aimed at determination of accuracy of relocation of Gill-Thomas-Cosman frame during fractionated stereotactic radiotherapy. The study aims to quantitatively determine the magnitudes of error in anteroposterior, mediolateral and craniocaudal directions, and determine the margin between clinical target volume to planning target volume based on systematic and random errors. Daily relocation error was measured using depth helmet and measuring probe. Based on the measurements, translational displacements in anteroposterior (z), mediolateral (x), and craniocaudal (y) directions were calculated. Based on the displacements in x, y and z directions, systematic and random error were calculated and three-dimensional radial displacement vector was determined. Systematic and random errors were used to derive CTV to PTV margin. The errors were within ± 2 mm in 99.2% cases in anteroposterior direction (AP), in 99.6% cases in mediolateral direction (ML), and in 97.6% cases in craniocaudal direction (CC). In AP, ML and CC directions, systematic errors were 0.56, 0.38, 0.42 mm and random errors were 1.86, 1.36 and 0.73 mm, respectively. Mean radial displacement was 1.03 mm ± 0.34. CTV to PTV margins calculated by ICRU formula were 1.86, 1.45 and 0.93 mm; by Stroom's formula they were 2.42, 1.74 and 1.35 mm; by van Herk's formula they were 2.7, 1.93 and 1.56 mm (AP, ML and CC directions). Depth helmet with measuring probe provides a clinically viable way for assessing the relocation accuracy of GTC frame. The errors were within ± 2 mm in all directions. Systematic and random errors were more along the anteroposterior axes. According to the ICRU formula, a margin of 2 mm around the tumor seems to be adequate.

Molecular variants of HPV-16 associated with cervical cancer in Indian population.

Human papilloma virus is a causative factor in the etiology of cervical cancer with HPV16 being the most prevalent genotype associated with it. Intratype variations in oncogenic E6/E7 and capsid L1 proteins of HPV 16 besides being of phylogenetic importance, are associated with risk of viral persistence and progression. The objective of this multicentric study was to identify HPV-16 E6, E7 and L1 variants prevalent in India and their possible biological effects. Squamous cell cervical cancer biopsies were collected from 6 centres in India and examined for the presence of HPV 16. Variants of HPV-16 were characterized by full length sequence analysis of L1, E6 and E7 genes in 412 samples. Similar distribution of the variants was seen from the different centres/regions, with the European variant E350G being the most prevalent (58%), followed by American Asian variant (11.4%). Fifty six changes were seen in E6 region, 31 being nonsynonymous. The most frequent being L83V (72.3%), Q14H (13.1%) and H78Y (12.1%). Twenty-nine alterations were seen in E7 region, with 12 being nonsynonymous. The most frequent being F57V (9%). L1 region showed 204 changes, of which 67 were nonsynonymous. The most frequent being 448insS (100%), and 465delD (100%), H228D (94%), T292A (85%). The identified variants some new and some already reported can disrupt pentamer formation, transcriptional regulation of the virus, L1 protein interface interaction, B and T cell epitopes, p53 degradation, and thus their distribution is important for development of HPV diagnostics, vaccine, and for therapeutic purpose.

Anti-proliferative and apoptotic effects of celecoxib on human chronic myeloid leukemia in vitro.

Celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, is the only non-steroidal anti-inflammatory drug so far which has been approved by the FDA for adjuvant treatment of patients with familial adenomatous polyposis. The molecular mechanism responsible for the anti-cancer effects of celecoxib is not fully understood. There is little data on the potential role of COX-2 in lymphoma pathogenesis. In view of the reported induction of apoptosis in cancer cells by cyclooxygenase-2 inhibitors, the present study is undertaken to test the effect of celecoxib on human chronic myeloid leukemia cell line, K562 and other hematopoietic cancer cell lines like Jurkat (human T lymphocytes), HL60 (human promyelocytic leukemia) and U937 (human macrophage). Treatment of these cells with celecoxib (10-100 microM) dose-dependently, reduced cell growth with arrest of the cell cycle at G0/G1 phase and induction of apoptosis. Further mechanism of apoptosis induction was elucidated in detail in K562 cell line. Apoptosis was mediated by release of cytochrome c into the cytoplasm and cleavage of poly (ADP-ribose) polymerase-1 (PARP-1). This was followed by DNA fragmentation. The level of anti-apoptotic protein Bcl-2 was decreased without any change in the pro-apoptotic Bax. Celecoxib also inhibited NF-kB activation. Celecoxib thus potentiates apoptosis as shown by MTT assay, cytochrome c leakage, PARP cleavage, DNA fragmentation, Bcl-2 downregulation and possibly by inhibiting NF-kB activation.

