Pegylated liposomal doxorubicin (PLD) in daily practice-A single center experience of treatment with PLD in patients with comorbidities and older patients with metastatic breast cancer.

PURPOSE: Real-world data about pegylated liposomal doxorubicin (PLD) in patients with metastatic breast cancer (MBC) are limited. We have aimed to highlight the role of PLD in daily practice focusing on older patients and patients with comorbidities with MBC. METHODS: We analyzed electronic records of all patients with advanced/metastatic breast cancer treated with single-agent PLD at the University Hospital Basel between 2003 and 2021. Primary endpoint was time to next chemotherapy or death (TTNC). Secondary endpoints were overall survival (OS), progression-free survival (PFS), and overall response rate (ORR). We performed univariate and multivariate analysis for clinical variables. RESULTS: 112 patients with MBC having received single-agent PLD in any treatment line were analyzed, including 34 patient who were older than 70 years and 61 patients with relevant comorbidities. Median TTNC, OS, and PFS for treatment with PLD were 4.6, 11.9, and 4.4 months, respectively. ORR was 13.6%. Age >70 years predicted shorter OS (median 11.2 months) in multivariate analysis (hazard ratio [HR] 1.83, 95% CI 1.07-3.11, p = 0.026). Age and comorbidities did not significantly affect other endpoints. Unexpectedly, hypertension predicted longer TTNC (8.3 months, p = 0.04) in univariate analysis, maintained in multivariate analysis as a trend for both TTNC (HR 0.62, p = 0.07) and OS (HR 0.63, p = 0.1). CONCLUSION: Age predicted shorter OS significantly but median OS was not relevantly shorter in older patients. PLD remains a treatment option in patients with comorbidities and older patients with MBC. However, our real-world results of PLD appear underwhelming compared to relevant phase II trials through all age groups, pointing to an efficacy-effectiveness gap, possibly due to sampling bias.

Targeting immunoliposomes to EGFR-positive glioblastoma.

BACKGROUND: We assessed the capacity of epidermal growth factor receptor (EGFR)-targeted immunoliposomes to deliver cargo to brain tumor tissue in patients with relapsed glioblastoma harboring an EGFR amplification. We aimed to assess the tolerability and effectiveness of anti-EGFR immunoliposomes loaded with doxorubicin (anti-EGFR ILs-dox) in glioblastoma multiforme patients. PATIENTS AND METHODS: Patients with EGFR-amplified, relapsed glioblastoma were included in this phase I pharmacokinetic trial. Patients received up to four cycles of anti-EGFR ILs-dox. Twenty-four hours later, plasma and cerebrospinal fluid (CSF) samples were obtained. In addition, we also treated three patients with anti-EGFR ILs-dox before resection of their relapsed glioblastoma. Doxorubicin concentrations were measured in plasma, CSF, and tumor tissue. Safety and efficacy parameters were also obtained. RESULTS: There were no or negligible levels of doxorubicin found in the CSF demonstrating that anti-EGFR ILs-dox are not able to cross the blood-brain barrier (BBB). However, significant levels were detected in glioblastoma tissue 24 h after the application, indicating that the disruption of BBB integrity present in high-grade gliomas might enable liposome delivery into tumor tissue. No new safety issues were observed. The median progression-free survival was 1.5 months and the median overall survival was 8 months. One patient undergoing surgery had a very long remission suggesting that neoadjuvant administration may have a positive effect on outcome. CONCLUSIONS: We clearly demonstrate that anti-EGFR-immunoliposomes can be targeted to EGFR-amplified glioblastoma and cargo-in this case doxorubicin-can be delivered, although these immunoliposomes do not cross the intact BBB. (The GBM-LIPO trial was registered as NCT03603379).

Focusing on cancer patients' intentions to use psychooncological support: A longitudinal, mixed-methods study.

