Beyond total mesorectal excision in locally advanced rectal cancer with organ or pelvic side-wall involvement.

BACKGROUND: In locally advanced rectal cancer (LARC), beyond total mesorectal excision (bTME) is often necessary to obtain complete resection (R0). The aim of this study was to identify prognostic determinants and compare morbidity and survival in LARC cases requiring bTME or TME surgery. METHOD: Single centre cohort study of LARC cases where all patients received neoadjuvant radiotherapy (n = 332). Data was registered prospectively in an institutional database linked to the National Registry. RESULTS: bTME surgery was performed in 224 patients, 171 with resections of adjacent organs (bTME-o group) and 53 with pelvic side-wall resections (bTME-pw group). TME surgery was performed in 108 patients. Six deaths occurred within 100 days and severe morbidity was registered in 23.8% of the whole cohort and in 25.4% of the bTME groups. The R0 rates were 93.5%, 84.2%, and 75.5% in the TME, bTME-o, and bTME-pw groups, respectively. Five-year disease free survival (DFS) was 67.3% (TME group), 54.5% (bTME-o group) and 48.7% (bTME-pw group), and five-year overall survival (OS) 78.7%, 69.0% and 60.4% respectively. Patients with involved resection margins (R1), high pT-stage, pN-positivity or poor response to neoadjuvant therapy were associated with inferior DFS and OS. CONCLUSION: In organ-threatening or infiltrating LARC, bTME surgery can be performed with low mortality and acceptable morbidity to obtain a good long-term outcome. Patients with pelvic side-wall infiltration were identified as a subgroup with increased risk of R1 resection and inferior long-term outcome.

Oxaliplatin-containing Preoperative Therapy in Locally Advanced Rectal Cancer: Local Response, Toxicity and Long-term Outcome.

AIMS: This non-randomised study was undertaken to examine oxaliplatin as possibly an intensifying component of sequential neoadjuvant therapy in locally advanced rectal cancer for improved local and metastatic outcome. MATERIALS AND METHODS: Ninety-seven patients (57 T2-3 cases, 40 T4 cases) received two cycles of the Nordic FLOX regimen (oxaliplatin 85 mg/m(2) day 1 and bolus 5-fluorouracil 500 mg/m(2) and folinic acid 100 mg days 1 and 2) before long-course chemoradiotherapy with concomitant oxaliplatin and capecitabine, followed by pelvic surgery. Treatment toxicity, local tumour response and long-term outcome were recorded. RESULTS: Good histologic tumour regression was obtained in 72% of patients. Implementing protocol-specific dose adjustments, tolerance was acceptable and 95% of patients received the total prescribed radiation dose. Estimated 5 year progression-free and overall survival were 61% and 83%, respectively. T4 stage was associated with an inferior local response rate, which again was highly associated with impaired long-term outcome. CONCLUSIONS: In this cohort of rectal cancer patients dominated by T4 and advanced T3 cases given sequential oxaliplatin-containing preoperative therapy with acceptable toxicity, high tumour response rates and overall survival were obtained, consistent with both local and systemic effects. However, tumour response and long-term outcome remained inferior for a significant number of T4 cases, suggesting that the T4 entity is biologically heterogeneous with subgroups of patients eligible for further individualisation of therapy.

Disseminated tumour cells in the bone marrow in early breast cancer: morphological categories of immunocytochemically positive cells have different impact on clinical outcome.

