Prognostic indicators in peritoneal carcinomatosis from gastrointestinal cancer

Peritoneal carcinomatosis from gastrointestinal cancer has new treatment options for surgical management. The approach uses cytoreductive surgery which combines peritonectomy and visceral resection in an effort to remove all visible cancer within the abdomen and pelvis. Then the peritoneal cavity is flooded with chemotherapy solution in an attempt to eradicate residual disease. In order to select patients for this approach the quantitative prognostic indicators for carcinomatosis were reviewed, compared and contrasted. Prognostic indicators to be used to select patients for this aggressive approach at the initiation of surgery and after completion of cytoreduction were studied. Four quantitative assessments to be used at the time of abdominal exploration were the Gilly staging, Japanese gastric cancer P score, peritoneal cancer index (PCI), and the simplified peritoneal cancer index (SPCI). All have value with the PCI being the most validated and most precise. Preoperative assessments include the tumor histopathology and the prior surgical score. The completeness of cytoreduction score is an assessment of residual disease after a maximal surgical effort. An opportunity for long-term survival following treatment for carcinomatosis requires a complete cytoreduction in all reports for gastrointestinal cancer. Quantitative prognostic indicators need to be knowledgeably employed when patients with carcinomatosis are being treated. Improved patient selection with greater benefit and reduced morbidity and mortality should result.     

Evaluation and treatment of men with biochemical prostate-specific antigen recurrence following definitive therapy for clinically localized prostate cancer

Early detection and monitoring by serum prostate-specific antigen (PSA) measurement has increased the number of men presenting with potentially curable prostate cancer. Most will choose radical prostatectomy or some form of radiation therapy for treatment, but some will have evidence of biochemical disease recurrence following therapy, shown by a rising PSA level without other clinical evidence of disease. Radical prostatectomy involves the removal of all prostate tissue, causing the serum PSA to decline to undetectable levels within four to six weeks following surgery; a subsequent rise in the serum PSA to a detectable level indicates disease recurrence. Patients should be evaluated to assess whether rising PSA levels indicate local recurrence or early metastatic disease. The advantages of salvage radiation, endocrine therapy, and other treatment modalities in local disease recurrence must be weighed against potential side effects and the resulting decrease in quality of life. Radiation therapy does not immediately eradicate all PSA-producing cells; therefore the persistence of a detectable PSA does not necessarily imply residual cancer, but rising PSA levels indicate treatment failure. Salvage surgery can be performed after radiotherapy for the purpose of removing all viable cancer cells, but should be weighed against a higher incidence of surgical complications; cryoablation offers a less invasive therapeutic modality.     

Treatment options after failure of radiation therapy-a review

Radioresistant or recurrent prostate cancer represents a serious health risk for approximately 20%-30% of patients treated with primary radiation therapy for clinically localized prostate cancer. The majority of patients exhibit large volume and poorly differentiated disease at the time of diagnosis, which limits the ability of salvage therapy to eradicate the cancer. Early detection with serum PSA monitoring and prostate needle biopsy following primary radiation therapy may identify residual adenocarcinoma at an earlier stage and increase the likelihood of successful salvage therapy. Radical prostatectomy, prostate cryoablation, and brachytherapy comprise the options for salvage treatment available for radiorecurrent prostate cancer. The goal of disease eradication must be balanced against the potential for serious treatment-related side effects. As a result, many patients receive noncurative therapy with androgen ablation despite the real risk of disease progression and mortality.     

Management of Breast Cancer in Old Age

In a retrospective survey of 301 women aged over 70 with breast cancer the factors affectingfive-year survival are evaluated. The local disease is more advanced when the patient presents with it in old age than in younger women, possibly associated with a lesser degree of awareness or a long history of the primary tumour. It is not associated with a different average rate of tumour growth in old age, as measured by scar recurrences after surgery. Radical surgery may be followed by a high five-year survival rate in patients carefully selected on medical grounds, but in this unselected series the five-year survival rate was practically the same whether the local disease was limited or extensive at presentation and whatever the treatment given. The probability of five-year survival in a woman over 70 with breast cancer will depend mainly on her general health.     