OBJECTIVE: Distress screening programs aim to ensure appropriate psychooncological support for cancer patients, but many eligible patients do not use these services. To improve distress management, we need to better understand patients' supportive care needs. In this paper, we report the first key finding from a longitudinal study that focused on patients' intentions to use psychooncological support and its association with distress and uptake of the psychooncology service. METHODS: We conducted a prospective, observational study in an Oncology Outpatient Clinic and assessed distress, intention to use psychooncological support, and uptake of the psychooncology service by using the Distress Thermometer, a semistructured interview, and hospital records. We analyzed data with a mixed-methods approach. RESULTS: Of 333 patients (mean age 61 years; 55% male; 54% Distress Thermometer ≥ 5), 25% intended to use the psychooncology service (yes), 33% were ambivalent (maybe), and 42% reported no intention (no). Overall, 23% had attended the psychooncology service 4 months later. Ambivalent patients reported higher distress than patients with no intention (odds ratio = 1.18, 95% confidence interval [1.06-1.32]) but showed significantly lower uptake behavior than patients with an intention (odds ratio = 14.04, 95% confidence interval [6.74-29.24]). Qualitative analyses revealed that ambivalent patients (maybe) emphasized fears and uncertainties, while patients with clear intentions (yes/no) emphasized knowledge, attitudes, and coping concepts. CONCLUSIONS: We identified a vulnerable group of ambivalent patients with high distress levels and low uptake behavior. To optimize distress screening programs, we suggest addressing and discussing patients' supportive care needs in routine clinical practice.

Do all patients with advanced HER2 positive breast cancer need upfront-chemo when receiving trastuzumab? Randomized phase III trial SAKK 22/99.

Background: HER2-targeted therapy plus chemotherapy is standard treatment in advanced HER2+ breast cancer. Trastuzumab alone followed by addition of chemotherapy at disease progression versus upfront combination therapy has not been elucidated. Patients and methods: One-hundred seventy-five patients with measurable/evaluable HER2+ advanced disease without previous HER2-directed therapy were randomized to trastuzumab alone followed, at disease progression, by the combination with chemotherapy (Arm A) or upfront trastuzumab plus chemotherapy (Arm B). Chemotherapy could be stopped after ≥6 cycles in responding patients, trastuzumab was continued until progression. The primary endpoint of this superiority trial was time to progression (TTP) on combined trastuzumab-chemotherapy (Combination-TTP) in both arms. Secondary endpoints included response rate, TTP, overall survival, quality of life and toxicity. Results: Combination-TTP was longer than expected in both arms, 12.2 months in Arm A and 10.3 months in Arm B and not significantly different (hazard ratio [HR] 0.7; 95% CI 0.5-1.1; P =0.1). Overall survival was also not significantly different (HR 0.9; 95% CI 0.6-1.5; P = 0.55). In Arm A, the median TTP before introduction of chemotherapy was 3.7 months (95% CI 2.3-5.4), yet at 2 years 6% of patients were still on trastuzumab alone. Patients without visceral disease had a Combination-TTP of 21.8 months in arm A, compared with 10.1 months in arm B (unplanned analysis HR 2.1, 95% CI 1.1-4.2, P = 0.03). Patients with visceral disease showed no difference. Toxicity was chemotherapy-related. Conclusion: The outcome of patients receiving sequential trastuzumab-chemotherapy or upfront combination was similar. We failed to demonstrate superiority of the sequential approach. These results nevertheless suggest chemotherapy and its toxicity can be deferred, especially in patients with indolent, non-visceral disease. Despite a larger non-inferiority confirmatory study would be needed, these findings represent an additional proof of concept that de-escalation strategies can be discussed in individual patients.

Somatostatin-based radiopeptide therapy with [177Lu-DOTA]-TOC versus [90Y-DOTA]-TOC in neuroendocrine tumours.

PURPOSE: Somatostatin-based radiopeptide treatment is generally performed using the ß-emitting radionuclides (90)Y or (177)Lu. The present study aimed at comparing benefits and harms of both therapeutic approaches. METHODS: In a comparative cohort study, patients with advanced neuroendocrine tumours underwent repeated cycles of [(90)Y-DOTA]-TOC or [(177)Lu-DOTA]-TOC until progression of disease or permanent adverse events. Multivariable Cox regression and competing risks regression were employed to examine predictors of survival and adverse events for both treatment groups. RESULTS: Overall, 910 patients underwent 1,804 cycles of [(90)Y-DOTA]-TOC and 141 patients underwent 259 cycles of [(177)Lu-DOTA]-TOC. The median survival after [(177)Lu-DOTA]-TOC and after [(90)Y-DOTA]-TOC was comparable (45.5 months versus 35.9 months, hazard ratio 0.91, 95% confidence interval 0.63-1.30, p = 0.49). Subgroup analyses revealed a significantly longer survival for [(177)Lu-DOTA]-TOC over [(90)Y-DOTA]-TOC in patients with low tumour uptake, solitary lesions and extra-hepatic lesions. The rate of severe transient haematotoxicities was lower after [(177)Lu-DOTA]-TOC treatment (1.4 vs 10.1%, p = 0.001), while the rate of severe permanent renal toxicities was similar in both treatment groups (9.2 vs 7.8%, p = 0.32). CONCLUSION: The present results revealed no difference in median overall survival after [(177)Lu-DOTA]-TOC and [(90)Y-DOTA]-TOC. Furthermore, [(177)Lu-DOTA]-TOC was less haematotoxic than [(90)Y-DOTA]-TOC.

