Management Strategies for Malignant Left-Sided Colonic Obstruction: A Systematic Review and Network Meta-analysis of Randomized Controlled Trials and Propensity Score Matching Studies.

BACKGROUND: The optimal treatment strategy for left-sided malignant colonic obstruction remains controversial. Emergency colonic resection has been the standard of care; however, self-expanding metallic stenting as a bridge to surgery may offer short-term advantages, although oncological concerns exist. Decompressing stoma may provide a valid alternative, with limited evidence. OBJECTIVE: To perform a systematic review and Bayesian arm random effects model network meta-analysis comparing the approaches for management of malignant left-sided colonic obstruction. DATA SOURCES: A systematic review was conducted from inception to August 22, 2023, of PubMed, Embase, Cochrane Library, and Google Scholar databases. STUDY SELECTION: Randomized controlled trials and propensity score matched studies. INTERVENTIONS: Emergency colonic resection, self-expanding metallic stent, decompressing stoma. MAIN OUTCOME MEASURES: Oncologic efficacy, morbidity, successful minimally invasive surgery, primary anastomosis, and permanent stoma rates. RESULTS: Nineteen articles from 5225 identified met our inclusion criteria. Stenting (risk ratio 0.57, 95% credible interval: 0.33, 0.79) and decompressing stomas (risk ratio 0.46, 95% credible interval: 0.18, 0.92) both resulted in a significant reduction in the permanent stoma rate. Stenting facilitated minimally invasive surgery more frequently (risk ratio 4.10, 95% credible interval: 1.45, 13.13) and had lower overall morbidity (risk ratio 0.58, 95% credible interval: 0.35, 0.86). A pairwise analysis of primary anastomosis rates showed an increase in stenting (risk ratio 1.40, 95% credible interval: 1.31, 1.49) as compared with emergency resection. There was a significant decrease in the 90-day mortality with stenting (risk ratio 0.63, 95% credible interval: 0.41, 0.95) when compared with resection. There were no differences in disease-free and overall survival rates, respectively. LIMITATIONS: There is a lack of randomized controlled trial and propensity score matching data comparing short and long-term outcomes for diverting stomas compared to self-expanding metallic stents. Two trials compared self-expanding metallic stents and diverting stomas in left-sided malignant colonic obstruction. CONCLUSION: This study provides high-level evidence that bridge-to-surgery strategy is safe for the management of left-sided malignant colonic obstruction, and may facilitate minimally invasive surgery, increase primary anastomosis rates, and reduce permanent stoma rates and postoperative morbidity as compared to emergency colonic resection.

A case report on the development of sacroiliitis post laparoscopic appendicectomy for acute appendicitis: a rare cause of sacroiliitis in an adult.

INTRODUCTION AND IMPORTANCE: Acute appendicitis is the most common abdominal surgical emergency in the world and often requires surgical intervention. One of the complications of appendicitis is abscess formation. In rare cases, a localised abscess can occur in the adjacent organs, such as the iliac and psoas muscles. Sacroiliitis occurring secondary to, or concomitant with, acute appendicitis is extremely rare. However, a missed diagnosis of either or both conditions can lead to serious complications, including mortality. CASE PRESENTATION: A 27-year-old male patient presented to the emergency department with a history of acute severe right hip pain that was aggravated by movement and associated with nausea and vomiting. CT suggested acute uncomplicated appendicitis with no localised contamination. He underwent an emergent laparoscopy which showed mild appendiceal inflammation and appendicectomy was performed. He became septic a few hours after the operation, resulting in admission to the high dependency care unit for close observation. On review the following day, he reported ongoing right hip pain and lower back pain with a new onset inability to weight-bear. An MRI scan was performed which showed features of infection around the right sacroiliac joint and Staphylococcus aureus grew in his blood culture. A diagnosis of acute pyogenic sacroiliitis was then made. The patient was treated with IV antibiotics for a total of four weeks, followed by two weeks of oral antibiotics. CLINICAL DISCUSSION: Acute pyogenic sacroiliitis is one of the rarer conditions seen that can mimic the acute abdomen, in this case acute appendicitis. MRI is the best diagnostic modality in sacroiliitis, in comparison to CT for appendicitis. In most cases of acute appendicitis, mixed bacteria including aerobes and anaerobes are seen in the blood culture while staphylococcus aureus is seen mostly in acute pyogenic sacroiliitis. Staphylococcus aureus-induced appendicitis is reported in less than 3.7 % of cases. An early diagnosis of either or both conditions can significantly reduce complications and, more importantly, expedite implementation of appropriate treatment. CONCLUSION: In our case we present a combination acute appendicitis, acute sacroiliitis and staphylococcus aureus septicaemia and provide proof that acute pyogenic sacroiliitis can be a rare complication of acute appendicitis. Thus, a high clinical index of suspicion should be considered in the appropriate clinical scenario.

