The side effect registry immuno-oncology (SERIO) - A tool for systematic analysis of immunotherapy-induced side effects.

BACKGROUND: Immunotherapies such as immune checkpoint inhibitors (ICI) are effective in multiple tumor entities but induce a plethora of side effects. Comprehensive real-world analyses are essential to identify new signals, characterize diagnostic features, enable risk assessment, determine pathomechanisms, assess effectiveness of side effect management and compare tumor outcomes. METHODS: The international online `Side-Effect Registry Immuno-Oncology´ (SERIO; www.serio-registry.org) collects rare, complex, and severe immunotherapy-induced side effects across all tumor entities with a strong focus on ICI-induced immune-related adverse events (irAE). The relational database management system (RDMS) contains structured data on patient and tumor characteristics, type of immunotherapy, treatment of side effects, and outcome of tumor and irAE. Data are captured within 25 organ modules including new modules for immune effector cell-associated neurotoxicity syndrome (ICANS) for CAR-T-cell therapies and cytokine release syndrome (CRS) for bispecific antibodies. Information on biological samples is gathered. RESULTS: A total of 1398 irAE cases have been documented by 58 centers from 13 countries in patients with 17 tumor types. IrAEs were induced by nine different immunotherapies including tebentafusp and CAR-T cell therapies, and resulted, among others, in neurological (7.6%), pulmonary (4.0%), and cardiac toxicities (2.9%). 50.0% of all irAEs were graded severe or life-threatening and 23.0% of patients received second-line therapy for steroid-refractory or steroid-dependent irAE. SERIO has contributed to 44 original publications on topics ranging from irMyocarditis to irEncephalitis to long-term persistent sequelae of immunotherapy. CONCLUSIONS: A reliable evidence base is crucial for decision-making in rare, complex or therapy-refractory irAE. SERIO can help optimize side effect management and thereby reduce morbidity and mortality induced by immunotherapy.

Treatment, outcome and re-vaccination of patients with SARS-CoV-2 vaccine-associated immune thrombocytopenia.

PURPOSE: Following the emergency use authorization of BNT162b2 by the Food and Drug administration (FDA) in early December 2020, mRNA- and vector-based vaccines became an important means of reducing the spread and mortality of the COVID-19 pandemic. The European Medicines Agency labelled immune thrombocytopenia (ITP) as a rare adverse reaction of unknown frequency after vector-, but not mRNA-vaccination. Here, we report on the long-term outcome of 6 patients who were diagnosed with de-novo, vaccine-associated ITP (VA-ITP), and on the outcome of subsequent SARS-CoV-2 re-vaccinations. METHODS: Patients were included after presenting to our emergency department. Therapy was applied according to ITP guidelines. Follow-up data were obtained from outpatient departments. Both mRNA- or vector-based vaccines were each used in 3 cases, respectively. RESULTS: In all patients, the onset of symptoms occurred after the 1st dose of vaccine was applied. 5 patients required treatment, 3 of them 2nd line therapy. All patients showed a complete response eventually. After up to 359 days of follow-up, 2 patients were still under 2nd line therapy with thrombopoietin receptor agonists. 5 patients have been re-vaccinated with up to 3 consecutive doses of SARS-CoV-2 vaccines, 4 of them showing stable platelet counts hereafter. CONCLUSION: Thrombocytopenia after COVID-19 vaccination should trigger a diagnostic workup to exclude vaccine-induced immune thrombotic thrombocytopenia (VITT) and, if confirmed, VA-ITP should be treated according to current ITP guidelines. Re-vaccination of patients seems feasible under close monitoring of blood counts and using a vaccine that differs from the one triggering the initial episode of VA-ITP.

Scalp Cooling for Prevention of Chemotherapy-Induced Alopecia for Women and Men with Various Cancer Entities: A Two-Year Survey of an Outpatient Cancer Center in Germany.