Detection of disseminated tumour cells (DTCs) in bone marrow by immunocytochemistry (ICC) includes morphological evaluation of cytokeratin immunopositive cells. The aim of this study was to disclose the prognostic significance of different morphological categories of ICC-positive cells according to treatment status and tumour subtype. Bone marrow samples (at surgery) were analysed for the presence of cytokeratin-positive DTCs by a standard immunocytochemical method. The immunopositive cells were classified into the following categories, prior to any analysis of the association between DTCs and clinical outcome: tumour cells (TC), uninterpretable cells (UIC), hematopoietic cells (HC), and questionable HC (QHC). The analysis included 747 early breast cancer patients. Median follow-up was 84 months for relapse, and 99 months for death. The categorisation of the ICC positive cells revealed TC in 13.3 % of the patients, whereas 13.1, 17.8, and 21.4 % of the cases were positive for UIC, QHC, and HC, respectively. Analysing all patients, only TC and UIC predicted systemic relapse. Separate analysis of all patients not receiving adjuvant systemic treatment (No-Adj; n = 389) showed that only QHC were associated with reduced survival (DDFS: p = 0.008; BCSS: p = 0.004, log rank) and the presence of QHC also remained significant in multivariate analysis. Primary tumour subgroup analysis (of all patients) by hormone receptors (HR) and HER2, demonstrated that only TC/UIC had prognostic impact in the HR+/HER2- patients, whereas presence of QHC was associated with unfavourable outcome only in triple negative patients (DDFS: p = 0.004; BCSS: p = 0.024). Patients with ≥3HC had improved outcome compared to those with fewer/no HC (DDFS: p = 0.005; BCSS: p = 0.009). Hence, morphological DTC subgroups may differ in clinical significance according to primary tumour subtype and treatment status. This emphasises the importance of DTC characterisation, and separate analyses of DTC categories according to tumour subtype. Hematopoietic ("false positive") cells might predict an immune-related favorable clinical outcome.

Evaluation of complete cytoreductive surgery and two intraperitoneal chemotherapy techniques in Pseudomyxoma peritonei.

BACKGROUND: Pseudomyxoma peritonei (PMP) is a low-grade malignancy characterized by mucinous tumor on the peritoneal surface. Treatment involves cytoreductive surgery (CRS) to remove all macroscopic tumor and perioperative intraperitoneal chemotherapy (PIC) to eliminate remaining microscopic disease. PATIENTS AND METHODS: Between 1994 and 2009, 93 patients were treated at the Norwegian Radium Hospital with complete CRS and PIC. PIC was administered as early postoperative intraperitoneal chemotherapy (EPIC) using mitomycin C (MMC) and 5-fluoruracil (n = 48) and as hyperthermic intraperitoneal chemotherapy (HIPEC) using MMC (n = 45). Patients were classified into three histopathological subgroups: Disseminated peritoneal adenomucinosis (n = 57), peritoneal mucinous carcinomatosis (n = 21) and an intermediate group (n = 15). Tumor distribution by peritoneal cancer index (PCI) was PCI ≤ 10 (n = 31), PCI 11-20 (n = 29), PCI ≥ 21 (n = 33). RESULTS: Recurrence was diagnosed in 38 patients and 25 patients died during follow-up. Estimated 10-year overall survival (OS) was 69% and 10-year disease-free survival (DFS) was 47%. Mean OS was 154 months (95% CI 131-171) and median OS was not reached (follow-up median 85 months (3-207)). Low-grade malignant histology (p = 0.001) and female gender (p = 0.045) were associated with improved OS. Almost equal OS and DFS were observed between patients treated with EPIC and HIPEC. CONCLUSIONS: Patients treated for PMP with complete CRS and PIC achieved satisfactory long-term outcome. The most important prognostic factor was histopathological differentiation, but acceptable survival was observed even in patients with aggressive histology and extensive intraperitoneal tumor growth. Administration of EPIC and HIPEC was equally efficacious with respect to long-term outcome.

Salvage surgery for locally recurrent rectal cancer: total mesorectal excision during the primary operation does not influence the outcome.