Nutritional risk predicts postoperative complications and length of stay, whereas sarcopenia risk predicts need for step-down care in a mixed elective surgery population.

BACKGROUND: Malnutrition and poor functional reserves place patients at risk for negative surgical outcomes. In this prospective study we aimed to measure preoperative nutritional and sarcopenia risk and evaluate their impact on postoperative outcomes. METHODS: Adults scheduled to undergo elective general and gastrointestinal surgery were screened for nutrition risk using the Malnutrition Universal Screening Tool screening tool. Sarcopenia risk was measured using the SARC-F tool and hand-grip strength. Patients were followed postoperatively. Incidence of complications, length of stay (LOS), readmission rates, and need for step-down care were recorded. RESULTS: One hundred and twenty-two patients were included. Mean age was 53.8 years (standard deviation [SD] 16.44). Sixty-six (54%) were scheduled for day-case procedures, and 56 (46%) for nonday-case procedures. About 18.9% (n = 23) were at nutritional risk preoperatively. Ten patients (8.2%) had probable sarcopenia based on SARC-F, whereas seven (5.7%) had measurably reduced HG. Incidence of postoperative complications was 23.8% (n = 29). Nutrition risk was associated with the development of complications (p = 0.018). In the nonday-case group, nutritional risk was associated with greater LOS (p = 0.013). Older age was associated with need for step-down care (p = 0.002) as was SARC-F (p = 0.003). CONCLUSIONS: Preoperative nutritional screening can predict postoperative complications and LOS, whereas sarcopenia screening is predictive of the need for step-down care after discharge. Screening tools are quick and inexpensive and could provide valuable information to clinicians and allow patients the opportunity to enhance their physical preparedness for surgery thereby mitigating their risk for negative surgical outcomes.

Mechanical bowel preparation and antibiotics in elective colorectal surgery: network meta-analysis.

BACKGROUND: The use of intravenous antibiotics at anaesthetic induction in colorectal surgery is the standard of care. However, the role of mechanical bowel preparation, enemas, and oral antibiotics in surgical site infection, anastomotic leak, and other perioperative outcomes remains controversial. The aim of this study was to determine the optimal preoperative bowel preparation strategy in elective colorectal surgery. METHODS: A systematic review and network meta-analysis of RCTs was performed with searches from PubMed/MEDLINE, Scopus, Embase, and the Cochrane Central Register of Controlled Trials from inception to December 2022. Primary outcomes included surgical site infection and anastomotic leak. Secondary outcomes included 30-day mortality rate, ileus, length of stay, return to theatre, other infections, and side effects of antibiotic therapy or bowel preparation. RESULTS: Sixty RCTs involving 16 314 patients were included in the final analysis: 3465 (21.2 per cent) had intravenous antibiotics alone, 5268 (32.3 per cent) had intravenous antibiotics + mechanical bowel preparation, 1710 (10.5 per cent) had intravenous antibiotics + oral antibiotics, 4183 (25.6 per cent) had intravenous antibiotics + oral antibiotics + mechanical bowel preparation, 262 (1.6 per cent) had intravenous antibiotics + enemas, and 1426 (8.7 per cent) had oral antibiotics + mechanical bowel preparation. With intravenous antibiotics as a baseline comparator, network meta-analysis demonstrated a significant reduction in total surgical site infection risk with intravenous antibiotics + oral antibiotics (OR 0.47 (95 per cent c.i. 0.32 to 0.68)) and intravenous antibiotics + oral antibiotics + mechanical bowel preparation (OR 0.55 (95 per cent c.i. 0.40 to 0.76)), whereas oral antibiotics + mechanical bowel preparation resulted in a higher surgical site infection rate compared with intravenous antibiotics alone (OR 1.84 (95 per cent c.i. 1.20 to 2.81)). Anastomotic leak rates were lower with intravenous antibiotics + oral antibiotics (OR 0.63 (95 per cent c.i. 0.44 to 0.90)) and intravenous antibiotics + oral antibiotics + mechanical bowel preparation (OR 0.62 (95 per cent c.i. 0.41 to 0.94)) compared with intravenous antibiotics alone. There was no significant difference in outcomes with mechanical bowel preparation in the absence of intravenous antibiotics and oral antibiotics in the main analysis. CONCLUSION: A bowel preparation strategy with intravenous antibiotics + oral antibiotics, with or without mechanical bowel preparation, should represent the standard of care for patients undergoing elective colorectal surgery.