Radiation Pneumonitis After Conventional Radiotherapy For Breast Cancer: A Prospective Study.

BACKGROUND: Loco-regional radiotherapy is an important treatment modality in breast cancer and radiation pneumonitis (RP) is one of the early toxicities. AIM: To study the occurrence, correlation of RP with patient and radiotherapy related factors and the effects on pulmonary function following conventional radiotherapy in breast cancer. SETTINGS AND DESIGN: Prospective study, from a tertiary hospital in a developing country. MATERIALS AND METHODS: Prospective analysis of clinical symptoms, pulmonary function and radiologic changes was done prior to and 12 weeks after adjuvant radiotherapy (n=46). Statistical analysis was done using SPSS version 10 software. RESULTS: Radiological and clinical RP was seen in 45.65% (n=21) and 19.56% (n=9) respectively. RP was significantly higher with age >50 years (OR 4.4), chest wall irradiation with electrons, (electrons 83.3% vs cobalt60 32.4%, p=0.02) and supraclavicular field treatment with 6 MV photons (p= 0.011). There was significant relationship between Inferior Lung Distance (ILD) and RP (p=0.013). The fall in Total Lung Capacity (TLC) was significantly more in those with RP (p=0.02). CONCLUSION: Clinical RP occurs in almost one-fifth of breast cancer patients treated with conventional radiotherapy. Chest wall irradiation with electrons, supraclavicular field irradiation with 6 MV photons, higher ILD and age >50 years was associated with increased RP. The pulmonary function parameter most affected was TLC. The factors associated with increased RP should be considered when adjuvant radiotherapy is planned to minimize its likelihood and intervene appropriately.

Hyperfractionation in advanced carcinoma of the uterine cervix: a preliminary report.

Experience with twice-a-day radiation therapy program for carcinoma of the uterine cervix (FIGO Stages IIB, IIIA & IIIB) is presented. The program consists of delivering 120 cGy per fraction, two fractions a day with 6 hours between fractions. A total of 6000 cGy was delivered in 50 fractions over 5 weeks. A control group was given conventional fractionation 5000 cGy in 25 fractions, 200 cGy per fraction over 5 weeks. This feasibility study enrolled 30 patients, 15 in each group. Normal tissue reactions in skin, mucosa and bowel were recorded. The acute normal tissue reactions were enhanced in the hyperfractionation group. This was significant with regard to the bowel complications. The tumor control rate did not show any significant difference between the two groups. A short follow-up period has revealed complete healing of all acute normal tissue reactions. This study shows that further dose escalation is feasible and a study with large sample size and longer follow-up is required to reach definite conclusions.

Adenoid cystic carcinoma of the external auditory canal with pulmonary, renal and liver metastases.

We report a patient with adenoid cystic carcinoma of the external auditory canal with multiple pulmonary, liver and renal secondaries. She had a palpable left renal mass. The clinical course and treatment of this unusual neoplasm as reported in literature are briefly reviewed.

Primary papillary carcinoma in a thyroglossal cyst.

Papillary carcinoma arising in a thyroglossal cyst is rare. There is controversy regarding optimum management. We report a case managed by Sistrunk's procedure and external radiotherapy and review the literature on the subject.

Translating evidence into practice in low resource settings: cervical cancer screening tests are only part of the solution in rural India.

BACKGROUND: The majority of women in rural India have poor or no access to cervical cancer screening services, although one-quarter of all cervical cancers in the world occur there. Several large trials have proven the efficacy of low-tech cervical cancer screening methods in the Indian context but none have documented the necessary components and processes of implementing this evidence in a low-resource setting. METHODS: This paper discusses a feasible model of implementation of cervical cancer screening programme in low-resource settings developed through a pilot research project carried out in rural Tamilnadu, India. The programme used visual inspection of cervix after acetic acid application (VIA) as a screening tool, nurses in the primary care centres as the primary screeners and peer educators within Self-Help Women groups to raise community awareness. RESULTS: The uptake of screening was initially low despite the access to a screening programme. However, the programme witnessed an incremental increase in the number of women accessing screening with increasing community awareness. CONCLUSIONS: The investigators recommend 4 key components to programme implementation in low-resource setting: 1) Evidence-based, cost-effective test and treatment available within the reach of the community; 2) Appropriate referral pathways; 3) Skilled health workers and necessary equipment; and 4) Optimisation of health literacy, beliefs, attitudes of the community.