Non-viral in vivo immune gene therapy of cancer: combined strategies for treatment of systemic disease

Many patients with various types of cancers have already by the time of presentation, micrometastases in their tissues and are left after treatment in a minimal residual disease state [Am J Gastroenterol 95(12), 2000]. To prevent tumour recurrence these patients require a systemic based therapy, but current modalities are limited by toxicity or lack of efficacy. We have previously reported that immune reactivity to the primary tumour is an important regulator of micrometastases and determinant of prognosis. This suggests that recruitment of specific anti-tumour mechanisms within the primary tumour could be used advantageously for tumour control as either primary or neo-adjuvant treatments. Recently, we have focused on methods of stimulating immune eradication of solid tumours and minimal residual disease using gene therapy approaches. Gene therapy is now a realistic prospect and a number of delivery approaches have been explored, including the use of viral and non-viral vectors. Non-viral vectors have received significant attention since, in spite of their relative delivery inefficiency, they may be safer and have greater potential for delivery of larger genetic units. By in vivo electroporation of the primary tumour with plasmid expressing GM-CSF and B7-1, we aim to stimulate immune eradication of the treated tumour and associated metastases. In this symposium report, we describe an effective gene based approach for cancer immunotherapy by inducing cytokine and immune co-stimulatory molecule expression by the growing cells of the primary tumour using a plasmid electroporation gene delivery strategy. We discuss the potential for enhancement of this therapy by its application as a neoadjuvant to surgical excision and by its use in combination with suppressor T cell depletion.This article is a symposium paper from the Annual Meeting of the “International Society for Cell and Gene Therapy of Cancer”, held in Shenzhen, China, on 9–11 December 2005.     

Use of thyroglobulin as a tumour marker

It is worthwhile to measure serum thyroglobulin(TG) level in thyroid cancer before subjecting patients to surgery for two reasons. Firstly, if the level is high, it may give a clue to the local and metastatic tumour burden at presentation; secondly, if the level is normal,it identifies the patients who are unlikely to show rising TG levels in the presence of thyroid cancer. Those who have high serum TG before surgery will show up recurrence as rising serum TG during the postoperative period. Those who do not have high serum TG before surgery will not show up rising serum TG in the presence of recurrent disease. In the latter situation, normal TG level gives only a false reassurance regarding recurrence of disease. Nevertheless, rising serum TG during the postoperative period must be interpreted cautiously because this could be due to the enlargement of noncancerous residual thyroid tissue inadvertently left behind during surgery.     

Adjuvant immunotherapy for solid tumors: from promise to clinical application

Although surgery remains the mainstay for the treatment of most solid tumors, investigators are seeking complementary therapies to eradicate microscopic disease, which causes tumor relapse even after an apparently complete surgical excision. Although adjuvant chemotherapy has achieved some significant results, the control of minimal residual disease is still a challenge for clinicians. Among novel therapeutic approaches, immunotherapy holds promise. This anticancer strategy aims at triggering a highly specific endogenous killing machine against tumor cells. Recent progress in tumor immunology has improved our understanding of host-immune system interactions. In particular, new technologies have fostered the identification of potentially immunogenic tumor antigens that can be used as suitable targets for immune effector cells. After observing immunotherapy-mediated clinical responses in patients with metastatic disease, investigators have started evaluating this anticancer modality in the adjuvant setting. Here, we review the immunological strategies so far explored in humans and report worldwide results following the clinical application of adjuvant immunotherapy for solid tumors.     

Completion total thyroidectomy in children with differentiated thyroid cancer

INTRODUCTION: The optimal surgical treatment of children with differentiated thyroid cancer remains an important point of discussion. Especially the need for completion operation is questioned in young patients. Our objective was to examine the rate of residual neoplastic disease after non radical initial operation. MATERIAL AND METHODS: From the 235 children diagnosed with differentiated thyroid cancer, 131 (56%) needed completion operation due to incomplete primary surgery. Completion operation involved thyroid bed, lymph nodes or both respectively in 91 (39%), 13 (6%) and 27 (11%) cases. Risk factors responsible for residual disease were evaluated by means of logistic regression analysis. RESULTS: Residual disease was detected in 46 (35%) of reoperated children (25% in thyroid bed and 85% in lymph node of lateral neck compartment). Sex and age did not influence the risk of residual disease in thyroid bed or lymph nodes. Papillary type of cancer and multifocality increased risk of residual disease in thyroid bed respectively by the factor of 15 (95% CI: 2-125) and 2.3 (95% CI: 1.2-4.4). Infiltration of thyroid capsule did not correlate with the risk of residual disease. Lymph node metastases in primary operation increased risk of residual disease by the factor of 16 (95% CI: 1.2-245). Histopathology, multifocality of primary tumour or infiltration of lymph node capsule did not influence the risk of residual disease in lymph nodes of lateral neck compartment. CONCLUSIONS: In children with differentiated thyroid cancer residual disease is diagnosed in about 1/3 of non radically operated cases. This high incidence justifies completion operations. The risk of residual disease is significantly increased in papillary thyroid cancer, multifocal tumours and cases with lymph node metastases.     