[Breast cancer - Treatment guidelines and new treatment options in 2012, a medical oncology prospective]. / Das Mammakarzinom - Therapiestandards und neue Therapiemöglichkeiten 2012, ein onkologisches Review.

Breast cancer is the leading cancer in women with an annual incidence rate of 110/100.000 women in all age groups in Europe. The incidence rate increases in older women. Treatment includes surgery, radiotherapy, chemotherapy with or without antibody therapy and hormonal treatment. During the last 40 years the survival rate has significantly improved. From the 1970ies to 2010 the five year survival rate has risen from 85% to 98% early breast cancer. Similarly, in metastatic breast cancer 5-year survival has increased from below 10% in 1970 to 26% in 2010. This was possible because of better treatment options and better screening causing earlier diagnosis of breast cancer. This article reviews the standard treatment of breast cancer according to ESMO/ASCO guidelines and discusses new treatment options and new therapeutic strategies for breast cancer.

Sentinel lymph node biopsy in primary breast cancer: trust the radiolabeled colloid method and avoid unnecessary procedures.

BACKGROUND: With regard to the sentinel lymph node (SLN) procedure in breast cancer, the study analyzed the impact of discrepancies between the number of clinically and histologically identified SLN, the impact of removing additional non-hot/non-blue but clinically conspicuous lymph nodes (LN), and whether the application of blue dye for mapping is necessary. METHODS: We analyzed 391 SLN procedures in which 928 SLN were removed. In all cases, radiolabeled colloid and blue dye were used for SLN mapping. RESULTS: In 60 cases (15.3%), additional LN that were not identified by the surgeon were found by histological examination. In 22 cases (5.3%), tissue which clinically resembled an SLN but was histologically connective tissue, was removed. In 76 cases (19.4%), 133 non-hot/non-blue but clinically conspicuous LN were removed. These additionally removed LN, however, did not alter the axillary staging. In 50.8% of the cases (n = 471), the SLN were marked only by radiolabeled colloid. In 27 cases (2.9%), the surgeon identified the LN through blue coloration alone; however, in all of the latter cases, these SLN were not deciding for axillary staging. CONCLUSION: The mapping agents may accumulate in axillary tissue and mimic the existence of an SLN. The radiolabeled colloid method alone gives excellent mapping results. The additional application of blue dye is avoidable. Exact surgical preparation enables removal of the SLN only and avoids removal of LN-containing adjacent tissue. The removal of further clinically identifiable enlarged non-hot LN should only be done if there is strong suspicion of metastatic involvement.

Combination of bevacizumab and 2-weekly pegylated liposomal doxorubicin as first-line therapy for locally recurrent or metastatic breast cancer. A multicenter, single-arm phase II trial (SAKK 24/06).

BACKGROUND: pegylated liposomal doxorubicin (PLD) and bevacizumab are active agents in the treatment of metastatic breast cancer (MBC). We carried out a multicenter, single-arm phase II trial to evaluate the toxicity and efficacy of PLD and bevacizumab as first-line treatment in MBC patients. METHODS: bevacizumab (10 mg/kg) and PLD (20 mg/m(2)) were infused on days 1 and 15 of a 4-week cycle for a maximum of six cycles. Thereafter, bevacizumab monotherapy was continued at the same dose until progression or toxicity. The primary objective was safety and tolerability, and the secondary objective was to evaluate efficacy of the combination. RESULTS: thirty-nine of 43 patients were assessable for the primary end point. Eighteen of 39 patients (46%, 95% confidence interval 30% to 63%) had a grade 3 toxicity. Sixteen (41%) had grade 3 palmar-plantar erythrodysesthesia, one had grade 3 mucositis, and one severe cardiotoxicity. Secondary end point of overall response rate among 43 assessable patients was 21%. CONCLUSIONS: in this nonrandomized single-arm trial, the combination of bimonthly PLD and bevacizumab in locally recurrent and MBC patients demonstrated higher than anticipated toxicity while exhibiting only modest activity. Based on these results, we would not consider this combination for further investigation in this setting.

