Defining T Cell States Associated with Response to Checkpoint Immunotherapy in Melanoma.

Treatment of cancer has been revolutionized by immune checkpoint blockade therapies. Despite the high rate of response in advanced melanoma, the majority of patients succumb to disease. To identify factors associated with success or failure of checkpoint therapy, we profiled transcriptomes of 16,291 individual immune cells from 48 tumor samples of melanoma patients treated with checkpoint inhibitors. Two distinct states of CD8+ T cells were defined by clustering and associated with patient tumor regression or progression. A single transcription factor, TCF7, was visualized within CD8+ T cells in fixed tumor samples and predicted positive clinical outcome in an independent cohort of checkpoint-treated patients. We delineated the epigenetic landscape and clonality of these T cell states and demonstrated enhanced antitumor immunity by targeting novel combinations of factors in exhausted cells. Our study of immune cell transcriptomes from tumors demonstrates a strategy for identifying predictors, mechanisms, and targets for enhancing checkpoint immunotherapy.

Evaluation of five scoring systems for cervical spondylogenic myelopathy.

BACKGROUND CONTEXT: Comparison of measured clinical deficits and outcomes is vital for international discussion about the identification and treatment of cervical spondylotic myelopathy (CSM). There is currently little information comparing outcomes as assessed by different CSM scoring systems. PURPOSE: To qualitatively and quantitatively analyze five specific CSM outcome scores that are frequently used to assess the grade of severity and outcome after operative decompression. STUDY DESIGN: This retrospective study evaluated the Nurick score, the Japanese Orthopedic Association score (JOA score), the Cooper myelopathy scale (CMS), the Prolo score, and the European myelopathy score (EMS). PATIENT SAMPLE: The study included 43 patients with clinical and morphological signs of CSM, who underwent ventral decompression. Data were evaluated in sufficient detail to objectively assess the scores. OUTCOME MEASURES: Clinical findings (funicular and radicular symptoms), recovery rate, symptom duration, age, economic situation, time away from employment, somatic-evoked potentials, and radiological findings were assessed. METHODS: Scores were assessed using both pre- and postoperative clinical data. Correlations between scores, score improvement, and how well the scores reflected the clinical, diagnostic, and anamnestic data were analyzed using nonparametric, descriptive statistical tests. The recovery rate, as a measure of cumulative outcome, was also assessed and compared for each scoring system. RESULTS: All five scores were suitable for qualitatively assessing the clinical characteristics and progression of cervical myelopathy. All showed a statistically significant correlation (p<.05), and measured postoperative improvement (p<.001). All scores also reflected clinical deficits except for the Prolo score, which rates the severity of CSM with an emphasis on data related to the economic impact on the patient's situation rather than on clinical symptoms per se. Quantitative assessment of clinical symptom improvement varied greatly among the scores, for example, Nurick score (33%) versus JOA score (81%). The recovery rates, as a measure of cumulative improvement, showed less variation among most of the scores. The Nurick score and the EMS measured clinical deficit improvements in significantly fewer patients than did the JOA score (p<.05). CONCLUSIONS: Evaluating the recovery rate is essential for comparing the results of the five CSM scores evaluated in this study. There was a large quantitative difference among the scores as the result of the different criteria used to produce each score. Qualitatively, all five scores allowed evaluation of cervical myelopathy, but only the recovery rate allowed for statistical comparison. Advancements in the treatment of CSM depend on the ability of clinicians to evaluate the therapeutic results of CSM studies. This study suggests that using the recovery rate to assess outcome is best for comparing studies that use different scores.

Coadministration of Sublingual Immunotherapy Tablets and Management of Potential Adverse Effects: Austrian, German, and Swiss Expert Recommendations.

Sublingual immunotherapy (SLIT) is currently available as liquid drops and tablets for treatment of allergic patients. Because several allergens are available and many patients are polyallergic, it is possible to treat patients with multiple clinically relevant allergies by >1 SLIT product. Austrian, German, and Swiss medical experts discussed the available data on allergen uptake at the oral mucosa and recently published data on coadministration of a grass and a ragweed tablet. The experts agreed on a schedule considering data from a North American trial on sequential administration of 2 SLIT-tablets with different allergens and their own experiences made during initiation of treatment with >1 SLIT-tablet in their clinics and subsequent self-administration by the patient and discussed the handling and management of potential adverse drug reactions (ADRs). According to the medical experts' opinion, tolerability at each phase of administration and patient preference should be taken into consideration to ensure a high level of adherence to treatment. Local ADRs that are uncomfortable for the patient may be alleviated by a 2- to 4-week course of antihistamine pretreatment. ADRs with severe swelling and/or systemic ADRs need the physician's particular attention and a decision together with the patient on continuation of treatment with SLIT or possible alternative routes of administration.