Therapeutic resistance and cancer recurrence mechanisms: Unfolding the story of tumour coming back

Cancer recurrence is believed to be one of the major reasons for the failure of cancer treatment strategies. This biological phenomenon could arise from the incomplete eradication of tumour cells after chemo- and radiotherapy. Recent developments in the design of models reflecting cancer recurrence and in vivo imaging techniques have led researchers to gain a deeper and more detailed insight into the mechanisms underlying tumour relapse. Here, we provide an overview of three important drivers of recurrence including cancer stem cells (CSCs), neosis, and phoenix rising. The survival of cancer stem cells is well recognized as one of the primary causes of therapeutic resistance in malignant cells. CSCs have a relatively latent metabolism and show resistance to therapeutic agents through a variety of routes. Neosis has proven to be as an important mechanism behind tumour self-proliferation after treatment which gives rise to the expansion of tumour cells in the injured site via production of Raju cells. Phoenix rising is a pro-recurrence pathway through which apoptotic cancer cells send strong signals to the neighbouring diseased cells leading to their multiplication. The mechanisms involved in therapeutic resistance and tumour recurrence have not yet been fully understood and mostly remain unexplained. Without doubt, an improved understanding of the cellular machinery contributing to recurrence will pave the way for the development of novel, sophisticated and effective anti-tumour therapeutic strategies which can eradicate tumour without the threat of relapse.     

Long-term follow-up of general immune competence in breast cancer

Summary Pre-treatment and sequential post-treatment (at 3 months, 6 months, 1, 2, 3, 4 and 5 years) examination of general immune competence was performed in 185 consecutive breast cancer patients. The patients were followed for 5 to 11 years to monitor the dynamic relationship between host immunity and cancer and to examine the effect of the treatment method. The tests of immune competence used were immunoglobulins IgG, IgA, IgM, leucocyte counts, percentage and total lymphocyte counts and Mantoux and DNCB skin hypersensitivity tests.Serum IgG and IgA showed no change relating to treatment method in recurrence-free patients; but IgG levels were higher when recurrent disease was imminent or established; IgM diminished (P<0.001) after treatment and this continued at 5 years in all patient groups. Simple lymphocyte counts showed the most interesting changes. They remained depressed for as long as 60 months following radiotherapy (P<0.01). After treatment by surgery, lymphocyte counts rose in patients without recurrence, but fell when systemic recurrence was imminent or established. This effect was not seen in patients with local recurrence only. There was no change in immune competence immediately before recurrence sufficient to be of clinical usefulness, but a low pre-treatment lymphocyte count with a steady rise after surgery carried a good prognosis. Similarly a high initial lymphocyte count with a fall after surgery was indicative of recurrence. Universal and prolonged depression of lymphocyte counts following radiotherapy was confirmed, and the effect was additive to that of tumour load in recurrent disease.Because of the large number of statistical calculations carried out, some of the apparently significant findings may be due to chance. However, the general trends emerging suggest that similar long-term studies, using the more sophisticated measures of lymphocyte function now available, might be rewarding.     

Detection and significance of minimal residual disease in colorectal cancer

Colorectal cancer (CRC) is one of the most common causes of cancer death in the developed world. Although the primary treatment for CRC is surgical, disease relapse due to minimal residual disease (MRD) following apparently curative surgery occurs in up to fifty percent of patients. Most patients who develop overt metastases beyond the regional lymph nodes eventually die of the disease. At present adjuvant chemotherapy is used to improve survival in patients with metastases to regional lymph nodes demonstrated by routine histopathology with no other evidence of spread. The ability to identify metastatic disease at an earlier stage could be of considerable benefit in directing adjuvant therapy to patients at high risk of relapse who are not identified by current methods. Several techniques have been developed for the detection of MRD, including immunohistochemical and molecular methods, however their role in clinical practise is not yet established. The purpose of this paper is to review these techniques and their potential clinical use in the management of CRC.     