Capecitabine and vinorelbine as first-line treatment in elderly patients (> or =65 years) with metastatic breast cancer. A phase II trial (SAKK 25/99).

BACKGROUND: We evaluated previously established regimens of capecitabine plus vinorelbine in older patients with advanced breast cancer stratified for presence versus absence of bone metastases. PATIENTS AND METHODS: Patients > or =65 years who had received no prior chemotherapy for advanced breast cancer received up to six 21-day cycles of vinorelbine 20 mg/m(2) i.v. on days 1 + 8 with oral capecitabine on days 1-14 (1,000 vs. 1,250 mg/m(2) daily in patients with vs. without bone involvement). RESULTS: Median age was 72 years in patients with bone metastases (n = 47) and 75 years in patients without bone metastases (n = 23). Response rates were 43% (95% confidence interval, CI, 28.3-58.8) and 57% (95% CI = 34.5-76.8), respectively. Median time to progression was 4.3 (95% CI = 3.5-6.0 months) and 7.0 months (CI = 4.1-8.3), respectively. Neutropenia was the most common toxicity, with grade 3/4 occurring in 43 and 39%, respectively. Pulmonary embolism was seen in 5 and grade 3 thrombosis in 3 patients. Other toxicities were mild to moderate. CONCLUSIONS: These regimens of capecitabine and vinorelbine are active and well tolerated in patients with advanced breast cancer > or =65 years. Response rates were comparable to published results. The lower capecitabine doses appeared appropriate given the advanced age, bone involvement and prior radiotherapy.

Scope and significance of non-uniform classification practices in breast cancer with non-inflammatory skin involvement: a clinicopathologic study and an international survey.

BACKGROUND: The study evaluates the scope of non-uniform classification practices concerning breast carcinomas with non-inflammatory skin involvement. PATIENTS AND METHODS: We compared the clinical course of patients with histologically proven non-inflammatory skin involvement: 119 (65.4%) with clinically obvious 'classical' skin changes (Group A) and 63 (34.6%) with no or only discreet changes (Group B). A questionnaire was circulated to pathology departments in 24 countries to assess the practice concerning the placement of skin- involved breast carcinomas in the TNM classification. RESULTS: Patients in Group B showed a significantly better disease specific survival (P=0.0002). Eighty-six respondents (70.5%) of the survey preferred the 'histological view' and classified tumors with only histological proven skin involvement as T 4 b/stage IIIB. The opposing classification principle ('clinical view'), which dictates that T 4 b breast cancer is a clinical diagnosis and the classical signs must be present, was supported by 31 respondents (25.4%). CONCLUSIONS: A large number of breast cancer patients with non-inflammatory skin involvement are only histologically proven and show, compared with cases exhibiting the classical clinical signs, significant differences in clinical course and prognosis. In general, both subsets were aggregated in one T category/stage (T 4 b/IIIB). This results in a considerable distortion of the reported statistical data.

A case of post-transplant lymphoproliferative disease presenting as CD20-expressing, Epstein-Barr-virus positive Hodgkin lymphoma.

Classical Hodgkin lymphoma (HL) is a rare complication after solid organ transplantation. We describe the first case of a patient developing CD20-positive HL after renal transplantation treated with the monoclonal antibody rituximab. Treatment with single agent rituximab led to partial remission. Subsequent combined modality treatment consisting of chemotherapy (adriamycin, bleomycin, vindesin and dacarbacin), immunotherapy (rituximab) and involved field irradiation achieved complete remission. Different therapeutic strategies in the treatment of patients developing lymphoproliferative disease - and particularly HL - after solid organ transplantation are discussed.

Toxic encephalopathy induced by capecitabine.

Toxic encephalopathy is a rarely described side effect of 5-fluorouracil which usually presents with cerebellar, neuropsychiatric, and focal neurological symptoms. Magnetic resonance imaging findings are described as patchy white matter alterations. We report the 1st case of capecitabine-induced toxic encephalopathy with epilepsy-like symptoms and diffuse white matter alterations on magnetic resonance imaging.

