[Synchronous oligometastatic renal cell carcinoma-what is the role of surgery?] / Primär oligometastasiertes Nierenzellkarzinom ­ Welchen Stellenwert hat heutzutage die Chirurgie?

BACKGROUND: Long-term remission can be achieved by surgery in patients with metastatic renal cell carcinoma (mRCC), without chronic toxicity due to systemic treatment. Data on metastasectomy are mostly based on observations of metachronous metastasis. However, it is unclear whether patients with synchronous oligometastasis may also benefit from surgery alone as an alternative to highly effective systemic treatment combined with resection of the primary tumor. MATERIALS AND METHODS: The authors performed an unstructured literature search in PubMed including systematic reviews and meta-analyses. Results are discussed in regard of the current data and clinical practice. RESULTS AND DISCUSSION: Although there is no uniform definition for oligometastasis in mRCC, cytoreductive nephrectomy in selected patients seems to be mandatory before metastasectomy is performed in primary oligometastatic RCC. In particular, in those patients with oligometastasis of the lung, bone, central nervous system, liver, adrenal gland, and thyroid, metastasectomy appears to be an important therapeutic option. Ultimately, among the therapeutic options, surgery is also an important therapeutic approach in primary oligometastatic mRCC. A balanced consideration between surgery, other local therapies, and modern systemic treatment demands interdisciplinary decision-making that takes into account the patients' preference.

[Oncologic aspects in treatment of pathologic fractures]. / Onkologische Aspekte der Behandlung pathologischer Frakturen.

BACKGROUND: Pathological fractures are not only incisive events for tumor patients often with the need of surgical treatment but also often represent a relevant challenge in the overall concept of oncological treatment. OBJECTIVE: The aim of this article is to illustrate the necessity of a pre-interventional interdisciplinary consideration of disease-specific and patient-specific characteristics. MATERIAL AND METHODS: A literature search and evaluation of existing guidelines were carried out including the keywords "bone metastases" and "pathological fractures" with respect to the oncological and radiotherapeutic treatment. RESULTS: An essential classification of the surgical and other needs for treatment is carried out by the identification of the underlying disease and dissemination situation. For tumor-related pathological fractures a palliative treatment situation is present in most cases. Nevertheless, a possible oligometastasis and an increasing number of effective systemic treatment methods must be taken into consideration when planning the surgical treatment. In addition to the therapeutic emergency indications in spinal compression or symptomatic hypercalcemia, both additive radiotherapy and supplementary pharmaceutical osteoprotection have to be addressed in this context. Radiotherapy in particular represents an effective alternative option for symptom and tumor control. CONCLUSION: The work-up of the multifaceted oncological treatment concept represents an interdisciplinary challenge, which ideally defines the further treatment procedure, including fracture treatment, in an interdisciplinary tumor board within an overall oncological concept.

Protective measures for patients with advanced cancer during the Sars-CoV-2 pandemic: Quo vadis?

Cancer patients represent a vulnerable cohort during the Sars-CoV-2 pandemic. Oncological societies have generated a plethora of recommendations, but precise instructions about routine oncological procedures remain scarce. Here, we report on local COVID-19 protection measures established in an interdisciplinary approach at a tertiary care center during the first wave of the pandemia in Germany. Following these measures, no additional morbidity or mortality during oncological procedures was observed, and no nosocomial infections were registered. However, Validation of our measures is outstanding and regional SARS-CoV-2 prevalence was low. However, specific oncological measures might be important to ensure optimal oncological results, especially for advanced cancer stages during this and future pandemia. In the future, communication about these measures might be crucial to a cancer patient´s assigned network to reduce the danger of excess mortality within the second wave of the COVID-19 pandemic.

[c-MET Oncogene in Renal Cell Carcinomas]. / c-Met Onkogen bei Nierenzellkarzinomen.

c-Met plays a significant role in multiple cellular processes. Being encoded by a proto-oncogene, tyrosine kinase supports aggressive tumour behaviour such as tumour invasiveness and formation of metastases. For some subtypes of renal cell carcinoma studies have shown a association between c-Met expression and clinical outcome or prognosis. Therefore, c-Met represents a prognostic marker in renal cell carcinoma.Furthermore, c-MET will play a decisive role as a possible target for targeted therapies in the era of personalised medicine. Especially for RCC, the dual inhibition of VEGF and c-MET tyrosine kinase in cases of metastatic, treatment-resistant tumours is gaining clinical relevance. The role of c-Met has not been fully elucidated for all subtypes of renal cell carcinomas. The relevance of c-Met for the remaining subtypes of renal tumours has yet to be clarified.