Comparison of Restorative Proctocolectomy with and Without Defunctioning Loop Ileostomy in Patients with Ulcerative Colitis: A Systematic Review and Meta-analysis.

BACKGROUND: Restorative proctocolectomy [RPC] without a defunctioning loop ileostomy [DLI] in patients with ulcerative colitis [UC] remains controversial. AIM: To compare safety and efficacy of RPC with and without DLI in patients exclusively with UC. METHODS: A systematic review was performed according to PRISMA/MOOSE guidelines. Dichotomous variables were pooled as odds ratios [OR]. Continuous variables were pooled as weighted mean differences [WMD]. Quality assessment was performed using the Newcastle-Ottawa score [NOS]. RESULTS: A total of 20 studies [five paediatric and 15 adult] with 4550 UC patients [without DLI, n = 2370, 52.09%; with DLI, n = 2180, 47.91%] were eligible for inclusion. The median NOS was 8 [range 6-9]. There was no increased risk of anastomotic leak [AL] (OR 1.13, 95% confidence interval [CI]: 0.92, 1.39; p = 0.25), pouch excision [OR 1.01, 95% CI: 0.68, 1.50; p = 0.97], or overall major morbidity [OR 1.44, 95% CI, 0.91, 2.29; p = 0.12] for RPC without DLI, and this technique was associated with fewer anastomotic strictures [OR 0.45, 95% CI: 0.29, 0.68; p = 0.0002] and less bowel obstruction [OR 0.73, 95% CI: 0.57, 0.93; p = 0.01]. However, RPC without DLI increased the likelihood of pelvic sepsis [OR 1.68, 95% CI: 1.03, 2.75; p = 0.04] and emergency reoperation [OR 1.74, 95% CI: 1.22, 2.50; p = 0.002]. CONCLUSION: RPC without DLI is not associated with increased clinically overt AL or pouch excision rates. However, it is associated with increased risk of pelvic sepsis and emergency reoperation. RPC without DLI is feasible, but should only be performed judiciously in select UC patient cohorts in high-volume, specialist, tertiary centres.

A contemporary series of surgical outcomes following subtotal colectomy and/or completion proctectomy for management of inflammatory bowel disease.

BACKGROUND: The main indications for emergency subtotal colectomy (SC) include management of toxic colitis, refractory haemorrhage and/or perforation. Alternatively, elective surgery is performed for those refractory to medical therapy or with evidence of multifocal dysplasia. Overall, the annual incidence of SC has fallen since the introduction of biologic therapies and we aimed to review our current practices. METHODS: A retrospective review of inflammatory bowel disease (IBD) patients undergoing subtotal colectomy between 2013 and 2020 was performed. Medical records, operative notes, discharge summaries, histopathology reports and other supporting documents were reviewed. Indication for surgery, management of the rectum (i.e. maintenance of rectal stump, progression to completion proctectomy or IPAA formation) associated morbidity (Clavien-Dindo classification) and length of hospital stay were examined. RESULTS: Fifty-six IBD patients underwent a subtotal colectomy. Twenty-five patients (UC 14, Crohn's 11) had an elective procedure, and 31 patients (UC 19 Crohn's 12) had an emergency/semi-urgent procedure. Interestingly, 80% (n = 25) of the emergency cohort and 68% (n = 17) of the elective cohort had a laparoscopic resection. Major morbidity (Clavien-Dindo > 2) was higher among the emergency group (39% vs. 24%). Deep surgical site infection was the commonest morbidity (13%) in the emergency group, while superficial surgical site infection was commonest in the elective cohort (20%). Overall, there was no difference in surgical re-intervention rate (13% vs 12%), and there were no perioperative mortalities. Median post-operative length of stay was shorter in the elective cohort (9 versus 13 days). CONCLUSION: A significant proportion of IBD patients still require semi-urgent/emergency colectomy, which is associated with considerable length of stay and morbidity. The results of our study provide real-world outcomes to help counsel patients on expected outcomes.