Capecitabine in hormone-resistant metastatic prostatic carcinoma - a phase II trial.

The objective of the trial is to evaluate the efficacy of capecitabine in patients with metastatic hormone-resistant prostate carcinoma (HRPC), in terms of prostate-specific antigen (PSA) response and clinical benefit (decrease of pain or analgesic score) and its safety profile. In all, 25 patients with HRPC were enrolled on a phase II trial of capecitabine (Xeloda) at a dose of 1250 mg m(-2) orally twice daily on days 1-14 every 21 days. The inclusion criteria were PSA serum levels >3 x upper limit of normal, a WHO performance status 0-2, age <85 years and adequate bone marrow, liver and renal function. In patients with grade 2 or higher haematological toxicity on day 1 of the treatment cycle, therapy was first delayed, and then continued at a lower dose. Trial end points were PSA response and clinical benefit defined by quality of life (QL) data and analgesic consumption. The median age of patients was 70 years (range 54-85 years). A median of three cycles of capecitabine was administered (range 1-8). PSA response was observed in three patients (12%, 95% CI 3-31%), with times to tumour progression of 18, 21 and 35 weeks, respectively. In these patients, the response durations were 12, 17 and 32 weeks, respectively. Minor PSA regression was also seen in two further patients. The median time to tumour progression of all patients was 12 weeks (95% CI 9-15 weeks). Haematological toxicity was minor, with leukopenia grade 3 observed in one patient. There were three deaths during trial treatment, respectively, due to sepsis following mucositis and leukopenia, presumed sepsis with mucositis induced by chemotherapy and concomitant radiotherapy and cerebral dysfunction progressing to coma. Hand-foot syndrome grades 2 and 3 were observed in four patients each. Clinical benefit was observed in five patients (20%, CI 7-41%). Based on toxicity data, we recommend a lower starting dose of 1000 mg x m(-2) orally twice daily. While capecitabine has some activity in HRPC, as suggested by observed PSA responses, we conclude that it is not worthwhile to investigate capecitabine monotherapy in a phase III trial. Combinations of capecitabine with other agents, such as vinorelbine or docetaxel, may prove to be more effective.

Predictions and associations of cholecystectomy in patients with cholecystolithiasis treated with extracorporeal shock wave lithotripsy.

Extracorporeal shock wave lithotripsy (ESWL) is effective in the treatment of symptomatic cholecystolithiasis in well-selected patients. We analyzed the predictors of cholecystectomy in a large series of gallstone patients after ESWL. This was a retrospective follow-up cohort-study of consecutive patients undergoing ESWL for symptomatic cholecystolithiasis over a 9-year period. It was possible to analyze a total of 297 patients; there were 211 women and 86 men, with a mean age of 52 years (range, 8-81 years). Patients that had been cholecystectomized after ESWL were compared to patients with their gallbladder still in situ and determinants of cholecystemctomy in terms of clinical, stone, and gallbladder parameters and symptoms analyzed. The mean duration of follow-up was 99 months (range, 27-134 months). During follow-up, 106 (36%) patients underwent a cholecystectomy at a mean of 34 months (range, 0-127 months) after ESWL. Histological data showed a normal gallbladder wall in only 4 cases; 101 examinations revealed some kind of (chronic) inflammation, which was not different from histological gallbladder results in patients without prior lithotripsy. Three gallbladder polyps were found, but no carcinoma. Cholecystectomy after ESWL of gallbladder stones was strongly associated with persitent and/or renewed biliary symtoms. Nevertheless, only three of four patients became asymptomatic after CE. Thus, ESWL proved to be a valuable organ-preserving alternative to cholecystectomy in selected patients.

Infrequent mutation of the tumour-suppressor gene Smad4 in early-stage colorectal cancer.