INTRODUCTION: The aim of this survey was to assess the efficacy and the feasibility of scalp cooling (SC) in an outpatient hematological and oncological center in a real-world setting. METHODS: We prospectively monitored cancer patients from August 2017 to October 2019 receiving oncological treatments with SC, using the sensor-controlled system "DigniCap." Effectiveness was defined by a self-estimated hair loss < Grad 2 (<50%) according to the Common terminology Criteria for adverse events V4.0 or not requiring a wig. Withdrawal from SC on patient's demand was considered as failure. Tolerability and safety were also evaluated. RESULTS: Ninety-four patients with chemotherapy for their primary (52%) or metastatic (48%) disease had a total of 634 SC sessions. SC was well accepted with increasing experience of the nurses (withdrawal for any reason 29/94). Among the female population (N = 85) 54% received a (neo-)adjuvant chemotherapy. Forty-eight percentages received a taxane-based therapy, 35% anthracycline-based, 17% platin compounds, and others. The overall success rate in the female sample was 72%. In the male group (N = 9), the majority had a metastatic disease (6/9) and received a taxane-based therapy (5/9). The rate of withdrawal by discomfort and pain was high, and the success rate was 44%. CONCLUSION: Our study confirms the satisfaction of patients with SC to prevent chemotherapy-induced alopecia. SC increases acceptance of the recommendation and administration of chemotherapy and decreases the degree of distress of patients and their treating physicians. Reimbursement remains a major issue in the out patient setting.

Landscape of Biomarkers and Actionable Gene Alterations in Adenocarcinoma of GEJ and Stomach-A Real World Data Analysis.

After several years of negative phase III trials in gastric and esophageal cancer, a significant breakthrough in the treatment of metastatic adenocarcinomas of the gastroesophageal junction (GEJ) and stomach (GC) is now becoming evident with the emerging of precision oncology and implementation of molecular targets in tumor treatment. In addition, new generation studies such as umbrella and basket trials are focused on these molecular targets, which makes an early molecular diagnosis based on IHC/ISH and NGS necessary. The required companion diagnostics of Her2neu overamplification or PD-L1 expression is based on immunohistochemistry (IHC) or additionally in situ hybridization (ISH) in case of an IHC Her2neu score of 2+. However, there are investigator-dependent differences in the assessment of Her2neu amplification and different PD-L1 scoring systems obtained by IHC/ISH. The use of high-throughput technologies such as next-generation sequencing (NGS) holds the potential to standardize the analysis and thus make them more comparable. In the presented study, real-world multigene sequencing data of 72 Caucasian patients diagnosed with metastatic adenocarcinomas of GEJ and stomach were analyzed. In the clinical companion diagnostics, we found ESCAT level I molecular targets in one-third of our patients, which directly determined the therapy. In addition, we found potential targets in 14/72 patients (19.4%) who potentially qualify for precision therapies in corresponding molecular studies. The study highlights the importance of comprehensive molecular profiling for precision treatment of GEJ/GC and indicates that a biomarker evaluation should be performed for all patients with metastatic adenocarcinomas before the initiation of first-line treatment and during second-line or subsequent treatment.

Rare SARS-CoV-2 antibody development in cancer patients.

SARS-CoV-2 antibody development and immunity will be crucial for the further course of the pandemic. Until now, it has been assumed that patients who are infected with SARS-CoV-2 will develop antibodies as has been the case with other coronaviruses, like MERS-CoV and SARS-CoV. In the present study, we analyzed the development of antibodies in 77 patients with an oncologic diagnosis 26 days after positive RT-qPCR testing for SARS-CoV2. RT-qPCR and anti-SARS-CoV2-antibody methods from BGI (MGIEasy Magnetic Beads Virus DNA/RNA Extraction Kit) and Roche (Elecsys Anti-SARS-CoV-2 immunoassay) were used, respectively, according to the manufacturers' specifications. Surprisingly, antibody development was detected in only 6 of 77 individuals with a confirmed history of COVID-19. Despite multiple testing, the remaining patients did not show measurable antibody concentrations in subsequent tests. These results undermine the previous hypothesis that SARS-CoV2 infections are regularly associated with antibody development and cast doubt on the provided immunity to COVID-19. Understanding the adaptive and humoral response to SARS-CoV2 will play a key role in vaccine development and gaining further knowledge on the pathogenesis.

SARS-CoV-2 infections in cancer outpatients-Most infected patients are asymptomatic carriers without impact on chemotherapy.

