Photodynamic antimicrobial chemotherapy (PACT) for the treatment of malaria, leishmaniasis and trypanosomiasis

A photodynamic effect occurs when photosensitiser molecules absorb light and dissipate the absorbed energy by transferring it to biological acceptors (usually oxygen), generating an excess of reactive species that are able to force cells into death pathways. Several tropical diseases present physiopathological aspects that are accessible to the application of a photosensitiser and local illumination. In addition, disease may be transmitted through infected blood donations, and many of the aetiological agents associated with tropical diseases have been shown to be susceptible to the photodynamic approach. However, there has been no systematic investigation of the application of photoantimicrobial agents in the various presentations, whether to human disease or to the disinfection of blood products or even as photo-insecticides. We aim in this review to report the advances in the photoantimicrobial approach that are beneficial to the field of anti-parasite therapy and also have the potential to facilitate the development of low-cost/high-efficiency protocols for underserved populations.

Accelerating aging chemotherapy on aged animals: Protective effect from nutraceutical modulation

The aim of this study was to test a novel phytocompound in an experimental model of antitumor-induced immunosuppression. Five groups of mice were considered: young (Y) and aged (A) that were given intraperitoneally 10 doses of cyclophosphamide (CPX, 25mg/kg/bw) or CPX plus (150 mg/kg/bw) of the nutraceutical DTS (Denshichi-Tochiu-Sen), and control. After sacrifice, macrophage chemotaxis and serum levels of IFN-gamma, IL-2, and GM-CSF were determined. Liver and urinary bladder were examined histologically, as were the liver and kidney for redox enzymes. CPX significantly decreased macrophage chemotaxis and all cytokines (p < 0.05, A >> Y). DTS restored macrophage function and cytokine concentration (p < 0.001) and partly improved the necro-inflammatory score and substance P receptor expression in the bladder and the redox status in liver and kidney (p < 0.05). Such data suggest that DTS effectively prevents CPX-induced immune suppression and oxidative-inflammatory damage, which are particularly enhanced in aged organisms.

Treatment of Osteomyelitis in the Feet of Diabetic Patients by Photodynamic Antimicrobial Chemotherapy

Objective: This article describes two inexpensive photodynamic antimicrobial chemotherapy (PACT) protocols to provide intensive local care on ulcerated feet of diabetic patients with osteomyelitis. Background Data: Patients with this condition generally have poor quality of life. The usual treatment consists of the administration of a cocktail of drugs including anti-inflammatories, promoters of blood circulation, and systemic antibiotics. However, depending on the conditions of the tissues, amputation may be required. Consequently, it is important to develop PACT protocols that can help avoid amputation. Materials and Methods: Two PACT protocols were applied to two diabetic patients with osteomyelitis. These protocols were based on several PACT sessions that consisted of: (1) local injection of mixtures of phenothiazines (2% in water) and Hypericum perforatum extract (10% in propylene glycol), and (2) illumination, lasting 10 min, applied to the lesion's interior and exterior using, respectively, an optical fiber and a non-coherent light source. The frequency of PACT was daily or every other day in the beginning, and weekly after tissue recovery begun. The patients were followed clinically and by radiographic testing. Results: Both PACT protocols helped cure these patients who were about to have amputation of their feet. Radiograms showed that bone had healed and that the bone's texture had improved. Conclusion: Here we have described efficient and affordable PACT protocols to treat osteomyelitis in the feet of diabetic patients. This treatment modality should be considered by vascular surgeons and by orthopedists to treat osteomyelitis that is resistant to conventional treatments.

The Outcomes of Visualization and Acupuncture on the Quality of Life of Adult Cancer Patients Receiving Chemotherapy

Background: The use of complementary and alternative medicine (CAM) to treat cancer patients has increased around the world, and its benefits have been described. These therapies represent an important theme in oncology and have been used in parallel with conventional therapies. Objective: This study aimed to assess the outcomes of using relaxation with visualization and acupuncture on the quality of life of cancer patients undergoing chemotherapy treatment and to compare these outcomes with patients who did not choose to receive the intervention. Methods: Participants chose to be in either the intervention group (IG) or control group (CG). They completed the Quality of Life Questionnaire-Core 30 at the start and end of chemotherapy. The IG was chosen by 38 patients with different types of cancer who completed weekly relaxation with visualization and acupuncture sessions, whereas the CG was composed of 37 patients who did not receive the intervention. Results: Statistically significant results evidenced an increase in global health and emotional and social functions and a decrease in fatigue and loss of appetite for the IG, and an increase in global health for the CG (P <= .05). A highly significant difference was found when comparing the post-chemotherapy scores of the Quality of Life Questionnaire-Core 30 in the global health domain between the CG and the IG (P <= .001), indicating positive outcomes of the CAM intervention. Conclusion: Adults with cancer are able to choose between involvement or not with this kind of CAM intervention. Global health could be improved by participating in this type of intervention. Implications for Practice: Choosing whether to be involved may be assisted by knowing the positive outcomes for some patients.