AIM: This study investigated whether total mesorectal excision (TME), when carried out at the original operation for rectal cancer, influenced the effectiveness of subsequent salvage treatment for pelvic recurrence. METHOD: Between September 1990 and January 2006, 124 patients underwent radiotherapy and salvage surgery at the Norwegian Radium Hospital for locally recurrent rectal cancer without known distant metastases. Most of the primary operations had been performed at other hospitals: 62 patients had undergone a non-TME procedure (most operations in this group of patients were carried out before 1994); and 62 patients had undergone a TME procedure (all operations in this group of patients were carried out after 1992). In the TME group, 17 patients also received radiosensitizing chemotherapy. RESULTS: A lower proportion of primary abdominoperineal resection and more sensitizing chemotherapy seemed to be to the advantage of the TME group, while a higher frequency of intra-operative radiotherapy might be beneficial in the non-TME group. The 5-year survival and R0 stage achievement were 30/24% and 44/40% for non-TME/TME groups. The local re-recurrence rates were nearly identical, at around 50%, for both groups. There was no change in R stage over time. CONCLUSION: A primary operation which includes TME does not reduce the effectiveness of subsequent salvage treatment for locally recurrent rectal cancer.

Pain after palliative radiotherapy for spine metastases.

AIMS: The purpose of the study was to evaluate the response to palliative radiotherapy in patients with painful spinal metastatic disease (SMD). MATERIALS AND METHODS: Three hundred and fifty-five patients admitted to the Norwegian Radium Hospital for radiotherapy for painful SMD were included in a prospective study and were followed up 2 months later. The Brief Pain Inventory was used to assess pain. Analgesic consumption was recalculated into the daily oral morphine-equivalent dose. The radiotherapy-related response rates were calculated using the criteria of the International Bone Metastases Consensus Group (IBMCG), taking into account the use of concomitant analgesics. The response to radiotherapy was assessed as complete or partial and non-response as stable pain, pain progression or 'other'. RESULTS: Brief Pain Inventory forms were obtained at follow-up from 229 of the 355 patients. Two months after radiotherapy, the median self-reported worst pain decreased significantly, but the median oral morphine-equivalent dose increased from 40 to 60 mg (P<0.001). Forty-three per cent of the patients reported pain relief, but a radiotherapy-related response was found in 37% of the patients. Overall correspondence between the patients' self-reported changes in pain experience and the IBMCG-based response categories was obtained in 63% of the patients. CONCLUSIONS: The radiotherapy-related response rates in our study were lower than those reported previously in patients with bone metastases in general, which possibly indicates the presence of more complex pathophysiological mechanisms of pain in SMD.

A population-based study of spinal metastatic disease in South-East Norway.

AIMS: Spinal metastatic disease (SMD) is a serious complication of cancer. To our knowledge, only one population-based study of metastatic spinal cord compression (MSCC) has been carried out. The purpose of the present study was to describe population-based incidences of SMD that required local treatment, such as radiotherapy, surgery or vertebroplasty, including patients with or without cord compression, and to characterise the neurological status of these patients. MATERIALS AND METHODS: During 18 months, all patients with SMD who received local treatment in the South-Eastern Health Region of Norway (population 2.6 million inhabitants) were identified and their medical records were reviewed. RESULTS: In total, 1002 patients were included; 83% had multiple lesions in the spine; 39% had SMD at the time of the primary cancer diagnosis. At the start of local treatment, 31% had MSCC and 11% were not able to walk. The prevalence of MSCC at the time of cancer diagnosis was 0.36%. The annual incidences per 100,000 inhabitants were 26.0 for SMD and 8.1 for MSCC. CONCLUSION: Population-based incidences of SMD requiring local treatment have been reported for the first time. The prevalence of MSCC at the time of cancer diagnosis was higher than previously reported. A more precise definition of MSCC and more population-based studies are needed to reduce selection bias when comparing different studies.

Extended total mesorectal excision in locally advanced rectal cancer (T4a) and the clinical role of MRI-evaluated neo-adjuvant downstaging.