Oncologic patients are regarded as the population most at risk of developing a severe course of COVID-19 due to the fact that malignant diseases and chemotherapy often weaken the immune system. In the face of the ongoing SARS-CoV-2 pandemic, how particular patients deal with this infection remains an important question. In the period between the 15 and 26 April 2020, a total of 1227 patients were tested in one of seven oncologic outpatient clinics for SARS-CoV-2, regardless of symptoms, employing RT-qPCR. Of 1227 patients, 78 (6.4%) were tested positive of SARS-CoV-2. Only one of the patients who tested positive developed a severe form of COVID-19 with pneumonia (CURB-65 score of 2), and two patients showed mild symptoms. Fourteen of 75 asymptomatic but positively tested patients received chemotherapy or chemo-immunotherapy according to their regular therapy algorithm (±4 weeks of SARS-CoV-2 test), and 48 of 78 (61.5%) positive-tested patients received glucocorticoids as co-medication. None of the asymptomatic infected patients showed unexpected complications due to the SARS-CoV-2 infection during the cancer treatment. These data clearly contrast the view that patients with an oncologic disease are particularly vulnerable to SARS-CoV-2 and suggest that compromising therapies could be continued or started despite the ongoing pandemic. Moreover the relatively low appearance of symptoms due to COVID-19 among patients on chemotherapy and other immunosuppressive co-medication like glucocorticoids indicate that suppressing the response capacity of the immune system reduces disease severity.

Real world data analysis of next generation sequencing and protein expression in metastatic breast cancer patients.

Next generation sequencing (NGS) together with protein expression analysis is back bone of molecularly targeted therapy in precision medicine. Our retrospective study shows our experience with NGS of 324 genes in combination with protein expression in patients with advanced breast cancer (aBC). The primary purpose was to analyze the prevalence of individual genetic alterations combined with protein expression to define potential targets for an individualized therapy. Between April 2018 and September 2019, 41 patients with aBC were offered a NGS test. The test was used to detect clinically relevant genomic alterations and to support further targeted therapy decisions. Hormone receptors, ERBB2 of tumors and PD-L1 was stained by immunohistochemistry. The data was recorded up to September 2019. After prior consent 41 results were available for further analysis. The most common BC subtypes were triple-negative (n = 16), HR+/ERBB2- (n = 15), and ERBB2+ (n = 9), with one missing data of the primary tumor. 27 patients had more than one genetic alteration. The most common alterations were PIK3CA (n = 14) and ERBB2 alterations (n = 11). Followed by ESR1 (n = 10), FGFR1 (n = 7) and PTEN (n = 7). 68% of the alterations were clinically relevant (tier I and II of ESCAT classification). The most common treatment recommendation was ERBB2-directed therapy (single or double blockade, trastuzumab emtansine and lapatinib) followed by alpelisib in combination with fulvestrant. Comprehensive genomic profiling combined with protein expression analysis in aBC allowed a guided personalized therapy for half of our patients. So far there are no well-defined tools allowing interpretations of genomic alterations detected by NGS in combination with protein expression and other factors.

Building a National Framework for Adolescent and Young Adult Hematology and Oncology and Transition from Pediatric to Adult Care: Report of the Inaugural Meeting of the "AjET" Working Group of the German Society for Pediatric Oncology and Hematology.

Adolescents and young adults (AYAs) with hemato-oncological problems constitute a heterogenous group with characteristic particularities, specific needs, and age-related clinical and unique psychosocial features. Strong collaboration between pediatric and adult hemato-oncology settings is essential to address their needs appropriately. This is not only true for patients who first become ill during adolescence or young adulthood, but equally so for people who contract hemato-oncological diseases congenitally or as younger children and who are now becoming old enough to leave the pediatric setting and have to transit into "adult" medical care. Efforts to create environments that meet the specific needs of the AYA population affected by hemato-oncological diseases have been initiated in many countries. Due to international variations between societies in general and healthcare infrastructures in particular, the challenges posed to creating such environments vary considerably from country to country. Aiming at addressing these on a national basis for Germany, a dedicated Working Group on Adolescents, Young Adults, and Transition (Arbeitsgemeinschaft Adoleszenten, junge Erwachsene, Transition, AjET) was established. This meeting report depicts the content and discussions of the first interdisciplinary conference on treatment, transition, and long-term follow-up in AYAs with cancer or chronic/inborn hematological diseases. The AjET group of the German Society for Pediatric Oncology and Hematology (GPOH) intends to increase the national awareness for AYAs; strengthen the collaboration of pediatric and adult care givers; and initiate, promote, and coordinate collaborative activities in the fields of basic and translational research, clinical care, and long-term follow-up aimed at improving the current situation.