Intratumoral expression of programmed death ligand 1 (PD-L1) in patients with clear cell renal cell carcinoma (ccRCC).

The immunological checkpoints of programmed death 1 and its ligand (PD-L1) are currently in focus as novel therapeutic targets in renal cell carcinoma (RCC). The aim of this study was to evaluate the prognostic association of PD-L1 expression in clear cell (cc) RCC with clinical parameters, tumor aggressiveness and overall survival (OS). Patients who underwent renal surgery due to RCC between 1994 and 2003 were retrospectively evaluated. Tumor specimens were analyzed for PD-L1 expression by immunohistochemistry. One hundred and seventy-seven ccRCC patients were eligible for analysis, in which 140 (79.1 %) were negative and 37 (20.9 %) were positive for PD-L1 expression. PD-L1 positivity was associated with female gender (p = 0.001), lymph node metastasis (p = 0.004), distant metastasis (p = 0.002), higher AJCC stage (p = 0.004), as well as advanced disease (pT3/4 and/or N+ and/or M1) (p < 0.001). Kaplan-Meier analysis revealed a significantly diminished 5- and 10-year overall survival of 46.7 and 28.3 % for PD-L1(+) compared to PD-L1(-) tumors with 66 and 53.4 % (p = 0.005), respectively. Univariate analysis showed a significant negative association of OS with PD-L1 positivity [p = 0.005; HR: 2 (95 % CI 1.2-3.3)], even though PD-L1 positivity only tends to predict independently the OS using multivariate analyses [p = 0.066; HR: 1.6 (95 % CI 0.98-2.7)]. PD-L1 expression in ccRCC is associated with parameters of aggressiveness, as well as with poor OS, even though PD-L1 status was not identified as a significant independent prognostic parameter. However, further studies in larger cohorts are warranted.

Does the onset of bone metastasis in sunitinib-treated renal cell carcinoma patients impact the overall survival?

PURPOSE: To evaluate the impact of bone metastasis (BM) onset toward prognosis in metastatic renal cell carcinoma (mRCC) patients treated with sunitinib. METHODS: mRCC patients with BM and sunitinib as first targeted therapy between May 2005 and December 2012 were retrospectively analyzed. Patients with synchronous (s) BM or metachronous (m) BM were compared with regard to treatment and outcome [time to clinical progression (TTcP), overall survival (OS), skeletal-related events (SRE)]. Descriptive statistics, Kaplan-Meier estimation of TTcP and OS, Cox regression analyses, and a landmark analysis were administered. RESULTS: BM was identified in 127 mRCC patients; thereof, 82 sunitinib-treated patients were analyzed [sBM n = 57 (69.5 %), mBM n = 25 (30.5 %)]. Higher tumor grading (p = 0.029), male predominance (p = 0.02), and less second-line therapy (p = 0.001) were detected in sBM compared to mBM. SRE remained similar between subgroups (p = 0.462). TTcP during sunitinib was similar [median sBM 8.1 (95 % CI 3.9-12.3) vs. mBM 8.7 (95 % CI 2.7-14.8) months, p = 0.903]. OS remained significantly inferior in sBM patients compared to mBM [median sBM 21.1 (95 % CI 16-26.2) months vs. mBM 38.5 (95 % CI 15-62) months, p = 0.001], which was confirmed by landmark analyses at 1.5, 3, 6, 9, and 12 months. However, OS after occurrence of BM was similar in both groups [median sBM 24.2 (95 % CI 17.3-31.1) months vs. mBM 17.2 (95 % CI 8.4-26) months, p = 0.519]. CONCLUSIONS: mBM is associated with an improved OS compared to sBM in mRCC with sunitinib treatment, despite similar efficacy of sunitinib treatment in both groups of patients.