Endoscopic management versus transanal surgery for early primary or early locally recurrent rectal neoplasms-a systematic review and meta-analysis.

BACKGROUND: Both endoscopic techniques and transanal surgery are viable options that allow organ preservation for early rectal neoplasms. Whilst endoscopic approaches are less invasive and carry less morbidity, it is unclear whether they are as oncologically effective. AIM: To compare endoscopic techniques with transanal surgery in the management of early rectal neoplasms. METHODS: A systematic literature search was performed for randomised and observational studies comparing these techniques. The pre-specified main outcomes measured were en bloc and R0 resection rates and recurrence. Pair-wise meta-analysis was performed. RESULTS: This review included 1044 patients. Transanal surgery had increased R0 resection rates (odds ratio (OR) 2.66; 95% CI 1.64; 4.31; p < 0.001) versus endoscopic management. The latter was associated with higher rates of incomplete resection (OR 2.25; 95% CI 1.14, 4.46; p = 0.02) and further intervention (OR 1.78; 95% CI 1.09, 2.88; p = 0.02). There was no difference in the rates of late recurrence (OR 1.01; 95% CI 0.53, 1.91; p = 0.99) or further major surgery (OR 0.87; 95% CI 0.39, 1.94; p = 0.73) between the groups. Endoscopic treatment was associated with a shorter operating time (weighted mean difference (WMD) - 12.08; 95% CI - 18.97, - 5.19; p < 0.001) and LOS (WMD - 1.94; 95% CI - 2.43, - 1.44; p < 0.001), as well as lower rates of urinary retention post-operatively (OR 0.12; 95% CI 0.02, 0.63; p = 0.01). CONCLUSION: Endoscopic techniques should be favoured in the setting of benign early rectal neoplasms given their decreased morbidity and increased cost-effectiveness. However, where malignancy is suspected transanal surgery should be the preferred option given the superior R0 resection rate.

Effective treatment of intractable cutaneous metastases of breast cancer with electrochemotherapy: Ten-year audit of single centre experience.

PURPOSE: Electrochemotherapy (ECT) is the application of electric pulses to tumour tissue to render the cell membranes permeable to usually impermeant hydrophilic anti-cancer drugs, thereby enhancing cytotoxic effects. We sought to ascertain whether ECT can be an effective palliative treatment for cutaneous metastases of breast cancer. METHODS: This work reports data from the European Standard Operating Procedures for Electrochemotherapy trial (EudraCT Number: 2004-002183-18). In combination with systemic and/or intratumoural bleomycin, optimised electric pulses were delivered to locally recurrent or metastatic cutaneous breast cancer lesions. Follow-up continued until December 2014. RESULTS: Between February 2004 and December 2014, twenty-four patients were treated. All patients had received prior multimodal therapy. In total, the patient cohort had, or developed, 242 lesions. Two hundred and 36 lesions were treated, with 34 lost to follow-up. An objective response was seen in 161 of 202 lesions (79.7%), with a complete response observed in 130 (64.3%). Thirty-nine lesions (19.3%) did not respond, while 2 (1%) progressed following ECT. 17 (73.9%) patients received two or fewer treatments. A minimum of a partial response was seen in at least 50% of treated lesions in 18 of the 24 (75%) patients. Smaller lesions were more likely to have an objective response (Chi-square test for trend, p < 0.001). CONCLUSIONS: Electrochemotherapy is an effective treatment for cutaneous breast cancer lesions that have proven refractory to standard therapies. As smaller lesions were found to be more responsive, we suggest that ECT should be considered as an early treatment modality, within multimodal treatment strategies.

Tubedown regulation of retinal endothelial permeability signaling pathways.