The therapeutic potential of recombinant BCG expressing the antigen S1PT in the intravesical treatment of bladder cancer

Purpose: Bacillus Calmette-Guerin (BCG) continues to be employed as the most effective immunotherapy against superficial bladder cancer. We have developed an rBCG-S1PT strain that induces a stronger cellular immune response than BCG. This preclinical study was designed to test the potential of rBCG-S1PT as an immunotherapeutic agent for intravesical bladder cancer therapy. Materials and methods: A tumor was induced in C57BL/6 mice after chemical cauterization of the bladder and inoculation of the tumor cell line MB49. Next, mice were treated by intravesical instillation with BCG, rBCG-S1PT, or PBS once a week for 4 weeks. After 35 days, the bladders were removed and weighed, Th1 (IL-2, IL-12, INOS, INF-gamma, TNF-alpha), and Th2 (IL-5, IL-6, IL-10, TGF-beta) cytokine mRNA responses in individual mice bladders were measured by quantitative real time PCR, and the viability of MB49 cells in 18-hour coculture with splenocytes from treated mice was assessed. In an equivalent experiment, animals were observed for 60 days to quantify their survival. Results: Both BCG and rBCG-S1PT immunotherapy resulted in bladder weight reduction, and rBCG-S1PT increased survival time compared with the control group. There were increases in TNF-alpha in the BCG treated group, as well as increases in TNF-alpha and IL-10 mRNA in the rBCG-S1PT group. The viability of MB49 cells cocultured with splenocytes from rBCG-S1PT-treated mice was lower than in both the BCG and control groups. Conclusions: rBCG-S1PT therapy improved outcomes and lengthened survival times. These results indicate that rBCG could serve as a useful substitute for wild-type BCG. (C) 2010 Elsevier Inc. All rights reserved.

Uptake by breast carcinoma of a lipidic nanoemulsion after intralesional injection into the patients: A new strategy for neoadjuvant chemotherapy

Objective. Previously we showed that after intravenous injection a lipidic nanoemulsion concentrates in breast carcinoma tissue and other solid tumors and may carry drugs directed against neoplastic tissues. Use of the nanoemulsion decreases toxicity of the chemotherapeutic agents without decreasing the anticancer action. Currently, the hypothesis was tested whether the nanoemulsion concentrates in breast carcinoma tissue after locoregional injection. Methods. Three different techniques of injection of the nanoemulsion were tested in patients scheduled for surgical treatment: G1 (n=4) into the mammary tissue 5 cm away from the tumor; G2 (n=4) into the peritumoral mammary tissue; G3 (n=6) into the tumoral tissue. The nanoemulsion labeled with radioactive cholesteryl oleate was injected 12 h before surgery; plasma decay of the label was determined from blood samples collected over 24 h and the tissue fragments excised during the surgery were analyzed for radioactivity uptake. Results. Among the three nanoemulsion injection techniques, G3 showed the greatest uptake (data expressed in c.p.m/g of tissue) by the tumor (44,769 +/- 54,749) and by the lymph node (2356 +/- 2966), as well as the greatest concentration in tumor compared to normal tissue (844 +/- 1673). In G1 and G2, uptakes were, respectively, tumor: 60 +/- 71 and 843 +/- 1526; lymph node: 263 +/- 375 and 102 +/- 74; normal tissue: 139 +/- 102 and 217 +/- 413. Conclusions. Therefore, with intralesional injection of the nanoemulsion, a great concentration effect can be achieved. This injection technique may be thus a promising approach for drug-targeting in neoadjuvant chemotherapy in breast cancer treatment. (C) 2008 Published by Elsevier Inc.

Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial

Background Treatment with adjuvant trastuzumab for 1 year improves disease-free survival and overall survival in patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer. We aimed to assess disease-free survival and overall survival after a median follow-up of 4 years for patients enrolled on the Herceptin Adjuvant (HERA) trial. Methods The HERA trial is an international, multicentre, randomised, open-label, phase 3 trial comparing treatment with trastuzumab for 1 and 2 years with observation after standard neoadjuvant, adjuvant chemotherapy, or both in patients with HER2-positive early breast cancer. The primary endpoint was disease-free survival. After a positive first interim analysis at a median follow-up of 1 year for the comparison of treatment with trastuzumab for 1 year with observation, event-free patients in the observation group were allowed to cross over to receive trastuzumab. We report trial outcomes for the 1-year trastuzumab and observation groups at a median follow-up of 48.4 months (IQR 42.0-56.5) and assess the effect of the extensive crossover to trastuzumab. Our analysis was by intention-to-treat. The HERA trial is registered with the European Clinical Trials Database, number 2005-002385-11. Findings The HERA trial population comprised 1698 patients randomly assigned to the observation group and 1703 to the 1-year trastuzumab group. Intention-to-treat analysis of disease-free survival showed a significant benefit in favour of patients in the 1-year trastuzumab group (4-year disease-free survival 78.6%) compared with the observation group (4-year disease-free survival 72.2%; hazard ratio [HR] 0.76; 95% CI 0.66-0.87; p<0.0001). Intention-to-treat analysis of overall survival showed no significant difference in the risk of death (4-year overall survival 89.3% vs 87.7%, respectively; HR 0.85; 95% CI 0.70-1.04; p=0.11). Overall, 885 patients (52%) of the 1698 patients in the observation group crossed over to receive trastuzumab, and began treatment at median 22.8 months (range 4.5-52.7) from randomisation. In a non-randomised comparison, patients in the selective-crossover cohort had fewer disease-free survival events than patients remaining in the observation group (adjusted HR 0.68; 95% CI 0.51-0.90; p=0.0077). Higher incidences of grade 3-4 and fatal adverse events were noted on 1-year trastuzumab than in the observation group. The most common grade 3 or 4 adverse events, each in less than 1% of patients, were congestive cardiac failure, hypertension, arthralgia, back pain, central-line infection, hot flush, headache, and diarrhoea. Interpretation Treatment with adjuvant trastuzumab for 1 year after chemotherapy is associated with significant clinical benefit at 4-year median follow-up. The substantial selective crossover of patients in the observation group to trastuzumab was associated with improved outcomes for this cohort.

Durable Complete Responses in Metastatic Colorectal Cancer Treated with Chemotherapy Alone

Background/Purpose: The median survival for patients with metastatic colorectal cancer (mCRC) has progressively increased over the past decades. Since the introduction of 5-fluorouracil (5-FU)-based chemotherapy, followed by hepatic resection of metastases, and more recently the adoption of newer chemotherapeutic regimens associated with targeted therapy, the gains are getting more substantial. Despite the recognition of the potential for long-term survival after surgical resection of metastatic disease, long-term survival data to determine the potential curative role of chemotherapy alone is lacking. Methods: We performed a retrospective review of 2751 patients who presented with mCRC at The MD Anderson Cancer Center from 1990 through 2003. Patients alive at 5 years who achieved complete response with chemotherapy and were not submitted to any surgical or interventional procedures directed to the metastatic sites were included in the analysis. Results: The 5-year overall survival rate for all patients with mCRC during this period was 10.8%. Among these long-term survivors, 2.2% achieved a sustained complete response after chemotherapy (all 6 with fluoropyrimidines and 2 with irinotecan) as the only treatment modality and were without evidence of disease until the last follow-up visit (median of 10.3 years). This number corresponds to 0.24% (6 of 2541) of all patients with mCRC included in this review. Conclusion: Cure with chemotherapy alone is possible for a very small number of patients with metastatic colorectal cancer. Improved therapies are increasing complete response rates, but the impact of modern chemotherapy on durable complete responses will require additional follow up.

Increasing the Rates of Complete Response to Neoadjuvant Chemoradiotherapy for Distal Rectal Cancer: Results of a Prospective Study Using Additional Chemotherapy During the Resting Period

OBJECTIVES: Addition of chemotherapy in the resting period between radiotherapy completion and response assessment during neoadjuvant treatment for distal rectal cancer could potentially increase rates of complete tumor regression. The purpose of this study was to evaluate toxicity rates and the impact of an extended neoadjuvant chemoradiation regimen on complete response rates. METHODS: Thirty-four consecutive patients with nonmetastatic distal rectal cancer were prospectively included. Patients were managed by 5,400 Gy of radiation and 5-fluorouracil/leucovorin-based chemotherapy given for three consecutive days every 21 days for six cycles (three cycles concomitant with radiotherapy). Tumor response assessment was performed at ten weeks from radiation completion. Patients with complete clinical response were strictly monitored and were not immediately operated on. Patients with incomplete clinical response were referred to surgery. RESULTS: Twenty-nine patients had completed 12 months of follow-up and were included in this preliminary analysis. Twenty-eight (97%) successfully completed treatment. Fifteen of 16 patients had Grade III toxicities that were skin-related (93%). Median follow-up was 23 months. Fourteen patients (48%) were considered as complete clinical responders sustained for at least 12 months (median, 24 months) after chemoradiation completion by clinical assessment alone. An additional five patients (17%) were considered as complete responders with ypT0 results after full-thickness local excision. Overall, the complete response rate was 65%. CONCLUSIONS: The addition of chemotherapy during the resting period after neoadjuvant chemoradiation is associated with acceptable toxicity and high tolerability rates. The considerably high rates of complete response in this preliminary series requires further follow-up, but they may provide valuable information for future prospective, randomized trials.