[Systemic Treatment of Metastatic Renal Cell Cancer--Back to the Future?]. / Die Systemische Behandlung des metastasierten Nierenzellkarzinoms--Zurück in die Zukunft?

A variety of therapeutic agents are currently available for the systemic treatment of metastatic renal cell carcinoma (mRCC). It was only when targeted treatment was developed in the past decade that a significant improvement was achieved in tumour therapy. This also led to the development of sequential treatment for mRCC.7 molecular targeted agents are available today (axitinib, bevacizumab/ IFNα, everolimus, pazopanib, sorafenib, sunitinib, and temsirolimus). Due to the individualisation of treatment it remains a challenge to choose the most appropriate drug in a given setting, with the choice being based on the knowledge of the relevant clinical data as well as individual patient parameters.During the recent past, efforts have been made to test different inhibitors or combinations without a major breakthrough. Instead, the development of novel specific immunotherapeutic approaches now heralds the next level of treatment in mRCC. The first significant trial results will be expected this year, and further trials for optimisation of treatment are warranted.

TEMHEAD: a single-arm multicentre phase II study of temsirolimus in platin- and cetuximab refractory recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN) of the German SCCHN Group (AIO).

BACKGROUND: Squamous cell carcinoma of the head and neck (SCCHN) is a common disease, which has a poor prognosis after failure of therapy. Activation of the PI3K-AKT-mTOR axis is commonly detected in recurrent or metastatic SCCHN, and provided the rationale for the clinical phase II trial in pretreated SCCHN. PATIENTS AND METHODS: The primary end point was the progression-free survival rate (PFR) at 12 weeks. Forty eligible patients have been recruited after failure of platinum chemotherapy and cetuximab. A preplanned futility analysis was successfully passed after ≥1 success was detected in 20 patients. Secondary objectives consisted of progression-free survival (PFS), disease control rate (DCR), overall survival (OS), safety and tolerability, and predictive biomarkers for KRAS, BRAF, PIK3CA mutations, and HPV status. Archived tumor tissue was analyzed for DNA sequence. RESULTS: A total of 40 patients were eligible. The PFR at 12 weeks was 40% (95% CI 25.0-54.6). The median PFS and OS were 56 days (95% CI 36-113 days) and 152 days (76-256 days), respectively. In 33 assessable patients, disease stabilization occurred in 57.6%, with tumor shrinkage in 13 patients (39.4%). Overall, the treatment was well tolerated. Fatigue (47.5%), anemia (25.0%), nausea (20.0%), and pneumonia (20.0%) were the most common adverse events. Neither PIK3CA mutations, nor HPV status were predictive for success with temsirolimus treatment. No mutations were found for KRAS or BRAF. CONCLUSION: Tumor shrinkage and efficacy parameter indicate that inhibition of the PI3K-AKT-mTOR axis was a putative novel treatment paradigm for SCCHN. We could not identify parameters predictive for treatment success of temsirolimus, which underscores the need for refinement of the molecular analysis in future studies. CLINICAL TRIALS NUMBER: NCT01172769.

Phenotyping established chronic lung allograft dysfunction predicts extracorporeal photopheresis response in lung transplant patients.

Chronic lung allograft dysfunction (CLAD) remains the leading cause of mortality in lung transplant recipients after the first year. Treatment remains limited and unpredictable. Existing data suggests extracorporeal photopheresis (ECP) may be beneficial. This study aimed to identify factors predicting treatment response and the prognostic implications. A single center retrospective analysis of all patients commencing ECP for CLAD between November 1, 2007 and September 1, 2011 was performed. In total 65 patients were included, 64 of whom had deteriorated under azithromycin. Median follow-up after commencing ECP was 503 days. Upon commencing ECP, all patients were classified using proposed criteria for emerging clinical phenotypes, including "restrictive allograft syndrome (RAS)", "neutrophilic CLAD (nCLAD)" and "rapid decliners". At follow-up, 8 patients demonstrated ≥10% improvement in FEV1 , 27 patients had stabilized and 30 patients exhibited ≥10% decline in FEV1 . Patients fulfilling criteria for "rapid decliners" (n=21, p=0.005), RAS (n=22, p=0.002) and those not exhibiting neutrophilia in bronchoalveolar lavage (n=44, p=0.01) exhibited poorer outcomes. ECP appears an effective second line treatment in CLAD patients progressing under azithromycin. ECP responders demonstrated improved progression-free survival (median 401 vs. 133 days). Proposed CLAD phenotypes require refinement, but appear to predict the likelihood of ECP response.