Gemcitabine and cisplatin combined with regional hyperthermia as second-line treatment in patients with gemcitabine-refractory advanced pancreatic cancer.

PURPOSE: There is no standard second-line therapy for patients with advanced pancreatic cancer (APC) after gemcitabine (G) failure. Cisplatin (Cis)-based chemotherapy has shown activity in APC. It is proven that cytotoxicity of G and Cis is enhanced by heat exposure at 40° to 42°C. Therefore G plus Cis with regional hyperthermia (RHT) might be beneficial for patients with G-refractory APC. PATIENTS AND METHODS: We retrospectively analysed 23 patients with advanced (n = 2) or metastatic (n = 21) pancreatic cancer with relapse after G mono first-line chemotherapy (n = 23). Patients had received G (day 1, 1000 mg/m(2)) and Cis (day 2 and 4, 25 mg/m(2)) in combination with RHT (day 2 and 4, 1 h) biweekly for 4 months. We analysed feasibility, toxicity, time to second progression (TTP2), overall survival (OS) and clinical response. RESULTS: Between October 1999 and August 2008 23 patients were treated. Haematological toxicity was low with no grade 4 event. Hyperthermia-associated toxicity consisted of discomfort because of bolus pressure (3%), power-related pain (7%) or position-related pain (17%). Median TTP1 was 5.9 months (95% confidence interval (CI): 2.6-9.2), median TTP2 was 4.3 months (95%CI: 1.2-7.4) and OS 12.9 months (95%CI: 9.9-15.9). The disease control rate in 16 patients with available CT scans was 50%. CONCLUSION: We show first clinical data of G plus Cis with RHT being clinically active in G-pretreated APC with low toxicity. A prospective controlled phase II second-line clinical trial (EudraCT: 2005-003855-11) and a randomised phase III adjuvant clinical trial offering this treatment (HEAT; EudraCT: 2008-004802-14) are currently open for recruitment.

Assembléias de peixes associados às macrófitas aquáticas em ambientes alagáveis do Pantanal de Poconé, MT, Brasil / Fish assemblages associated to aquatic macrophytes in wetland environments of Pantanal de Poconé, State of Mato Grosso, Brazil

Este estudo avaliou a composição, riqueza e a biomassa das assembléias de peixes associadas às macrófitas aquáticas em ambientes temporários do Pantanal de Poconé - MT. A coleta foi realizada em abril de 2008, em cinco caixas de empréstimo e cinco locais na baía do Coqueiro, por meio de rede de cerco, em três pontos dentro de cada local. Foram capturados 9646 exemplares, distribuídos em sete ordens, 17 famílias e 59 espécies. A comunidade de peixes foi composta principalmente por espécies de pequeno porte (Characidae) e alguns juvenis de espécies de médio porte (Erythrinidae e Gymnotidae). Poucas espécies foram muito abundantes, algumas apresentaram abundância intermediária e a maioria apresentou baixa abundância. A análise de similaridade (Anosim) mostrou que não existe diferença na composição de espécies entre os ambientes. A riqueza de espécie e a biomassa dos peixes também não diferiram espacialmente. Desta forma, nossos resultados sugerem que a similaridade da ictiofauna é uma conseqüência da inundação, uma vez que esta permite a homogeneização das características abióticas e amplia a área de distribuição dos peixes. Este fato aparenta ser de grande importância para estes pequenos peixes, considerando que muitas espécies necessitam de lugares específicos em determinados estágios, como, por exemplo, esses ambientes temporários que podem servir de refúgio. Este aspecto pode garantir a sobrevivência de muitos indivíduos até atingirem uma fase da vida em que a predação sobre si diminui consideravelmente.

We examined the composition, richness and biomass of fish assemblages associated with aquatic macrophytes in temporary environments of the Pantanal de Poconé, State of Mato Grosso, Brazil. The fish were captured in April 2008 in five loan boxes and five locations along Coqueiro Bay, using seine nets at three points within each site. A total of 9646 specimens were captured, distributed in seven orders, 17 families and 59 species. The fish community was composed mainly of small-sized species (Characidae) and some juveniles of medium-sized species (Erythrinidae and Gymnotidae). In this study, few species were very abundant, some showed intermediate abundance, and most had low abundance. According to an analysis of similarity (Anosim) there was no difference in species composition between the environments. Species richness, total abundance and biomass did not vary spatially. Thus, the results suggest that the similarity of the fish fauna can be attributed to flooding, since this phenomenon homogenizes the abiotic characteristics and enlarges the area for the distribution of fish. This fact seems to be very important for these small fish species, since many species need to inhabit specific sites during certain stages; for example, these environments may function as temporary refuges. This aspect may ensure the survival of many individuals until they reach a stage in life where predation is significantly reduced.