OBJECTIVE: To compare the clinical ability of MRl taken before and after neo-adjuvant treatment in locally advanced rectal cancer (LARC) to predict the necessary extension of TME (ETME) and the possibility to achieve a R0 resection. METHOD: Prospective registration of 92 MRI evaluated T4a cancers undergoing elective surgery between 2002 and 2007 in a tertiary referral centre for multimodal treatment of rectal cancer. RESULTS: MRI identified patients in need of neo-adjuvant treatment and predicted T-downstaging in 10% and N-downstaging in 59%. Seventy-nine percent R0 resections, 18% R1 and 3% R2 were obtained after ETME in 95% of the patients and TME in the rest. Higher tumour regression grade (TRG) was achieved in higher ypT-stage (P < 0.01). Preoperative chemo radiotherapy resulted in that more patients obtained TRG1-3 compared to those receiving radiotherapy (79% vs. 57%, P = 0.02). The pelvic wall was the area of failure in 70% of the R1 resections. Tumour cells outside the mesorectal fascia scattered within fibrosis was found in 18 TRG2-3 among 33 ypT4 tumours (55%). CONCLUSION: MRl cannot discriminate tumour within fibrosis. Therefore, if a R0 resection is the goal, we advocate optimal surgery in accordance with the pre-treatment MRI. Post treatment MRI is a poor predictor of final histology and should not be relied upon to guide the extent of surgical resection. The study has initiated a new approach to histopathological classification of the removed specimen where we introduce a MRI assisted technique for investigating the areas at risk outside the mesorectal fascia in the specimen.

Adenocarcinomas on the rise--does it influence survival from oesophageal cancer?

BACKGROUND AND AIMS: A significant change in the occurrence of oesophageal squamous cell carcinomas (SCCs) in relation to adenocarcinomas (ACs) has been observed in the Norwegian population during the last 20 years (1988-2007). The AC incidence has increased from 5-10% to more than 50% nowadays, while the incidence of SCCs has decreased. Our goal was to evaluate if the change from SCC to AC and the increased effort to control reflux could be reflected in tumour stage, patient demographics and treatment results. MATERIAL AND METHODS: We analysed clinical and pathological data from 347 patients with oesophageal AC (n = 189) and SCC (n = 158) treated at The Norwegian Radium Hospital during said period for patient- and tumour characteristics, treatment modalities and survival. RESULTS: An oesophageal resection was performed in 169 of 347 patients. The median survival rate for all patients was 15 months, with a 5-year survival rate of 10%. The median survival time for operated and non-operated patients was 25 and 12 months respectively, with the corresponding 5-year survival rate of 13% and 2%. Patients with N0M0 disease operated with free resection margins presented a 5-year survival rate of 28%. CONCLUSIONS: The change from SCC to AC and the ensuing considerable efforts made in surveillance and treatment of AC did not lead to improved long time survival for our patients.

Preoperative irradiation and surgery for local recurrence of rectal and rectosigmoid cancer. Prognostic factors with regard to survival and further local recurrence.

OBJECTIVE: Local recurrence after rectal cancer surgery is an important clinical problem. METHOD: 150 patients with local recurrence after rectal/rectosigmoid cancer, stage M0, underwent surgery after preoperative irradiation (46-50 Gy). RESULTS: The overall 5-year survival was 27% (44% R0, 38% R1 and 17% R2-stage). Corresponding survival/local recurrence rates were 52%/27% for R0- and 14%/63% for R1-stage. No R2-resected survived 4 years. A normal pretreatment CEA level was significantly associated with increased survival but normalization following preoperative therapy was not associated with an improvement in prognosis. Survival and local recurrence were also significantly influenced by the type of primary operation. Several factors were significant for the prediction of an R0-resection in univariate analysis, but only CEA and symptoms at the time of recurrence predicted an R0-resection in multivariate analysis. A long latency time to recurrence did not significantly influence prognosis. CONCLUSION: Preoperative irradiation and surgery can result in an R0-resection and a long survival in patients with recurrence after initial treatment for rectal or rectosigmoid cancer. Also patients with an R1-resection can benefit from surgery since a substantial number will die without further local recurrence. An R0-resection is the main prognostic factor followed by CEA level, sex and type of primary operation. Normalization of CEA after preoperative treatment is not of prognostic significance. The value of the Norwegian follow-up regimen is questioned.