Smad4 is a candidate tumour-suppressor gene identified recently on chromosome 18q21.1. Both alleles are inactivated in nearly one-half of pancreatic carcinomas, but its role in the tumorigenesis of other tumours is still unknown. The aim of this study was to investigate the potential involvement of the Smad4 locus in early-stage colorectal cancers (stages I-III) in tumour samples from a randomised multicentre trial. Of a large collection of DNA samples, 73 with a loss of one allele of the Smad4 gene were analysed for the presence of point mutations in the remaining gene. Patients, from whom biopsies were isolated, were part of a previous randomised multicentre study of the Swiss Group for Clinical Cancer Research on the benefit of adjuvant chemotherapy (SAKK study 40/81). Mutation analysis was restricted to the highly conserved C-terminal domain (exons 8, 9, 10 and 11) of Smad4, using PCR and single-strand conformational variant analysis. Two of the 73 patients (3%) with loss of one allele of Smad4 had a point mutation in the remaining allele. These results indicate that whereas Smad4 point mutations are prevalent in pancreatic carcinoma, they are infrequent in early stages (I-III) of colorectal cancer.

SMAD4 is a predictive marker for 5-fluorouracil-based chemotherapy in patients with colorectal cancer.

The gene for the transducer of transforming growth factor-beta/bone morphogenetic protein signalling SMAD4, a potential suppressor of colorectal carcinogenesis, is located at the chromosomal region 18q21. In order to evaluate the clinical relevance of SMAD4 deletion, gene copy alterations were determined by copy dosage using real-time quantitative PCR in 202 colorectal tumour biopsies from a previous randomised study of adjuvant chemotherapy. Patients with normal SMAD4 diploidy turned out to have a three-fold higher benefit of 5-fluorouracil-based adjuvant chemotherapy with a border line significance (overall survival: 3.23, P=0.056; disease-free survival: 2.89, P=0.045). These data are consistent with the previous observation that patients whose cancer had retention of the 18q21 region had a significantly higher benefit from 5-fluorouracil-based therapy. Moreover, these results may provide a refinement at the gene level of the clinical relevance of 18q21 deletion, thereby suggesting SMAD4 as a predictive marker in colorectal cancer. This data also indicate that integrity of this component of the transforming growth factor-beta/bone morphogenetic protein signalling pathway may be a critical factor for benefit of chemotherapy in patients with colorectal cancer.

Cell fusion: an approach to generating constitutively proliferating human tumor antigen-presenting cells.

Somatic cell hybrids of HLA-A2(+) EBV-transformed B- or dendritic cells (DC) and allogeneic HLA-A2(-) melanoma cell line Me15 were obtained by in vitro electrofusion using an electroporator. Before fusion, melanoma cells were stably transfected with green fluorescent marker protein (GFP) and neomycin resistance gene (neo(+)). Stably growing hybrid antigen-presenting cells (HAPC) expressing HLA-DR and HLA-A2 (or HLA-A30/31), and melanoma-associated antigens (MART-1, gp100) were selected by a double strategy of immunomagnetic MACS and neomycin selection. Fusion efficiency ranged between 3% and 18% (mean: 8.0+/-4.7%) as defined by simultaneous GFP and HLA-A2 detection. Expression of melanoma-associated antigens (MART-1, gp100) in hybrid cells was determined by reverse transcription-polymerase chain reaction (RT-PCR). HLA-restricted antigen-specific presentation of melanoma antigens was demonstrated by killing of semi-allogenic HAPC by HLA-A2-restricted MART-1 or gp100-specific cytotoxic T lymphocyte (CTL) clones. HLA restriction and antigen specificity were confirmed by inhibition of specific cytotoxicity by anti-HLA antibodies and cold target inhibition. During long-term (42-70 days) neomycin selection of HAPC, a drastic loss of antigen-presenting cell (APC)-derived determinants (e.g. HLA-DR, HLA-A2) was observed which, however, could be "reversed" by repeated MACSorting (days 10, 21 and 49). Our method allows the generation of semi-allogenic HAPC that constitutively proliferate in vitro. This opens the possibility of establishing a number of tumor-APC hybrids expressing defined HLA haplotypes and tumor antigens, of investigating their specific properties (e.g. antigen processing), and testing their diagnostic or therapeutic potential.

Metastatic primitive neuroectodermal tumor of the kidney in adults.