Use of cell therapy as a means of targeting chemotherapy to inoperable pancreatic cancer

Although approved for the treatment of pancreatic cancer, the chemotherapeutic agent ifosfamide is not an effective therapy for this type of tumour. Ifosfamide must be activated by cytochrome P450 (P450) enzymes in the liver, initially to a short lived intermediate and then to toxic metabolites that are subsequently distributed by the circulatory system. Particularly for pancreatic cancer, this liver-mediated conversion results in relatively high systemic toxicities and poor therapeutic concentrations at the liver-distant site of the tumour. Activation of ifosfamide at the site of the tumour may allow lower doses to be used, while increasing the therapeutic index due to the resultant active concentrations generated locally. A cell-based therapy has been conceived where encapsulated, 293-derived cells genetically modified to overexpress a cytochrome P450 enzyme, are implanted near solid tumours. The cells are encapsulated in polymers of cellulose sulphate in order to provide a means of immunoprotection in vivo as well as to physically constrain them to the vicinity of the tumour. A major advantage of this strategy is that it allows one standard cell line to be applied to all patients and this approach can be extended to the treatment of other tumour types. After proof of principle studies in animal models, a phase I/II clinical trial was initiated in patients with stage III/IV nonresectable pancreatic cancer. Encapsulated cells were angiographically placed into the tumour vasculature of 14 patients and followed by systemic low dose ifosfamide treatment. Angiographic delivery of encapsulated cells proved feasible in all but one patient, and was well tolerated with no capsule or ifosfamide treatment-related adverse events. Four of the treated patients showed tumour regressions after capsule delivery and ifosfamide treatment in computer-tomography scans. The other 10 patients showed no further tumour growth (i.e. stable disease) during 20 weeks observation period. The median life expectancy of the patient collective was extended two fold as compared to age and status matched historical controls, with a 3-fold improvement in one year survival being attained. Evidence for a clinical benefit of the treatment was also obtained on the basis of standard parameters for quality of life. This approach has been evaluated by the European Medicines Evaluation Agency (EMEA) and orphan drug status has been granted. A pivotal clinical trial is now being planned with the help of the EMEA. Taken together, the data from this clinical trial suggest that encapsulated cytochrome P450-expressing cells combined with chemotherapy may be useful for the local treatment of a number of solid tumours and support the performance of further clinical studies of this new treatment.     

Multifocality and multicentricity are not contraindications for sentinel lymph node biopsy in breast cancer surgery

Extra-abdominal desmoid tumours are slow-growing, histologically benign tumours of fibroblastic origin with variable biologic behaviour. They are locally aggressive and invasive to surrounding anatomic structures. Magnetic resonance imaging is the modality of choice for the diagnosis and the evaluation of the tumours. Current management of desmoids involves a multidisciplinary approach. Wide margin surgical resection remains the main treatment modality for local control of the tumour. Amputation should not be the initial treatment, and function-preserving procedures should be the primary treatment goal. Adjuvant radiation therapy is recommended both for primary and recurrent lesions. Chemotherapy may be used for recurrent or unresectable disease. Overall local recurrence rates vary and depend on patient's age, tumour location and margins at resection.     

Metastatic breast cancer: mechanisms and opportunities for cytology

Despite significant advances in diagnosis, surgical techniques, general patient care, and local and systemic adjuvant therapies, metastatic disease remains the most critical condition limiting the survival of patients with breast cancer. Therefore, the development of effective treatment against late‐arising metastasis has become the centre of clinical attention and is one of the current challenges in cancer research. A deeper understanding of the metastatic cascade is fundamental, and the need for repetitive tumour assessments for the evaluation of tumour evolution is a relatively new practice in routine medical care. As such, fine needle aspiration cytology (FNAC) is ideally placed to monitor biological changes in metastasis that may affect treatment and response. As FNAC is a minimally invasive method, it can be performed repeatedly with relatively little trauma, and selective ancillary tests can be applied to FNAC specimens, including for tumour whose primary nature is known. Herein, we review how the linear and parallel models explain metastatic dissemination, thus influencing therapeutic and clinical decisions, and how cytology, together with immunocytochemistry and molecular analysis, can be a tool for routine clinical practice and clinical trials aimed at metastatic disease with a special emphasis on breast cancer.     

Immunotherapy for head and neck cancer

Head and neck cancer represents a challenging disease. Despite recent treatment advances, which have improved functional outcomes, the long-term survival of head and neck cancer patients has remained unchanged for the past 25 years. One of the goals of adjuvant cancer therapy is to eradicate local regional microscopic and micrometastatic disease with minimal toxicity to surrounding normal cells. In this respect, antigen-specific immunotherapy is an attractive therapeutic approach. With the advances in molecular genetics and fundamental immunology, antigen-specific immunotherapy is being actively explored using DNA, bacterial vector, viral vector, peptide, protein, dendritic cell, and tumor-cell based vaccines. Early phase clinical trials have demonstrated the safety and feasibility of these novel therapies and the emphasis is now shifting towards the development of strategies, which can increase the potency of these vaccines. As the field of immunotherapy matures and as our understanding of the complex interaction between tumor and host develops, we get closer to realizing the potential of immunotherapy as an adjunctive method to control head and neck cancer and improve long-term survival in this patient population.     