Tubedown (Tbdn; Naa15), a subunit of the N-terminal acetyltransferase NatA, complexes with the c-Src substrate Cortactin and supports adult retinal homeostasis through regulation of vascular permeability. Here we investigate the role of Tbdn expression on signaling components of retinal endothelial permeability to understand how Tbdn regulates the vasculature and supports retinal homeostasis. Tbdn knockdown-induced hyperpermeability to Albumin in retinal endothelial cells was associated with an increase in the levels of activation of the Src family kinases (SFK) c-Src, Fyn and Lyn and phospho-Cortactin (Tyr421). The knockdown of Cortactin expression reduced Tbdn knockdown-induced permeability to Albumin and the levels of activated SFK. Inhibition of SFK in retinal endothelial cells decreased Tbdn knockdown-induced permeability to Albumin and phospho-Cortactin (Tyr421) levels. Retinal lesions of endothelial-specific Tbdn knockdown mice, with tissue thickening, fibrovascular growth, and hyperpermeable vessels displayed an increase in the levels of activated c-Src. Moreover, the retinal lesions of patients with proliferative diabetic retinopathy (PDR) associated with a loss of Tbdn expression and hyperpermeability to Albumin displayed increased levels of activated SFK in retinal blood vessels. Taken together, these results implicate Tbdn as an important regulator of retinal endothelial permeability and homeostasis by modulating a signaling pathway involving c-Src and Cortactin.

Is there a role for locoregional surgery in stage IV breast cancer?

Current guidelines do not recommend locoregional surgery for Stage IV breast cancer at presentation despite some studies suggesting a survival benefit. We aimed to assess outcomes in patients with Stage IV breast cancer who underwent surgery. In a cohort study of all Stage IV breast cancers diagnosed at our tertiary-referral specialist centre between 2006 and 2012, we assessed patient survival in the context of demographics, histopathology, metastatic burden, and type of surgery performed. One hundred and nine patients were included; 52 underwent surgery. Patients in the surgery group had longer 5-year-survival (p = 0.003). Survival was also significantly longer in those with just one site of metastatic disease (p < 0.001). Patients with axillary cytology positive for regional metastases were less likely to proceed to surgery. Locoregional surgery does confer a survival advantage in Stage IV breast cancer. Assessment of preoperative axillary cytology may preclude some patients from proceeding to potentially beneficial locoregional surgery.

Oral tolerance to cancer can be abrogated by T regulatory cell inhibition.

Oral administration of tumour cells induces an immune hypo-responsiveness known as oral tolerance. We have previously shown that oral tolerance to a cancer is tumour antigen specific, non-cross-reactive and confers a tumour growth advantage. We investigated the utilisation of regulatory T cell (Treg) depletion on oral tolerance to a cancer and its ability to control tumour growth. Balb/C mice were gavage fed homogenised tumour tissue--JBS fibrosarcoma (to induce oral tolerance to a cancer), or PBS as control. Growth of subcutaneous JBS tumours were measured; splenic tissue excised and flow cytometry used to quantify and compare systemic Tregs and T effector (Teff) cell populations. Prior to and/or following tumour feeding, mice were intraperitoneally administered anti-CD25, to inactivate systemic Tregs, or given isotype antibody as a control. Mice which were orally tolerised prior to subcutaneous tumour induction, displayed significantly higher systemic Treg levels (14% vs 6%) and faster tumour growth rates than controls (p<0.05). Complete regression of tumours were only seen after Treg inactivation and occurred in all groups--this was not inhibited by tumour feeding. The cure rates for Treg inactivation were 60% during tolerisation, 75% during tumour growth and 100% during inactivation for both tolerisation and tumour growth. Depletion of Tregs gave rise to an increased number of Teff cells. Treg depletion post-tolerisation and post-tumour induction led to the complete regression of all tumours on tumour bearing mice. Oral administration of tumour tissue, confers a tumour growth advantage and is accompanied by an increase in systemic Treg levels. The administration of anti-CD25 Ab decreased Treg numbers and caused an increase in Teffs. Most notably Treg cell inhibition overcame established oral tolerance with consequent tumor regression, especially relevant to foregut cancers where oral tolerance is likely to be induced by the shedding of tumour tissue into the gut.

Are community pharmacists equipped to ensure the safe use of oral anticancer therapy in the community setting? Results of a cross-country survey of community pharmacists in Canada.