Gene expression profile of residual breast cancer after doxorubicin and cyclophosphamide neoadjuvant chemotherapy

In breast cancer patients, primary chemotherapy is associated with the same survival benefits as adjuvant chemotherapy. Residual tumors represent a clinical challenge, Lis they may be resistant to additional cycles of the same drugs. Our aim was to identify differential transcripts expressed in residual tumors, after neoadjuvant chemotherapy, that might be related with tumor resistance. Hence, 16 patients with paired tumor samples, collected before and after treatment (4 cycles doxorubicin/cyclophosphamide, AC) had their gene expression evaluated on cDNA microarray slides containing 4,608 genes. Three hundred and eighty-nine genes were differentially expressed (paired Student`s t-test, pFDR<0.01) between pre- and post-chemotherapy samples and among the regulated functions were the JNK cascade and cell death. Unsupervised hierarchical clustering identified one branch comprising exclusively, eight pre-chemotherapy samples and another branch, including the former correspondent eight post-chemotherapy samples and other 16 paired pre/post-chemotherapy samples. No differences in clinical and tumor parameters could explain this clustering. Another group of I I patients with paired samples had expression of selected genes determined by real-time RT-PCR and CTGF and DUSP1 were confirmed more expressed in post- as compared to pre-chemotherapy samples. After neoadjuvant chemotherapy some residual samples may retain their molecular signature while others present significant changes in their gene expression, probably induced by the treatment. CTGF and DUSP1 overexpression in residual samples may be a reflection of resistance to further administration of AC regimen.

Systemic chemotherapy-induced microsatellite instability in the mononuclear cell fraction of women with breast cancer can be reproduced in vitro and abrogated by amifostine

Objectives Microsatellite instability (MSI) induction by alkylating agent-based chemotherapy (ACHT) may underlie both tumor resistance to chemotherapy and secondary leukaemias in cancer patients. We investigated if ACHT could induce MSI in tumor-derived plasma-circulating DNA (pfDNA) and in normal peripheral blood mononuclear (PBMN) cells. We also evaluated if amifostine could interfere with this process in an in-vitro model. Methods MSI was determined in pfDNA, PBMN cells and urine cell-free DNA (ufDNA) of 33 breast cancer patients before and after ACHT. MCF-7 cells and PBMN from normal donors were exposed in vitro to melphalan, with or without amifostine. Results We observed at least one MSI event in PBMN cells, pfDNA or ufDNA of 87, 80 and 80% of patients, respectively. In vitro, melphalan induced MSI in both MCF-7 and normal PBMN cells. In PBMN cells, ACHT-induced MSI occurred together with a significant decrease in the expression of the DNA mismatch repair gene hMSH2. Amifostine decreased hMSH2 expression and also prevented MSI induction only in normal PBMN cells. Conclusions ACHT induced MSI in PBMN cells and in tumour-derived pfDNA. Because of its protective effect against ACHT induction of MSI in normal PBMN cells in vitro, amifostine may be a potential agent for preventing secondary leukaemias in patients exposed to ACHT.

Assessment of disease-free survival in patients with laryngeal squamous cell carcinoma treated with radiotherapy associated or not with chemotherapy

In early stage (I and II) laryngeal squamous cell carcinoma, both surgery and radiotherapy results in significant local and regional control. In advanced tumors (III and IV), radiotherapy alone has local-regional control rates of 32-43%. Aim: To assess disease-free survival in SCC laryngeal carcinoma patients submitted to radiotherapy alone and/or associated with chemotherapy. Materials and Methods: Retrospective study involving 84 cases of laryngeal SCC treated with radiotherapy or chemotherapy together with radiotherapy. Fifty-three cases were treated with intension to cure and 31 because of impossibility to resect the disease. As to clinical stage (CS), 12 were CS I, 15 II, 21 III and 5 IV. In the second group, 11 cases were EC III and 20 IV. Results: Mean age was 60 years, 84.5% were men. Fifty-eight (69.1%) cases had complete response and 26 (30.9%) had persistent or residual disease. Five-year disease-free survival was of 42.5%; 62.5% of the patients with organ preservation indication and 9.75 in the group of irressecable disease. Conclusion: disease-free survival of those patients submitted to radiotherapy because of laryngeal SCC was of 62.5%