Prognostic factors after preoperative irradiation and surgery for locally advanced rectal cancer.

AIMS: The experience of preoperative irradiation in clinically locally advanced rectal cancer for the period 1991-2003 is reported. Prognostic factors for survival and recurrence, and parameters for obtaining a free circumferential margin were evaluated. METHODS: A prospective cohort study of 204 M0 patients given >45 Gy preoperatively (median age 66 years; 29% women; tumour level <16 cm from the anal verge). RESULTS: Multivisceral and/or pelvic wall resections were performed in 61% of the patients. R0, R1 and R2 resections were achieved in 74%, 21% and 5%. Five-year survival was 52% for all patients, 60% for R0 resections, 31% for R1 and 0% for R2. The calculated 5-year recurrence rates were 13% for R0 resections and 24% for R1 resections (p<0.035). R-stage, N-stage, age, type of rectal resection and pelvic wall resection remained significant in Cox multivariate analysis for survival. Regarding local recurrence, the following parameters were independent: N-stage, carcinoembryonic antigen (CEA) response and pelvic wall resection. Medium high tumour level and reduced histopathological differentiation are important individual factors that seem to predict increased risk for not obtaining a R0 resection. CONCLUSIONS: After preoperative irradiation and surgery, about 50% of the patients with locally advanced rectal cancer without overt metastases (M0) can be cured.

Surgery and pre-operative irradiation for locally advanced or recurrent rectal cancer in patients over 75 years of age.

OBJECTIVE: Reports of multimodal treatment regimens especially focusing on locally advanced or recurrent rectal cancer in the elderly, aged>75 years, are unavailable. We have tried to identify and evaluate pre- and peri-operative risk factors for morbidity and mortality and outcome after irradiation/surgery regimens in such patients. PATIENTS AND METHODS: Prospective registration of 86 consecutive patients aged>75 years undergoing elective surgery after irradiation 46-50 Gy for either primary locally advanced rectal cancer (n=51) or recurrent rectal cancer (n=35) from January 1991 to August 2003, 51 men and 35 women, median age 78 years (range 75-85 years) in a national cancer hospital. RESULTS: Multivisceral resections were needed in 63% of patients and 70% R0 resections were obtained in locally advanced cases and 46% in recurrent ones. Both in-hospital- and 30-day-mortality was 3.5%. Sixty-two postoperative complications occurred in 38 patients, three of them fatal. Both operation times over 5 h and transfusion of more than 3 SAG were prognostic factors regarding infections. Estimated five-year survival in R0 patients was 46%. Estimated five-year survival for patients with nonmetastatic tumours with locally advanced primary cancer was 29% and for locally recurrent rectal cancer 32%. Old males had a higher mortality rate the first year after surgery than females with only 65% relative survival compared to a matched normal population. The estimated five-year local recurrence rates were 24% for R0 resections and 54% for R1 resections (P=0.434 ns) and 24% and 45% for locally advanced and recurrent rectal cancer (P=0.248 ns), respectively. CONCLUSION: Thorough pre-operative evaluation and preparation and judicious surgery are important for achieving potentially curative treatment with acceptable morbidity in locally advanced and recurrent rectal cancer in patients over 75 years of age. We suggest that these patients should be evaluated and considered for treatment by multidisciplinary teams as younger patients.

Radical prostatectomy for locally advanced primary or recurrent rectal cancer.