Response of renal lesions during systemic treatment with sunitinib in patients with metastatic renal cell carcinoma: a single center experience with 14 patients.

PURPOSE: The tyrosine kinase inhibitor (TKI) sunitinib induces partial remissions (PR) in a substantial proportion of patients with metastatic renal cell carcinoma (mRCC). Only little is known about the activity of sunitinib in renal lesions in patients with metastatic disease, as most patients with synchronous metastases receive palliative nephrectomy. METHODS: Fourteen patients with clear cell mRCC with renal lesions and sunitinib therapy (50 mg OD, 4/2 scheme) were retrieved retrospectively from clinic records. Tumor assessment consisted of CT scans at least every two cycles, analyzed according to RECIST. In 5 of 14 patients, renal tumors were considered as the primary tumor, while the remaining patients had kidney metastases. In total, 65 target lesions were evaluated. RESULTS: The median progression-free survival (PFS) of sunitinib was 8.7 months (range: 2.7-40.2). Median overall survival (OS) from initiation of TKI therapy was 26 months (range: 3-55). Best response according to RECIST consisted of partial remission (PR) in 4 patients, stable disease (SD) in 7 patients, a complete remission (CR) in 1 patient, and 2 patients with progressive disease (PD). Analyzing the response of renal lesions only, 1 patient had PD, 8 patients had SD, 4 patients had PR, and 1 had a CR. Palliative nephrectomy was performed after two courses of sunitinib in 2 patients. CONCLUSIONS: In our cohort, similar responses of renal tumors and peripheral metastases were achieved with sunitinib treatment. Our results support the use of sunitinib to control renal tumor lesions in metastatic patients.

Self-expanding metallic stent placement with laryngeal mask in lung transplant recipients.

BACKGROUND: Bronchial stent insertion is a suitable method to treat airway complications. We present our experience with laryngeal mask airway (LMA) for stent insertion in lung transplant (LT) recipients. METHODS: From April 2007 to March 2009, 27 LT recipients underwent insertion of self-expanding nitinol stents to manage airway complications after LT, using LMA for general anesthesia. All procedures were performed with flexible fiberoptic bronchoscopy without fluoroscopy; stent release was visualized with ultrathin bronchoscopes. We followed technical success, safety, improvement of lung function, and clinical symptoms. RESULTS: Forty-one stents were inserted in 27 patients in 32 sessions. The indications for stent insertion were necrotic lesions (7%) and obstructive lesions (90%). Technical success and safety were 94%. Twice, the stent dislocated, requiring replacements. In 91% of patients, postinterventional improvement in graft function (1 minute forced expiratory volume) was >10% after the intervention. Improvement of clinical symptoms was achieved in 94%. The median procedure time was 38 minutes (range, 30-85 minutes). CONCLUSIONS: LMA offered an excellent condition for stent insertion in LT recipients with airway complications. It provided adequate ventilation and safe airway control during the procedure. This technique may serve as alternative to established techniques using fluoroscopy and rigid bronchoscopy.

Sexual dimorphism, but not testosterone itself, is responsible for ankylosing enthesitis of the ankle in B10.BR (H-2k) male mice.

BACKGROUND: Ankylosing enthesopathy (ANKENT) with progressive stiffening of ankle and tarsal joints of the hind limbs is a naturally occurring arthropathy in B10.BR mice. Some features are similar to those of the spondyloarthropathies in humans. OBJECTIVE: To study the role of sexual dimorphism and testosterone in the development of ANKENT. METHODS: The incidence of ANKENT was observed in non-castrated, castrated, and testosterone substituted castrated male mice, and in control and testosterone treated female mice. RESULTS: ANKENT occurred only in males; it did not develop in males castrated at age 2-3 months but occurred in castrated males injected with testosterone. Females injected with testosterone did not develop ANKENT. CONCLUSION: Testosterone can replace what castration eliminates, at least in the postpubertally castrated males, but is itself not sufficient to induce joint disease.