Nanotechnology in oncology: Characterization and in vitro release kinetics of cisplatin-loaded albumin nanoparticles: Implications in anticancer drug delivery.

CONTEXT: Nanotechnology is an empowering technology that holds promise in cancer therapeutics by increasing the ratio of tumor control probability to normal tissue complication probability. It can increase the bioavailability of the drug at the target site, reduce the frequency of administration and reach otherwise lesser-accessible sites. The present study shows the feasibility of the cisplatin-loaded albumin nanoparticle as a sustained delivery system. AIMS: Cisplatin is one of the most widely used chemotherapeutic agents for the treatment of malignant disorders. Conventional cisplatin formulation given as intravenous infusion has low bioavailability to the target organ in addition to significant side-effects, like ototoxicity and nephrotoxicity. The aim of this study was to develop a protein-based nanoparticulate system for sustained release of cisplatin. MATERIALS AND METHODS: Nanoparticles were prepared by the coacervaton method of microcapsulation and chemical cross-linking with glutaraldehyde. Particle size was characterized by dynamic light scattering and transmission electron microscopy. RESULTS AND CONCLUSIONS: Using the coacervation method, nanoparticles of less than 70 nm diameter were produced. Drug encapsulation measured by ultraviolet spectroscopy varied from 30% to 80% for different ratios of cisplatin and protein. In vitro release kinetics shows that the nanoparticle-based formulation has biphasic release kinetics and is capable of sustained release compared with the free drug (80% release in 45 h). The study proves the feasibility of the albumin-based cisplatin nanoparticle formulation as a sustained release vehicle of cisplatin.

Transient asymptomatic bradycardia in patients on infusional 5-fluorouracil.

The incidence of 5-fluorouracil (5-FU)-related cardiotoxicity seems to be dosage and schedule dependent. Although various other cardiac events have been reported in literature, a series of patients having transient asymptomatic bradycardia has not been reported in the literature as yet. We report such a series of patients who had transient asymptomatic bradycardia after being treated with continuous infusion 5-FU. We plan to do a Holter study during the period of bradycardia in subsequent patients and this may throw more light on the issue.

Primary small intestinal lymphoma.

Gastro-intestinal tract is the most common site of extranodal presentation in non-Hodgkin's lymphoma. Among the subsites the small intestine predominates. This paper presents a review of 21 cases of primary gastro-intestinal lymphoma seen at the Department of Radiation Oncology, Christian Medical College, Vellore, during the period 1979-1986. All patients had laparotomy, and biopsy from the primary site. Histopathological subtypes were done in the International Working Formulation. Stage groupings were done applying the Crowther and Blackledge staging system. Post-laparotomy treatment decision was made depending on the patient's general condition, completeness of surgery and histological subtype. The overall survival rate was 31.5% at 5 years. Early stage disease and high-grade lymphomas have a better prognosis if treated adequately.

Pulmonary metastases from ameloblastoma of the mandible treated with cisplatin, adriamycin, and cyclophosphamide.

A case of delayed pulmonary metastases from an ameloblastoma of the mandible, which occurred 20 years after surgical resection of the primary tumor but with no recurrence at the primary site, is reported. Combination chemotherapy using cisplatin, adriamycin, and cyclophosphamide has produced a very good clinical and radiologically documented response in this case.

C-Phycocyanin, a selective cyclooxygenase-2 inhibitor, induces apoptosis in lipopolysaccharide-stimulated RAW 264.7 macrophages.

C-Phycocyanin (C-PC) is one of the major biliproteins of Spirulina platensis, a blue green algae, with antioxidant and radical scavenging properties. It is also known to exhibit anti-inflammatory and anti-cancer properties. However, the mechanism of action of C-PC is not clearly understood. Previously, we have shown that C-PC selectively inhibits cyclooxygenase-2 (COX-2), an inducible isoform that is upregulated during inflammation and cancer. In view of the reported induction of apoptosis in cancer cells by cyclooxygenase-2 inhibitors, the present study is undertaken to test the effect of C-PC on LPS stimulated RAW 264.7 mouse macrophage cell line. These studies have shown a dose dependent reduction in the growth and multiplication of macrophage cell line by C-PC. This decrease in cell number appears to be mediated by C-PC induced apoptosis as evidenced by flow cytometric and confocal microscopic studies. Cells treated with 20 micro M C-PC showed typical nuclear condensation and 16.6% of cells in sub-G(o)/G(1) phase. These cells also showed DNA fragmentation in a dose dependent manner. The studies on poly(ADP ribose) polymerase (PARP) cleavage showed typical fragmentation pattern in C-PC treated cells. This C-PC induced apoptosis in RAW 264.7 cells appears to be mediated by the release of cytochrome c from mitochondria and independent of Bcl-2 expression. These effects of C-PC on RAW 264.7 cells may be due to reduced PGE(2) levels as a result of COX-2 inhibition.