AIM: Three papers including five patients have described en bloc radical prostatectomy for locally advanced rectal cancer. METHODS: Six patients (median age 63 years) underwent en bloc radical prostatectomy for locally advanced (3) or recurrent (3) rectal cancer involving the prostate. Quality of life questionnaires were answered postoperatively and the data prospectively entered in a database. RESULTS: One primary case had low anterior resection (LAR), the others abdominoperineal resections (APR) of R0 stage. Two recurrent cases had APRs and one tumour resection-all R1 stage. Anastomotic leakage led to construction of an ileal conduit in one patient and in two healed on conservative treatment. Follow up was 10-50 months. One patient died from distant metastases at 29 months postoperatively, one was operated for a single lung metastasis and one has disseminated lung metastases. None has developed local recurrence. Four of the five with anastomoses had good quality of life and none wanted an ileal conduit. CONCLUSION: In spite of a relatively high urinary leak rate the total complication rate seems to be lower than after pelvic exenteration. En bloc radical prostatectomy seems an option in selected patients otherwise needing pelvic exenteration for locally advanced or recurrent rectal cancer.

Quality of life in patients with urinary diversion after operation for locally advanced rectal cancer.

AIMS: When locally advanced or recurrent rectal cancer involves the bladder or prostate, curative treatment often requires pelvic exenteration. The aim was to assess the quality of life (QoL) in disease-free patients with urinary diversion after extensive surgery for advanced rectal cancer. METHODS: Twelve patients with urinary diversion (cases) were compared with 25 randomly selected patients given the same treatment, but without urinary diversion (controls). An age- and gender-adjusted general population was identified (reference). QoL was assessed with the EORTC questionnaires QLQ-C30, QLQ-CR38, and parts of the QLQ-BLM30. RESULTS: The cases did not report significantly worse overall QoL than the controls or the reference population. Both cases and controls had low mean scores of sexual function, and high mean scores of male sexual problems. In the nine cases that had two stomas, overall QoL was not worse than in the control or reference groups. CONCLUSIONS: Tumour-free patients did not report worse QoL scores than the controls or the general population, despite most having two stomas and low sexual function. Fear of reducing the patient's QoL should not be a major contraindication when surgery with urinary diversion is warranted to obtain curative resection.

COX-2 inhibition and prevention of cancer.

The potential for cyclo-oxygenase inhibition in cancer prevention and treatment is founded on epidemiology (reduction of colorectal cancer in aspirin users), animal experiments and molecular genetics. Trials using the NSAID sulindac also reduced the number of polyps in patients with familial adenomatous polyposis, but the well-known gastrointestinal toxic effects of aspirin and NSAIDs have discouraged the exploitation of their antineoplastic potential. The advent of specific COX-2 inhibitors, which do not interfere with the cytoprotective constitutive COX-1 enzyme, and the demonstration of increased COX-2 expression in many common malignancies beside colorectal cancer, has opened up new therapeutic possibilities. Recently a non-cyclo-oxygenase effect of COX-2 inhibitors, which combines the PPARdelta and the APC tumour suppressor activity, was also demonstrated. The selective COX-2 inhibitor celecoxib has been approved by the FDA for adjuvant treatment of familial adenomatous polyposis, and a large number of prevention and treatment trials of colorectal and other common cancers (prostate and breast cancer) have been started.

A follow-up study of recurrence and cosmesis in completely responding superficial and nodular basal cell carcinomas treated with methyl 5-aminolaevulinate-based photodynamic therapy alone and with prior curettage.

BACKGROUND: Methyl 5-aminolaevulinate (mALA) is an ester derivative of 5-aminolaevulinic acid (ALA) with increased lipophilicity compared with ALA. OBJECTIVES: To assess long-term cure rate, cosmesis, recurrence rate and extent of fibrosis after mALA-based photodynamic therapy (PDT) of superficial and nodular basal cell carcinomas (BCCs) showing early complete response to treatment. METHODS: Of 350 BCCs treated, 310 responded completely. These were in 59 patients who were followed for 2-4 years (mean 35 months) after mALA-PDT. Nodular tumours were curetted before PDT, and mALA 160 mg g(-1) was applied to all tumours for 24 h or 3 h before illumination from a broad-band halogen light source with light doses from 50 to 200 J cm(-2). Fibrosis was assessed histologically in 23 biopsies. RESULTS: The overall cure rate for 350 BCCs, including non-responders and recurrences was 79%. Of 310 lesions, 277 (89%) remained in complete response, and the cosmetic outcome was excellent or good in 272 of the completely responding lesions (98%). Histological examination showed dermal fibrosis in one of 23 biopsies. CONCLUSIONS: We conclude that mALA-based PDT with prior curettage of nodular lesions is a promising new method for the treatment of BCC.