PURPOSE: Oral anticancer agents offer significant benefits over parenteral anticancer therapy in terms of patient convenience and reduced intrusiveness. Oral anticancer agents give many cancer patients freedom from numerous hospital visits, allowing them to obtain their medications from their local community pharmacy. However, a major concern with increased use of oral anticancer agents is shift of responsibility in ensuring the proper use of anticancer agents from the hospital/clinical oncology team to the patient/caregiver and other healthcare providers such as the community pharmacists who may not be appropriately trained for this. This study assessed the readiness of community pharmacists across Canada to play this increased role with respect to oral anticancer agents. METHODS: Using a structured electronic mailing strategy, a standardized survey was mailed to practicing pharmacists in five provinces where community pharmacists were dispensing the majority of oral anticancer agents. In addition to collecting basic demographic and their practice setting, the survey assessed the pharmacists' knowledge regarding cancer therapy and oral anticancer agents in particular, their education needs and access to resources on oral anticancer agents, the quality of prescriptions for oral anticancer agents received by them in terms of the required elements, their role in patient education, and steps to enhance patient and personal safety. RESULTS: There were 352 responses to the survey. Only 13.6% of respondents felt that they had received adequate oncology education at the undergraduate level and approximately 19% had attended a continuing education event related to oncology in the past 2 years. Only 24% of the pharmacists who responded were familiar with the common doses of oral anticancer agents and only 9% felt comfortable educating patients on these medications. CONCLUSIONS: A substantial portion of community pharmacists in Canada lack a solid understanding of oral anticancer agents and thus are poorly equipped to play a major role in ensuring their appropriate use. More education and training on oral anticancer agents are urgently required.

Outcomes assessment of a pharmacist-directed seamless care program in an ambulatory oncology clinic.

The primary goal of seamless care is improved patient outcomes and improved standards of care for patients with cancer. The pharmacy service of the Newfoundland Cancer Treatment and Research Foundation conducted a randomized control study that measured clinical and humanistic outcomes of a pharmacist-directed seamless care program in an ambulatory oncology clinic. This article focuses on the intervention group, particularly the identification of drug-related problems (DRPs) and utilization of health care services as well the satisfaction of 3 types of health professionals with the services provided by the pharmacist-directed seamless care program. Overall, the seamless care pharmacist (SCP) identified an average of 3.7 DRPs per intervention patient; the most common DRP reported was a patient not receiving or taking a drug therapy for which there is an indication. The SCP identified more DRPs in patients receiving adjuvant treatment compared to those receiving palliative treatment. On average, family physicians, oncology nurses, and hospital pharmacists were satisfied with the SCP intervention indicating that they agreed the information collected and distributed by the SCP was useful to them. Pharmacist-directed seamless care services in an ambulatory oncology clinic have a significant impact on clinical outcomes and processes of patient care. The presence of a SCP can help identify and resolve DRPs experienced by patients in an outpatient oncology clinic, ensuring that patients are receiving the highest standard of care.

Loss of tubedown expression as a contributing factor in the development of age-related retinopathy.

PURPOSE: Tubedown (Tbdn), a cortactin-binding acetyltransferase subunit, regulates retinal vascular permeability and homeostasis in adulthood. Here the authors explore whether Tbdn loss during aging might contribute to the mechanisms underlying age-related neovascular retinopathy. METHODS: A conditional endothelial-specific transgenic model of Tbdn loss was compared with aged mouse and human specimens from 5- to 93-year-old individuals. Specimens were analyzed by morphometric measurements and for functional markers using immunohistochemistry and Western blot analysis. RESULTS: An age-dependent decrease in Tbdn expression in endothelial cells of the posterior pole of the eye correlated with pathologic changes in choroidal and retinal tissues of aged mice. In humans, aged specimens without eye disease exhibited a moderate decrease in retinal and choroidal endothelial Tbdn expression compared with younger persons, whereas a greater decrease in choroid vascular Tbdn expression was observed in patients with age-related macular degeneration. In mice, Tbdn loss resulting from old age or conditional Tbdn knockdown was associated with retinal lesions showing significant extravascularly localized albumin and correlated with increased activity of senescence-associated ß-galactosidase in the retinal pigment epithelium. A range of abnormalities in RPE, Bruch's membrane, and choriocapillaris observable at the ultrastructural level in Tbdn-knockdown eyes recapitulate those present in human AMD. CONCLUSIONS: This work provides evidence that the marked decrease in the level of expression of Tbdn in the retinal and choroidal vasculature during aging contributes to the multifactorial process that leads to the development of age-related retinopathy and choroidopathy.

Topoisomerase 2 alpha and the case for individualized breast cancer therapy.