The epitope recognized by pan-HLA class I-reactive monoclonal antibody W6/32 and its relationship to unusual stability of the HLA-B27/beta2-microglobulin complex.

A broadly used pan-HLA class I-reactive monoclonal antibody W6/32 is believed to recognize a conformational epitope dependent on association between heavy chains and beta2-microglobulin (beta2m). However, in the present study we report that W6/32 does recognize at least some free HLA class I heavy chains under the partially denaturating conditions of nonreducing Western blotting, namely nearly all HLA-B allelic products. Furthermore, we confirm and largely extend our previous observation that complexes of beta2m with heavy chains of a few HLA class I allelic forms (most notably HLA-B27) exhibit unusual resistance to dissociation by SDS, which is reminiscent of MHC class II molecules. In addition, our data indicate the existence of covalent (disulfide-linked) heterodimers of certain HLA class I heavy chains (namely Cw1 and Cw4) and beta2m.

Germ-free mice do not develop ankylosing enthesopathy, a spontaneous joint disease.

Ankylosing enthesopathy (ANKENT) is a naturally occurring joint disease in mice with numerous parallels to human ankylosing spondylitis (AS). Similarities between AS and ANKENT include not only affected tissue (joint entheses) but also association of the disease with genetic background, including MHC genes, gender, and age. Young males with the C57Bl/10 background have been described to suffer from ANKENT and, among H-2 congenic strains, high frequency of afflicted joints has been recorded in B10.BR (H-2(k)) males. Interestingly, the incidence of ANKENT is higher in conventional (CV) males that in their specific-pathogen-free (SPF) counterparts. The latter finding suggests that microbes could play a role as an ANKENT-triggering agent. To further examine this hypothesis we have established a germ-free (GF) colony of B10.BR mice and observed ANKENT incidence in both GF males and their conventionalized (ex-GF) male littermates; 20% of ex-GF males developed ANKENT before 1 year of age. In contrast, no joint disease was observed under GF conditions (p < 0.0001). Our results show that live microflora is required in ANKENT pathogenesis.

Strong association of HLA-B27 heavy chain with beta 2-microglobulin.

Monoclonal antibody TG1 recognizes specifically antigens HLA-B27, B7, B22 and B17 on cell surface in cytotoxicity and cytofluorometry tests. When cell detergent extracts were subjected to SDS PAGE under mild conditions (no heating and no reduction of the sample) followed by Western blotting, TG1 detected exclusively a complex of B27 heavy chains with beta(2)-microglobulin (as a 50 kDa band) whereas the other B-locus antigens (B7, B22, B17) were detected as free 43 kDa heavy chains under the same conditions. When the samples were boiled prior to SDS PAGE, TG1 detected again the 43 kDa free heavy chains of B7, B22 and B17 but no zone corresponding to B27 could be detected indicating that the epitope in free B27 chains is more sensitive to denaturation by SDS. Thus, our main finding is that the interaction of HLA-B27 heavy chain with beta(2)-microglobulin appears to be stronger than that of the other HLA-B chains. The resistance of the HLA-B27/beta(2)-microglobulin complex to the SDS dissociation is strikingly similar to the behavior of MHC class II molecules under similar conditions. Thus, it may be speculated that HLA-B27 complexes can be also more stable than other MHC class I molecules under more physiological dissociative conditions (e.g. in endosomal compartments). This feature might potentially influence antigen presentation by HLA-B27 and contribute to the well known disease linkage of HLA-B27.

Histopathology of murine ankylosing enthesopathy.

Ankylosing enthesopathy is a spontaneously occurring progressive stiffening of the ankle and/or tarsal joints in mice of C57Black background. In C57BL/10 mice and mice of the same genetic background that had been made transgenic for HLA-B27, the start of the disease was detected by weekly testing for decreased mobility in the ankle/tarsus region. Ankylosing enthesopathy was found to begin with a short phase of proliferative inflammation of the joints and adjacent tissues, with some fibrinous exsudation, some leucocytic infiltration and slight bone erosion. This inflammation is soon accompanied and followed by proliferation of cartilaginous cells at the bone insertions of joint capsule ligaments (entheses). Ossification of the cartilage proliferations and some desmal ossification lead to large osteophytes that inhibit mobility. Fusion of osteophytes occasionally leads to marginal ankylosis. The histopathology of the successive stages of murine ankylosing enthesopathy and the preponderance in males and HLA-B27 transgenic mice are reminiscent of ankylosing spondylitis in man. The spine, however, was not affected.