Combination of hyperthermia and bortezomib results in additive killing in mantle cell lymphoma cells.

The proteasome inhibitor bortezomib exhibits antitumor activity in many malignancies including mantle cell lymphoma (MCL). Unfortunately, many patients fail to respond to treatment or become refractory. Hyperthermia is an effective chemosensitizer that in combination with some chemotherapeutic agents has shown clinical activity in phase II and III studies. The aim of this study was to use MCL cell lines to investigate the potential benefit of combining clinically relevant doses of bortezomib with two different thermal doses (41.8 degrees C/120 min and 44 degrees C/30 min) that mimic the heterogeneity of the temperature distributions achieved within tumors during hyperthermia. Treated tumor cells were assessed for proliferation using the WST-1 assay and for apoptosis by annexin V staining, while heat shock protein (HSP) levels were determined following western blot analysis. Our results demonstrated that MCL cell lines that are sensitive to bortezomib are also thermosensitive and have low basal expression of hsp27, whereas the bortezomib-resistant MCL cell line strongly expresses hsp27 and is thermoresistant. Interestingly, pre-treatment of MCL cell lines with heat at the two different thermal doses, and the transient elevation of hsp27 and hsp70, do not impair their primary sensitivity to bortezomib. Finally, we show that the concurrent treatment of heat and bortezomib results in additive killing in MCL cell lines.In conclusion, these results suggest that the application of bortezomib, under thermal conditions, in mantle cell lymphoma cells may be beneficial and warrants further investigation.

Anti-tumor activity of patient-derived NK cells after cell-based immunotherapy--a case report.

BACKGROUND: Membrane-bound heat shock protein 70 (Hsp70) serves as a tumor-specific recognition structure for Hsp70-peptide (TKD) plus IL-2 activated NK cells. A phase I clinical trial has shown that repeated re-infusions of ex vivo TKD/IL-2-activated, autologous leukapheresis product is safe. This study investigated the maintenance of the cytolytic activity of NK cells against K562 cells and autologous tumor after 6 plus 3 infusions of TKD/IL-2-activated effector cells. METHODS: A stable tumor cell line was generated from the resected anastomotic relapse of a patient with colon carcinoma (pT3, N2, M0, G2). Two months after surgery, the patient received the first monthly i.v. infusion of his ex vivo TKD/IL-2-activated peripheral blood mononuclear cells (PBMNC). After 6 infusions and a pause of 3 months, the patient received another 3 cell infusions. The phenotypic characteristics and activation status of tumor and effector cells were determined immediately before and at times after each infusion. RESULTS: The NK cell ligands Hsp70, MICA/B, and ULBP-1,2,3 were expressed on the patient's anastomotic relapse. An increased density of activatory NK cell receptors following ex vivo stimulation correlated with an enhanced anti-tumoricidal activity. After 4 re-infusion cycles, the intrinsic cytolytic activity of non-stimulated PBMNC was significantly elevated and this heightened responsiveness persisted for up to 3 months after the last infusion. Another 2 re-stimulations with TKD/IL-2 restored the cytolytic activity after the therapeutic pause. CONCLUSION: In a patient with colon carcinoma, repeated infusions of ex vivo TKD/IL-2-activated PBMNC initiate an intrinsic NK cell-mediated cytolytic activity against autologous tumor cells.

TIMP-1-GPI in combination with hyperthermic treatment of melanoma increases sensitivity to FAS-mediated apoptosis.