BACKGROUND: Many patients with breast cancer receive no benefit from their treatment. This has led to a search for novel therapeutic targets whose identification may facilitate a more tailored approach, thereby avoiding unnecessary toxicity. Of these, topoisomerase 2 alpha (TOP2A), located at the HER2/neu amplicon on chromosome 17, has generated particular interest because its expression has been shown to correlate with response to anthracycline-based therapies. METHODS: We evaluated the relationship between TOP2A and its collocated gene, HER2/neu, and summarized the evidence for and against confining anthracycline-based therapies to those patients who demonstrate increased expression or amplification of these targets. RESULTS: The emerging consensus supports the restriction of anthracyclines to those patients who are HER2/neu positive, with the evidence suggesting that alterations in the status of TOP2A are almost completely restricted to this group of patients. CONCLUSIONS: It seems increasingly likely that response to anthracyclines is predicated on these alterations.

Sonoporation mediated immunogene therapy of solid tumors.

Development of gene-based therapies for the treatment of inherited and acquired diseases, including cancer, has seen renewed interest in the use of nonviral vectors coupled to physical delivery modalities. Low-frequency ultrasound (US), with a well-established record in a clinical setting, has the potential to deliver DNA efficiently, accurately and safely. Optimal in vivo parameters for US-mediated delivery of naked plasmid DNA were established using the firefly luciferase reporter gene construct. Optimized parameters were used to administer a therapeutic gene construct, coding for granulocyte-macrophage colony-stimulating factor (GM-CSF) and B7-1 costimulatory molecule, to growing murine fibrosarcoma tumors. Tumor progression and animal survival was monitored throughout the study and the efficacy of the US-mediated gene therapy determined and compared with an electroporation-based approach. Optimal parameters for US-mediated delivery of plasmid DNA to tumors were deduced to be 1.0 W/cm(2) at 20% duty cycle for 5 min (60 J/cm(2)). In vivo US-mediated gene therapy resulted in a 55% cure rate in tumor-bearing animals. The immunological response invoked was cell mediated, conferring resistance against re-challenge and resistance to tumor challenge after transfer of splenocytes to naïve animals. US treatment was noninjurious to treated tissue, whereas therapeutic efficacy was comparable to an electroporation-based approach. US-mediated delivery of an immune-gene construct to growing tumors was therapeutically effective. Sonoporation has the potential to be a major factor in the development of nonviral gene delivery approaches.

Electrochemotherapy: aspects of preclinical development and early clinical experience.

OBJECTIVE: To develop an optimized, reproducible system of electrochemotherapy, and to investigate its clinical application in patients with cutaneous or subcutaneous recurrences of inoperable or progressive disease recalcitrant to current anticancer treatments. BACKGROUND: Electrochemotherapy is the application of electric pulses to tumor tissue, rendering the cell membranes permeable to otherwise impermeant or poorly permeant anticancer drugs. This facilitates a potent local cytotoxic effect. STUDY DESIGN: The optimal parameters for electrical pulses and bleomycin concentration were obtained in vitro and then applied to tumors derived from 4 histologically distinct human cancer cell lines (7860, PC3, OE19, MCF-7) established in athymic nude mice. Comparison was made with tumors that received bleomycin alone, electric pulses alone, and untreated controls. The optimized electrochemotherapy was then applied to patients with cutaneous or subcutaneous tumors, of any histologic type, recurrent or metastatic and unresponsive to standard chemotherapy and/or radiotherapy regimens. Tumors were assessed at monthly intervals to determine response to the treatment. RESULTS: In vivo: Using the optimal parameters ascertained in vitro, all tumors treated by electrochemotherapy with bleomycin (n = 24) had significantly regressed (P < 0.001, all 4 lines) compared with control tumors (n = 72). Twelve tumors completely regressed (50%) following a single application, with 12 partial regressions (50%). Clinical: In 30 patients (111 tumors), none of the treated tumors progressed. Sixty percent of tumors (66 of 111) showed complete regression, 22% (24 of 111) partial response, and 18% (21 of 111) no change. Electrochemotherapy was more effective in smaller tumors (<3 cm), 71% (64 of 90) showing complete regression, 20% (18 of 90) partial response, and 9% (8 of 90) no change. CONCLUSIONS: Electrochemotherapy parameters optimized in vitro are applicable in vivo. This treatment is effective in athymic nude mice for all histologic types indicating a nonimmunologic mode of action. In clinical application, electrochemotherapy is an effective, safe, and reproducible therapy. Patients with cutaneous or subcutaneous tumors previously refractory to surgical intervention, systemic chemotherapy, and/or radiotherapy responded successfully irrespective of histologic type.