Cancer drug pan-resistance: pumps,cancer stem cells,quiescence, epithelial to mesenchymal transition,blocked cell death pathways,persisters or what?

Although chemotherapy of tumours has scored successes, drug resistance remains the major cause of death of cancer patients. Initial treatment often leaves residual disease, from which the tumour regrows. Eventually, most tumours become resistant to all available chemotherapy. I call this pan-resistance to distinguish it from multi-drug resistance, usually describing resistance caused by upregulation of drug transporters, such as P-glycoprotein. In this review, I discuss mechanisms proposed to explain both residual disease and pan-resistance. Although plausible explanations are at hand for residual disease, pan-resistance is still a mystery. My conclusion is that it is time for a major effort to solve this mystery using the new genetically modified mouse tumour models that produce real tumours resembling cancer in human patients.     

Targeting the primary tumor to generate CTL for the effective eradication of spontaneous metastases

Metastatic disease is the major cause of morbidity and mortality in cancer. Although surgery, chemotherapy, or radiation can often control primary tumor growth, successful eradication of disseminated metastases remains rare. We have now tested whether direct targeting tumor tissues to generate antitumor immune response before surgical excision produces sufficient CTL against micrometastases. One unsolved problem is whether such response allows coming CTL to be educated and then exit the tumor site. Another unsolved problem is whether these CTL can then patrol and effectively eliminate spontaneously metastasized tumor cells in the periphery. In this study, we have shown that adenovirus-expressing TNFSF14 [LIGHT (name derived from homologous to lymphotoxins, shows inducible expression, and competes with herpes simplex virus glycoprotein D for herpes virus entry mediator, a receptor expressed by T lymphocytes); Ad-LIGHT] inoculated directly into primary 4T1 tumor, a highly aggressive, spontaneously metastasizing mammary carcinoma, followed by surgical removal of the primary tumor can eradicate established and disseminated metastatic tumor cells in the peripheral tissues. Furthermore, we clearly show with a fibrosarcoma model Ag104L(d) that local treatment can generate plenty of tumor-specific CTL that exit the primary tumor and infiltrate distal tumors to completely eradicate distal tumors. Therefore, targeting the primary tumor with Ad-LIGHT before surgical excision is a new strategy to elicit better immune response for the eradication of spontaneous metastases.     

Tenth International Conference on Progress in Vaccination Against Cancer (PIVAC 10), Cambridge,UK, 27th–30th September 2010: New hopes and strategies for cancer vaccines

The Progress in Vaccination against Cancer (PIVAC) series of conferences celebrated 10 years of existence by returning to Cambridge, where the first meeting was held in the year 2001. This year, the conference at St Catharine’s college was full of hope for the future of immunotherapy against cancer with the introduction of prophylactic vaccines, combination therapies and the use of genetic vaccination (DNA vaccines) using old or new antigens vaccine formulations combined with the stimulation of innate immunity, the use of Toll-like receptor (TLR) agonists and inhibition of checkpoint blockade to overcome the immunosuppression created by the tumour microenvironment, offer exciting possibilities and new strategies. Indeed, enthusiasm is running high amongst immunologists who are working to eradicate cancers following the recent completion of several large scale, randomized phase III trials that have reported positive clinical results. The time when one will be able to immunize patients with minimal or no measurable disease is therefore getting closer as we understand more about the host—tumour relationship that influences regulatory immune pathways.     

Early production of HIV-1 neutralising antibodies in patients following highly active antiretroviral treatment (HAART) during primary HIV infection

We investigate the effects of highly active antiretroviral therapy (HAART) on humoral immune responses during a 24-month follow up of 15 HIV patients with acute primary HIV infection. The patients were divided into three groups on the basis of the therapeutic protocol they were following at the time of entry: a) five naive patients (untreated or treated with only ZDV or AZT); b) five patients following a triple combination of ZDV+ lamivudine (3TC)+ saquinovir (SQV); and c) five patients on a four-drug combination of ZDV+3TC+SQV+ ritonavir (RTV). The results show that the early introduction of HAART greatly reduces plasma viremia levels and restores the number of CD4 cells. A significant correlation was found between anti HIV neutralising activity and the four-drug, but not the three-drug combination. The reduction in infectivity was directed against viruses of different clades and associated with immunoglobulin fractions. Moreover, the neutralising antibodies in the HAART-treated patients appeared after two weeks of treatment and remained stable throughout the 24 months of follow up. The early appearance of neutralising antibodies represent an important component of immune responses during primary HIV infection, may contribute towards immune reconstitution in patients on HAART, and give further information that may be useful in developing new strategies designed to eradicate the disease.