Adjuvant chemotherapy for stage II colod cancer

The use of adjuvant chemotherapy following resection for all patients with stage III colon cancer is now part of the standard of care around the world. Recent trials have led to changes in the standard regimens, which now include the use of oxaliplatin (Eloxatin) for most patients with stage III colon cancer. The addition of oxaliplatin has resulted in a 23% reduction in the risk of recurrence compared with fluorouracil/leucovorin alone, with a small but statistically significant survival benefit. Unfortunately, no adequately powered trial has determined whether adjuvant chemotherapy is beneficial for stage II patients, and its use is much more controversial. Most investigators agree that adjuvant chemotherapy has some activity against stage H disease. However, its impact on progression-free and overall survival remains highly controversial. Despite the lack of data, there is growing acceptance of an informal classification system, which stratifies stage II patients by risk on the basis of clinical data, as a guide for deciding whether to use adjuvant therapy. The only phase III clinical trial for stage H patients currently ongoing in the United States uses molecular classification as the basis for patient randomization.

Experimental Chemotherapy in Paracoccidioidomycosis Using Ruthenium NO Donor

Paracoccidioidomycosis (PCM) is a granulomatous disease caused by a dimorphic fungus, Paracoccidioides brasiliensis (Pb). To determine the influence of nitric oxide (NO) on this disease, we tested cis-[Ru(bpy)2(NO)SO3](PF6), ruthenium nitrosyl, which releases NO when activated by biological reducing agents, in BALB/c mice infected intravenously with Pb 18 isolate. In a previous study by our group, the fungicidal activity of ruthenium nitrosyl was evaluated in a mouse model of acute PCM, by measuring the immune cellular response (DTH), histopathological characteristics of the granulomatous lesions (and numbers), cytokines, and NO production. We found that cis-[Ru(bpy)2(NO)SO3](PF6)-treated mice were more resistant to infection, since they exhibited higher survival when compared with the control group. Furthermore, we observed a decreased influx of inflammatory cells in the lung and liver tissue of treated mice, possibly because of a minor reduction in fungal cell numbers. Moreover, an increased production of IL-10 and a decrease in TNF-alpha levels were detected in lung tissues of infected mice treated with cis-[Ru(bpy)2(NO)SO3](PF6). Immunohistochemistry showed that there was no difference in the number of VEGF- expressing cells. The animals treated with cis-[Ru(bpy)2(NO)SO3](PF6) showed high NO levels at 40 days after infection. These results show that NO is effectively involved in the mechanism that regulates the immune response in lung of Pb-infected mice. These data suggest that NO is a resistance factor during paracoccidioidomycosis by controlling fungal proliferation, influencing cytokine production, and consequently moderating the development of a strong inflammatory response.

Impact of Surgical Staging in Locally Advanced Cervical Cancer and Subsequent Chemotherapy

Background: Surgical staging (SS) is the gold standard for determination of the true extent of a patient`s disease and is an important prognostic factor in cervical cancer. We investigated whether lymph node dissection (LND) prior to chemotherapy (CT) followed by radical surgery (RS) could modified overall (OS) and disease-free survival (DFS). Methods: We performed a cohort analysis of 98 patients with cervical carcinoma. The experimental group consisted of 36 patients who underwent SS followed by neoadjuvant chemotherapy, and then by RS (objective response) or chemo-radiation therapy (with or without subsequent surgery when not possible). The control group consisted of 62 similarly treated patients without pretreatment SS. The value of this procedure as a diagnostic tool in defining the extent of disease was evaluated. Furthermore, LND/CT-associated treatment complications and the impacts on OS and DFS were also evaluated. Results: Fourteen (38.9%) patients had pelvic LN metastases and three (8.3%) patients had pelvic and para-aortic LN metastases. The 39-month OS and DFS rates for the current study were 90.6% for the staged group and 52% for non-staged treatment (P < 0.001). Conclusion: SS in cervical cancer is a feasible and safe pretreatment procedure, and when associated with CT, it improves OS and DFS. J. Surg. Oncol. 2009;100:505-510. (C) 2009 Wiley-Liss, Inc.