Ex Vivo Profiling of PD-1 Blockade Using Organotypic Tumor Spheroids.

Ex vivo systems that incorporate features of the tumor microenvironment and model the dynamic response to immune checkpoint blockade (ICB) may facilitate efforts in precision immuno-oncology and the development of effective combination therapies. Here, we demonstrate the ability to interrogate ex vivo response to ICB using murine- and patient-derived organotypic tumor spheroids (MDOTS/PDOTS). MDOTS/PDOTS isolated from mouse and human tumors retain autologous lymphoid and myeloid cell populations and respond to ICB in short-term three-dimensional microfluidic culture. Response and resistance to ICB was recapitulated using MDOTS derived from established immunocompetent mouse tumor models. MDOTS profiling demonstrated that TBK1/IKKε inhibition enhanced response to PD-1 blockade, which effectively predicted tumor response in vivo Systematic profiling of secreted cytokines in PDOTS captured key features associated with response and resistance to PD-1 blockade. Thus, MDOTS/PDOTS profiling represents a novel platform to evaluate ICB using established murine models as well as clinically relevant patient specimens.Significance: Resistance to PD-1 blockade remains a challenge for many patients, and biomarkers to guide treatment are lacking. Here, we demonstrate feasibility of ex vivo profiling of PD-1 blockade to interrogate the tumor immune microenvironment, develop therapeutic combinations, and facilitate precision immuno-oncology efforts. Cancer Discov; 8(2); 196-215. ©2017 AACR.See related commentary by Balko and Sosman, p. 143See related article by Deng et al., p. 216This article is highlighted in the In This Issue feature, p. 127.

Analysis of five specific scores for cervical spondylogenic myelopathy.

The ability to compare various results that measure clinical deficits and outcome is a necessity for successful worldwide discussion about cervical spondylogenic myelopathy (CSM) and its treatment. There is hardly any information in literature how to value and compare outcome assessed by different scores. In a retrospective study we objectively evaluated the Nurick-score, Japanese-orthopaedic-association-score (JOA-Score), Cooper-myelopathy-scale (CMS), Prolo-score and European-myelopathy-score (EMS) using the data of 43 patients, all of whom showed clinical and morphological signs of CSM and underwent operative decompression. The scores were assessed pre- and postoperatively. The correlation between the score-results, anamnesis, clinical and diagnostic data was investigated. All the scores show a statistically significant correlation and measure postoperative improvement. With exception of the Prolo-score all scores reflect clinical deficits of CSM. The Prolo-score rates the severity of CSM on the state of the economic situation above clinical symptoms. The main differences of the scores are shown in the number of patients showing postoperative improvement, varying between 33% (Nurick-score) and 81% (JOA-score). The recovery-rates, as a measure of the cumulative improvement of all the symptoms, show less variation (23-37%). The differences of the recovery-rate were only statistically significant between JOA-score, Nurick-score and EMS (P < 0.05), whereas all the other scores showed no significant differences. To assess the postoperative successes, the evaluation of the recovery-rate is essential. There is no significant difference in the recovery-rate amongst the majority of the scores, which allows a good comparison of the results from different studies. Nevertheless, it is always important to differentiate the therapy results of CSM published worldwide.

Resistance to checkpoint blockade therapy through inactivation of antigen presentation.

Treatment with immune checkpoint blockade (CPB) therapies often leads to prolonged responses in patients with metastatic melanoma, but the common mechanisms of primary and acquired resistance to these agents remain incompletely characterized and have yet to be validated in large cohorts. By analyzing longitudinal tumor biopsies from 17 metastatic melanoma patients treated with CPB therapies, we observed point mutations, deletions or loss of heterozygosity (LOH) in beta-2-microglobulin (B2M), an essential component of MHC class I antigen presentation, in 29.4% of patients with progressing disease. In two independent cohorts of melanoma patients treated with anti-CTLA4 and anti-PD1, respectively, we find that B2M LOH is enriched threefold in non-responders (~30%) compared to responders (~10%) and associated with poorer overall survival. Loss of both copies of B2M is found only in non-responders. B2M loss is likely a common mechanism of resistance to therapies targeting CTLA4 or PD1.