Anti-inflammatory properties of BHUx, a polyherbal formulation to prevent atherosclerosis.

BHUx is a polyherbal formulation consisting of water-soluble fractions of five medicinal plants (Commiphora mukul, Terminalia arjuna, Boswellia serrata, Semecarpus anacardium and Strychnos nux vomica). The present study was undertaken to evaluate its antioxidant and antiinflammatory effects. BHUx, standardized by HPLC fingerprinting and filtered through 0.2 microm filter paper, was employed for different studies under in vivo and in vitro conditions. Under in vivo conditions, BHUx significantly reduced inflammation in the carrageenan-induced rat paw oedema model of inflammation, suggesting its anti-inflammatory properties. In order to test the mechanism of action of BHUx, further in vitro studies were undertaken on cumene-hydroperoxide-induced lipid peroxidation (CHP) in liver homogenate, LPS-induced NO production in peritoneal macrophages and on key enzymes of arachidonic acid cascade, involved in the mediation of inflammation. Under the conditions, BHUx showed concentration-dependent inhibition of CHP-induced lipid peroxidation in liver homogenate, suggesting its antioxidant properties. Similarly the potent anti-inflammatory effects of BHUx are evident by (a) preferential inhibition of COX-2 (IC50 for COX-2 = 80 microg/ml and IC50 for COX-1 = 169 microg/ml), (b) low ratios in the IC50 values of COX-2/COX-1 (0.47), (c) decreased production of NO in LPS-induced peritoneal macrophages and (d) inhibition of 5-LOX (IC50 = 795 microg/ml). BHUx also showed a preference for inhibiting 15-lipoxygenase (IC50 = 44 microg/ml), a key enzyme implicated in LDL oxidation. These studies suggest that BHUx is acting mainly at three levels, i.e., as a potent natural antioxidant, by reduction of key inflammatory mediators of arachidonic acid cascade and by preventing 15-LOX-mediated LDL oxidations, to prevent atherosclerosis.

Maternal plasma hypertonicity is accentuated in the postterm rat.

OBJECTIVE: In humans and rats, pregnancy-associated maternal plasma volume expansion and plasma hypotonicity may facilitate maternal-to-fetal water transfer. Although reduced amniotic fluid volume occurs commonly in postterm pregnancy, the mechanisms are unknown. We previously demonstrated a reversal of pregnancy-induced maternal plasma hypotonicity that occurs in the near term (20 days) pregnant rats. We sought to determine whether the relative maternal plasma hypertonicity continues in the postterm period. STUDY DESIGN: Rat gestation (normal, 21 days) was prolonged with subcutaneous progesterone injection. Pregnant rats at gestation, 18 days, 21 days, and 24 days and nonpregnant rats were studied. Maternal and fetal hematocrit levels, plasma osmolality, electrolyte levels, and amniotic fluid volume were determined. In addition, maternal and fetal tissues were analyzed for water and electrolyte content. RESULTS: Compared with term (21days), postterm pregnant rats (24 days) had a significant increase in maternal and fetal plasma osmolality (293.7+/-1.4 mOsm/kg vs 302.8+/-3.7 mOsm/kg and 301.0+/-2.0 mOsm/kg vs 310.3+/-3.2 mOsm/kg, respectively; P<.01) and sodium and chloride concentrations. Conversely, both maternal and fetal hematocrit levels decreased significantly in the postterm period. Postterm rats demonstrated an increased fetal mortality rate (24%) and a significantly reduced amniotic fluid volume (4.2+/-0.6 mL vs 6.6+/-0.6 mL, P<.01). CONCLUSION: These results indicate that the near-term reversal of maternal plasma hypotonicity that has been observed previously is further accentuated in the postterm pregnancy. This continued hypertonicity may induce a fetal-to-maternal water flow and contribute to postterm oligohydramnios and increased fetal morbidity and mortality rates.