Yeast colonization in surgical patients with intra-abdominal perforations.

A prospective study was conducted to determine (i) the degree of yeast colonization in surgical patients with intra-abdominal perforations and (ii) whether the frequency of colonization is different in patients with a complicated postoperative course than in patients recovering uneventfully. A total of 1,496 specimens taken per- and post-operatively from the mouth, stomach, feces, urine, trachea, and abdomen of 109 surgical patients with intra-abdominal perforations were examined. Yeast was recovered from 98 (90%) of the patients and from 634 (42%) of the specimens. Approximately 70% of the specimens from the mouth and stomach, 47% of fecal specimens, and 31% of abdominal specimens were positive for yeast. A total of 42 patients had a complicated postoperative course. The majority of these patients were colonized with yeast at multiple body sites: yeast was recovered on one or more occasions from two or more body sites in 90% and from three or more body sites in 71%. Many of the patients with an uncomplicated postoperative course also were colonized: yeast was recovered from two or more body sites in 69% and from three or more body sites in 34%. The results of this study indicate that treatment recommendations based on yeast colonization will expose a large number of patients to unnecessary or even harmful antifungal treatment. This does not mean that yeast colonization is insignificant; however, more accurate criteria and methods based on prospective clinical studies are needed to detect patients at risk of developing severe Candida infection.

Selective distribution of porphyrins in skin thick basal cell carcinoma after topical application of methyl 5-aminolevulinate.

Topical photodynamic therapy (PDT) of superficial basal cell carcinoma (BCC) with 5-aminolevulinic acid (ALA) has achieved promising clinical results. However, the efficacy of this therapy for thick BCC is dramatically decreased by a limited diffusion of hydrophilic ALA into the tumor. Lipophilic esters of ALA may enhance their penetration into the lesion. In this randomized, open clinical study, microscopic fluorescence photometry incorporating a light-sensitive thermo-electrically cooled charge-coupled device (CCD) camera was employed to investigate the penetration of methyl 5-aminolevulinate-induced porphyrin fluorescence in thick BCC lesions. Both the distribution pattern and the amount of porphyrins in 32 lesions of 16 patients were studied after topical application of 16, 80 or 160 mg/g of methyl 5-aminolevulinate for 3 or 18 h. A highly selective and homogeneous distribution of methyl 5-aminolevulinate-induced porphyrin fluorescence was seen in all lesions studied, with much less fluorescence in the adjacent normal skin tissues. In lesions of up to 2 mm thickness the application of 160 mg/g methyl 5-aminolevulinate for 3 h showed the highest ratio of porphyrin fluorescence depth to tumor depth (0.98+/-0.04), thus providing a biologic rationale for a clinical PDT trial with this regimen.

Antitumor effect of 5-aminolevulinic acid-mediated photodynamic therapy can be enhanced by the use of a low dose of photofrin in human tumor xenografts.