Resistance to apoptosis is a prominent feature of malignant melanoma. Hyperthermic therapy can be an effective adjuvant treatment for some tumors including melanoma. We developed a fusion protein based on the tissue inhibitor of matrix metalloproteinase-1 linked to a glycosylphosphatidylinositol anchor (TIMP-1-GPI). The TIMP-1-GPI-fusion protein shows unique properties. Exogenous administration of TIMP-1-GPI can result in transient morphological changes to treated cells including modulation of proliferation and decreased resistance to apoptosis. The effect of TIMP-1-GPI on the biology of melanoma in the context of a defined hyperthermic dose was evaluated in vitro. Clonogenic assays were used to measure cell survival. Gelatinase zymography determined secretion of MMP-2 and MMP-9. Monoclonal antibody against FAS/CD95 was applied to induce apoptosis. The expression of pro- and anti-apoptotic proteins and the secretion of immunoregulatory cytokines were then evaluated using Western blot and ELISA. TIMP-1-GPI combined with a sub-lethal hyperthermic treatment (41.8 degrees C for 2 h) suppressed tumor cell growth capacity as measured by clonogenic assay. The co-treatment also significantly suppressed tumor cell proliferation, enhanced FAS receptor surface expression increased tumor cell susceptibility to FAS-mediated killing. The increased sensitivity to FAS-induced apoptosis was linked to alterations in the apoptotic mediators Bcl-2, Bax, Bcl-XL and Apaf-1. The agent works in concert with sub-lethal hyperthermic treatment to render melanoma cells sensitive to FAS killing. The targeted delivery of TIMP-1-GPI to tumor environments in the context of regional hyperthermic therapy could be optimized through the use of thermosensitive liposomes.

Differential capacity of chaperone-rich lysates in cross-presenting human endogenous and exogenous melanoma differentiation antigens.

The goal of immune-based tumor therapies is the activation of immune cells reactive against a broad spectrum of tumor-expressed antigens. Vaccines based on chaperone proteins appear promising as these proteins naturally exist as complexes with various protein fragments including those derived from tumor-associated antigens. Multi-chaperone systems are expected to have highest polyvalency as different chaperones can carry distinct sets of antigenic fragments. A free-solution isoelectric focusing (FS-IEF) technique was established to generate chaperone-rich cell lysates (CRCL). Results from murine systems support the contention that CRCL induce superior anti-tumor responses than single chaperone vaccines. We established an in vitro model for human melanoma to evaluate the capacity of CRCL to transfer endogenously expressed tumor antigens to the cross-presentation pathway of dendritic cells (DC) for antigen-specific T cell stimulation. CRCL prepared from human melanoma lines contained the four major chaperone proteins Hsp/Hsc70, Hsp90, Grp94/gp96 and calreticulin. The chaperones within the melanoma cell-derived CRCL were functionally active in that they enhanced cross-presentation of exogenous peptides mixed into the CRCL preparation. Superior activity was observed for Hsp70-rich CRCL obtained from heat-stressed melanoma cells. Despite the presence of active chaperones, melanoma cell-derived CRCL failed to transfer endogenously expressed melanoma-associated antigens to DC for cross-presentation and cytotoxic T cell (CTL) recognition, even after increasing intracellular protein levels of tumor antigen or chaperones. These findings reveal limitations of the CRCL approach regarding cross-presentation of endogenously expressed melanoma-associated antigens. Yet, CRCL may be utilized as vehicles to enhance the delivery of exogenous antigens for DC-mediated cross-presentation and T cell stimulation.

Radiochemotherapy in combination with regional hyperthermia in preirradiated patients with recurrent rectal cancer.

BACKGROUND AND PURPOSE: Encouraging results of phase II studies combining chemotherapy with radiotherapy have been published. In this study, the results of a multimodal salvage therapy including radiochemotherapy (RCT) and regional hyperthermia (RHT) in preirradiated patients with recurrent rectal cancer are reported. PATIENTS AND METHODS: All patients enrolled had received previous pelvic irradiation (median dose 50.4 Gy). The median time interval between prior radiotherapy and the onset of local recurrence was 34 months. The combined treatment consisted of reirradiation with a median dose of 39.6 Gy (30.0-45.0 Gy), delivered in fractions of 1.8 Gy/day. 5-fluorouracil was given as continuous infusion 350 mg/m(2)/day five times weekly, and RHT (BSD-2000 system) was applied twice a week within 1 h after radiotherapy. The primary endpoint was local progression-free survival (LPFS); secondary endpoints were overall survival, symptom control, and toxicity. RESULTS: 24 patients (median age 59 years) with a previously irradiated locally recurrent adenocarcinoma of the rectum were enrolled. The median LPFS was 15 months (95% confidence interval 12-18 months] with a median follow-up of 27 months (16-37 months). The overall 1-year and 3-year survival rates were 87% and 30%, respectively. Pain was the main symptom in 17 patients. Release of pain was achieved in 12/17 patients (70%). No grade 3 or 4 hematologic or skin toxicity occurred. Grade 3 gastrointestinal acute toxicity was observed in 12.5% of the patients. Paratumoral thermometry revealed a homogeneous distribution of temperatures. CONCLUSION: RCT combined with RHT is an efficient salvage therapy showing high efficacy with acceptable toxicity and can be recommended as treatment option for this unfavorable group of preirradiated patients with local recurrence of rectal cancer.