OBJECTIVE: Primitive neuroectodermal tumors (PNET) of the kidney are rare and highly aggressive malignancies. The purpose of our study was to present information about the management of patients with metastatic disease. METHODS: The records of 2 patients (30-year-old female and 32-year-old male) with metastatic PNET of the kidney were reviewed and our data compared with the literature. RESULTS: Neither clinical evaluation nor radiological methods allowed to distinguish PNET from renal cell carcinoma. Immunohistochemistry revealed strong positivity for CD99 in tumor 1 and weak positivity for NSE and vimentin in both tumors. In tumor 2, EWS/FLI1 translocation was detected by RT-PCR. Patient 1 underwent nephrectomy, seven cycles of polychemotherapy, two cycles of high-dose chemotherapy, autologous bone marrow rescue, radiotherapy of suspicious skeletal foci and is without evidence of recurrent disease 28 months after therapy. Patient 2 underwent six cycles of polychemotherapy, nephrectomy, high-dose chemotherapy with cyclophosphamide and abdominal radiotherapy. Because of relapse high-dose chemotherapy with stem cell rescue was not performed. He underwent three further cycles of polychemotherapy and died one year after diagnosis due to cerebral metastasis. CONCLUSIONS: The diagnosis of renal PNET must be considered in young patients with renal neoplasm, particularly those with advanced disease at presentation. Achieving exact diagnosis has important clinical consequences because polychemotherapy and high-dose chemotherapy may lead to dramatic tumor reduction or even complete remission.

Combined copy status of 18q21 genes in colorectal cancer shows frequent retention of SMAD7.

Deletions of chromosome band 18q21 appear with very high frequency in a variety of carcinomas, especially in colorectal cancer. Potent tumor suppressor genes located in this region encode transforming growth factor beta (TGF-beta) signal transducers SMAD2 and SMAD4, and inactivation of either one leads to impaired TGF-beta-mediated cell growth/apoptosis. Following the assignment of SMAD7 to 18q21, we first refined the SMAD7 gene position within this region by genetically mapping SMAD7 between SMAD2 and SMAD4. Further, to compare the respective frequencies of genetic alterations of these three SMAD genes in colorectal cancer, we undertook a large-scale evaluation of the copy status of each of these genes on DNA samples from colorectal tumor biopsy material. Among a subset of 233 DNA samples for which data were available for all four genes, SMAD4, SMAD2, and the nearby gene DCC showed high deletion rates (66%, 64%, and 59%, respectively), whereas SMAD7 was deleted in only 48% of the tumors. Unexpectedly, we found some gene duplications; SMAD7 appears to be more frequently amplified (10%) than the three other genes (4-7%). Compiled data for SMAD genes in each tumor show that the most common combination (26% of all the tumors) consists of the simultaneous deletions of SMAD2 and SMAD4 associated with normal diploidy or even duplication of SMAD7. Since SMAD7 normally counteracts SMAD2 and SMAD4 in TGF-beta signaling, we hypothesize that the tumor might not benefit from simultaneous SMAD7 inactivation, thereby exerting selective pressure to retain or even to duplicate the SMAD7 gene.

Adenovirus-mediated wild-type p53 gene transfer in patients receiving chemotherapy for advanced non-small-cell lung cancer: results of a multicenter phase II study.

PURPOSE: To study the additional benefit from adenoviral p53 gene therapy in patients undergoing first-line chemotherapy for advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Twenty-five patients with nonresectable NSCLC were enrolled in an open-label, multicenter phase II study of three cycles of regimen A, carboplatin (area under the curve, 6; day 1) plus paclitaxel (175 mg/m(2), day 1), or regimen B, cisplatin (100 mg/m(2), day 1) plus vinorelbine (25 mg/m(2), days 1, 8, 15, and 22) in combination with intratumoral injection of 7.5 x 10(12) particles of SCH 58500 (rAd/p53, day 1). Responses of individual tumor lesions were assessed after each cycle, and gene transfer was examined in posttreatment tumor biopsies using reverse transcriptase polymerase chain reaction. RESULTS: There was no difference between the response rate of lesions treated with p53 gene therapy in addition to chemotherapy (52% objective responses) and lesions treated with chemotherapy alone (48% objective responses). Subgroup analysis according to the chemotherapy regimens revealed evidence for increased mean local tumor regressions in response to additional p53 gene therapy in patients receiving regimen B, but not in patients receiving regimen A. There was no survival difference between the two chemotherapy regimens, and the median survival of the cohort was 10.5 months (1-year survival, 44%). Transgene expression was confirmed in tumor samples from 68% of patients, and toxicities attributable to gene therapy were mild to moderate. CONCLUSION: Intratumoral adenoviral p53 gene therapy appears to provide no additional benefit in patients receiving an effective first-line chemotherapy for advanced NSCLC.