Preservation of immunological and colony-forming capacities of long-term (15 years) cryopreserved cord blood cells.

BACKGROUND: Cryopreserved cord blood may be stored for decades before being used for allogeneic stem cell transplantation. Little is known about the effect of long-term cryopreservation in liquid nitrogen on the viability and function of cord blood cells. We examined the recovery, viability, clonogenic capacity, and T-cell reactivity to HLA alloantigens of cord blood samples cryopreserved up to 15 years. METHODS: Progenitor cell recoveries were studied by (colony-forming unit-granulocyte-macrophage) clonogenic assays from 18 cord blood samples short-term frozen for 2-8 weeks and from 8 samples cryopreserved for 15 years. Proliferative and cytotoxic responses against HLA antigens of thawed cord blood mononuclear cells after short-term or long-term cryopreservation were tested in standard mixed lymphocyte cultures and cell-mediated lympholysis assays. RESULTS: After thawing, the mononuclear cell recovery from long-term frozen cord blood low-density fractions averaged 80% (range, 64% to 92%). The presented data show that long-term frozen cord blood cells keep their clonogenic potential. No damaging effect was seen on the proliferative and cytotoxic capacities of long-term frozen cord blood T cells. CONCLUSIONS: The results support the possibility of long-term storage of progenitor cells from umbilical cord blood for future bone marrow reconstitution.

The role of MHC class I heterodimer expression in mouse ankylosing enthesopathy.

Ankylosing enthesopathy (ANKENT) is a spontaneous mouse joint disease with strikingly similar pathology to human HLA-B27-associated enthesopathies such as ankylosing spondylitis. In C57Bl/10 mice, transgenic HLA-B*2702 as well as H2 genes have been shown to be relative risk factors for ANKENT. To investigate the role of major histocompatibility complex (MHC) class I expression in disease pathogenesis, ANKENT occurrence was compared among beta2-microglobulin (beta2m) knockout littermates with or without transgenes for HLA-B*2702 and human beta2m. In the knockout phenotype lacking beta2m, ANKENT occurrence is significantly reduced (P = 0.016). In the absence of beta2m, B*2702 is not detected on the cell membrane, nor does it increase the risk for ANKENT. This means that the previous finding that HLA-B*2702 increases susceptibility to ANKENT in C57Bl/10 mice cannot be ascribed to a transgene insertion effect. Rather, in order to increase disease susceptibility, B*2702 must be coexpressed with mouse beta2m (mo-beta2m). In contrast, when HLA-B*2702 is expressed with beta2m of human origin, disease susceptibility is not affected. Thus, both H2(b)-derived class I heterodimers and HLA-B*2702/mo-beta2m heterodimers contribute to ANKENT susceptibility.

Grouped caging predisposes male mice to ankylosing enthesopathy.

OBJECTIVE: To evaluate the number of males per cage as a possible risk factor for murine ankylosing enthesopathy (ANKENT)--a spontaneous joint disease with parallels to human seronegative spondylarthropathies--since ANKENT shows incomplete penetrance of genetic susceptibility factors among individuals living in a stable environment. METHODS: Frequency of ANKENT was compared among males housed with females, with other males, or alone. RESULTS: In three independent cohorts, a trend was observed that males housed with females rarely develop the disease, in contrast to males housed with other males (P < 0.25, P < 0.05, and P < 0.01). Furthermore, no males caged alone developed ANKENT, whereas disease did occur in males grouped together (P < 0.01). When healthy males (retired breeders) were recaged either alone or with other males, ANKENT developed among the grouped males only (P < 0.005). CONCLUSIONS: Caging males together is a relative risk factor for ANKENT. Grouped caging may perturb the immune system through endocrine pathways or modify microbiological load through behaviour (for example, infection due to biting).