Practically all of the exogenous photosensitizers used for clinical photodynamic therapy (PDT) target mainly vasculature. Although effective in tumor destruction, they also, unavoidably, induce phototoxicity of normal tissues. Porphyrins synthesized endogenously from 5-aminolevulinic acid (ALA) accumulate within cells. Tumor eradication would be more efficient if both cellular components and vascular stroma of a tumor could be targeted. Thus, PDT with a mixture of ALA and Photofrin (Pf, a vessel-targeted sensitizer) may simultaneously destroy the two elements. Using chemical extraction assays, pharmacokinetics of ALA and ALA-induced porphyrins were studied in the plasma and tumors of nude mice bearing human WiDr and KM20L2 colonic carcinomas after an i.p. injection of 250 mg/kg body weight of ALA. Subsequently, PDT efficacy of the two tumor models with ALA, Pf, or with the two drugs in combination was evaluated. The phototoxic effects on tumor cells in vitro with the combined drugs was also determined. Moreover, histological and ultrastructural alterations of the treated tumors were investigated, and tumor cell clonogenicity was assessed as a function of time after in vivo PDT using an in vitro colony formation assay. Finally, the photosensitivity of normal skin tissue treated according to various protocols was compared. The amounts of ALA peaked at 0.5 h after administration in both plasma and WiDr tumor. The rates of ALA clearance seemed to follow a one-compartment model with half-lives of approximately 18 and 58 min in the plasma and tumor, respectively. About 100 and 60 times higher concentrations of ALA were needed to induce a given concentration of porphyrins in the plasma and tumor, respectively, although the plasma porphyrins may not only be released from blood cells but also from other organs. Similar kinetics of distribution patterns of ALA- and ALA methylester-induced porphyrins were found in the plasma and tumors, and the elimination rates were consistent with a two-compartment model. ALA induced much more porphyrins than ALA methylester in both plasma and tumors. Tumors PDT-treated with ALA plus Pf at a low dose (1 mg/kg) grew significantly more slowly than those treated with either of the drugs in both WiDr and KM20L2 models. However, the enhanced antitumor effect was not found in the tumor cells under in vitro conditions. Morphological studies demonstrated that PDT with the combined regimen resulted in necrosis of neoplastic cells and severe disruption of tumor microvasculature. This was supported by the findings obtained from the studies of in vivo PDT and in vitro clonogenic assay that showed a progressive reduction in tumor cell viability with times following PDT. Such a combined PDT protocol did not induce any phototoxicity in normal skin tissue. These data indicate that targeting both neoplastic cells and stroma with ALA and Pf (a low dose) can potentiate antitumor PDT effect with no risk of prolonged skin photosensitivity.

Identification of two potential suppressor gene regions on chromosome arm 14q that are commonly lost in advanced colorectal carcinomas.

BACKGROUND: Remarkably little is known about the molecular alterations contributing to the establishment of a distant metastasis from a primary colorectal carcinoma. Previous studies on primary colorectal carcinomas have suggested an association between loss of chromosome 14 sequences and cancer progression. METHODS: In the present study, we analyzed 20 distant metastases and peripheral blood samples from 18 patients using 24 microsatellite markers spanning chromosome arm 14q. In addition, DNA from microdissected corresponding primary tumors (formalin-fixed and paraffin-embedded) was analyzed at selected 14q loci. RESULTS: Sixty-five percent (13/20) of the metastases, from 11/18 patients, showed loss of one or more markers at 14q, and the majority (94%) of the primary carcinomas showed identical 14q genotypes to those found in the metastasis. Two minimal common deleted regions were delineated in the metastases, one between markers D14S288-D14S52 at 14q13-21 and the other between D14S284-D14S81 at 14q24-31, pinpointing two previously unrecognized map positions for potential target genes. The genotype pattern of five tumors was consistent with monosomy or large chromosomal deletions spanning both potential suppressor regions. The reasons for monosomy in cancer remain unknown, but our data support the hypothesis that deletions of several tumor suppressor genes are more readily obtained by one chromosome loss than by several molecular events, and through this unison loss a growth advantage may be provided. CONCLUSION: Our data suggest that 14q loss is not a rate-limiting event in colorectal metastasis formation, but the high frequency of this alteration in primary tumors with metastatic ability, as well as in the metastases themselves, suggests it is part of the tumor clone with selective growth capacity.