Patient survival by Hsp70 membrane phenotype: association with different routes of metastasis.

BACKGROUND: Heat shock proteins (HSPs) play important roles in tumor immunity. The authors prospectively investigated the correlation between the tumor-specific Hsp70 membrane expression as an independent clinicopathological marker and overall survival in tumor entities that differ in their route of metastasis. METHODS: Hsp70 membrane expression was examined by flow cytometry in 58 colon, 19 gastric, 54 lower rectal carcinoma, and 19 squamous cell carcinoma specimens and the corresponding normal tissues at time of first diagnosis. Kaplan-Meier survival curves were analyzed to determine the relation of Hsp70 expression to the patients' prognosis. RESULTS: An Hsp70 membrane-positive phenotype was found in 40% (colon), 37% (gastric), 43% (lower rectal), and 42% (squamous cell) of the analyzed tumor specimens. None of the corresponding normal tissues was found to be Hsp70 membrane-positive. In patients with colon (P = .032) and gastric (P = .045) carcinomas, an Hsp70 membrane expression correlated significantly with an improved overall survival; a negative association was seen in lower rectal (P = .085) and squamous cell carcinoma (P = .048). CONCLUSIONS: The authors hypothesized that differing relations between surface expression of Hsp70 on tumor cells and clinical outcomes may reflect differences in the route of metastases. Colon and gastric carcinomas metastasize into the liver where hepatic natural killer cells may have the capacity to recognize and kill Hsp70 membrane-positive tumor cells and thus account for a better overall survival.

Effects of thermal stress on tumor antigenicity and recognition by immune effector cells.

The primary rationale for the application of clinical hyperthermia in the therapy of cancer is based on the direct cytotoxic effect of heat and the radio-chemosensitization of tumor cells. More recently, additional attention is given to the observation that heat and heat-shock proteins can activate the host's immune system. The expression of heat-shock genes and proteins provides an adaptive mechanism for stress tolerance, allowing cells to survive non-physiologic conditions. However, the same adaptive mechanism can ultimately favor malignant transformation by interfering with pathways that regulate cell growth and apoptosis. Cytoprotection and thermotolerance raised the concern that heat-treated tumor cells might also be resistant to attack by immune effector mechanisms. Many studies, including those from our group, address this concern and document that heat-exposure, although transiently modulating sensitivity to CTL, do not hinder CTL attack. Moreover, there are promising reports of heat-related upregulation of NK-activating ligands, rendering those tumors which have lost MHC class I molecules target for NK cell attack. Heat-induced cytoprotection, therefore, does not necessarily extend protection from cytotoxic immune mechanisms. When interpreting the effects of heat, it is important to keep in mind that thermal effects on cell physiology are strongly dependent on the thermal dose, which is a function of the magnitude of change in temperature and the duration of heat exposure. The thermal dose required to induce cell death in vitro strongly varies from cell type to cell type and depends on microenvironmental factors (Dewey 1994). Therefore, to dissect the immunological behaviour of a given tumor and its micro-environment at different thermal doses, it is essential to characterize the thermosensitivity of every single tumor type and assess the proportion of cells surviving a given heat treatment. In this review, we summarize the pleiotropic effects that heat exposure has on tumor cells. In particular, we focus on the effects of heat on the antigen presentation of tumor cells and their susceptibility to immune effector mechanisms. We emphasize that the response to thermal stress is not a one-time point event, but rather a time period starting with the heat exposure and extending over several days of recovery. In addition, the response of tumor cells and their susceptibility to immune effector cells is strongly dependent on the model system, on the magnitude and duration of the thermal stress and on the time of recovery after heat exposure. Consideration of these aspects might help to explain some of the conflicting results that are reported in the field of thermal stress response.