Comparative genomic hybridization pattern of non-anaplastic and anaplastic oligodendrogliomas--a meta-analysis.

Many oligodendrogliomas (ODG) have been investigated by comparative genomic hybridization (CGH). To visualize characteristic aberration profiles of non-anaplastic in a comparison with anaplastic ODGs, we performed a meta-analysis of the CGH results of all 89 cases published so far. Therefore, we expanded all given aberrations to the maximum of 850 GTG band resolution. The frequencies of each chromosomal band affected by a genetic imbalance were calculated for WHO grades II and III separately. In non-anaplastic ODGs, -1p and -19q were the most prominent aberrations. In anaplastic ODGs, +7, -4q, -9p, -10, and -15q emerged additionally. We could confirm the existence of three disjunct genetically defined subgroups of ODGs, characterized by -1p/-19q (n=58, 65%, subgroup A), +7/-10 (n=6, 7%, subgroup B) or the absence of either of the two patterns (n=25, 28%, subgroup C). Interestingly, we found a unique aberration pattern in subgroup C (-1p31, -4q, -11p15, -18q, -22q, +17p, +17q) that was different from subgroups A and B, which could indicate a unique molecular carcinogenetic pathway of this ODG subset. Scrutinizing published putative progression markers of ODG, we found that only +7, -10, and -15q significantly correlated with a higher grade of malignancy. Summing up, the expansion of the CGH results to the 850 GTG band resolution enabled a meta-analysis to visualize WHO grade-specific aberration profiles in ODG for the first time.

Anatomical data on the craniocervical junction and their correlation with degenerative changes in 30 cadaveric specimens.

OBJECT: The goal of this project was to measure vertebral dimensions at the craniocervical junction and to investigate degenerative changes in this region and their correlations with the anatomical data. These studies will assist in an understanding of biomechanical conditions in this region, which are clinically relevant in cases of cervicogenic headaches and vertigo. METHODS: The authors examined 30 cadaveric specimens obtained from patients ranging in age from 24 to 88 years at death. Measurements of angles of the vertebrae were conducted using an imprint method. Microsections of osseous endplates and articular cartilage were graded according to their degrees of degeneration by using the Petersson classification (0, no sign of degeneration; I, superficial degeneration with several fragmentations; II, deeper degeneration with cartilaginous disintegration and penetrating ulceration; or III, complete cartilaginous degeneration with the appearance of subchondral bone in > 50% of the articular surface). The authors found Grade I changes in 100% of the occiput specimens. In the superior articular cartilage of C-1 no changes (Grade 0) were found in two specimens, whereas 6% of the specimens exhibited Grade II changes and 89% exhibited Grade I changes. In the inferior articular cartilage of C-1, 57% of the specimens displayed Grade I changes, 14% Grade II, and 20% Grade III changes. In the superior articular cartilage of C-2, 62.5% of the specimens displayed Grade I changes and 25% Grade II changes. At the occiput-C1 level the authors found a higher frequency of degeneration at the upper left articular surface of the atlas (Quadrants 1 and 3), and at the C1-2 level they found a higher frequency of degeneration at the upper left and upper right articular surfaces of the axis (Quadrants 2 and 3, respectively). Using the McNemar test, the authors investigated the frequency of affection of single quadrants in a left-right side comparison (lateral reversal). Significant differences were identified for Quadrant 2 of the upper left articular surface of C-2 and Quadrant 3 of the upper right articular surface of C-2. These results correlate with the analysis of single articular surfaces of the axis, but contradict the results for the atlas, in which no significant difference in the left-right side comparison was found. CONCLUSIONS: Severe degeneration in the atlantooccipital joints appears to be a rare condition, with no Grade II or III degeneration found in the occipital condyles and 6% Grade I, 89% Grade II, but no Grade III changes in the superior articular cartilage of the atlas. Degeneration of the inferior articular cartilage of C-1 and the superior articular cartilage of C-2 indicates that the atlantoaxial joint faces more intense mechanical exposure, which is increased at the upper joint surfaces.

NEUROGATE: a new MR-compatible device for realizing minimally invasive treatment of intracerebral tumors.

The authors report on the handling and the practicability of a newly developed MR-compatible device, the NEUROGATE (Daum GmbH, Germany), which allows precise planning, simulation and control of stereotactic biopsy in patients with suspect intracranial lesions, and which allows minimally invasive maneuvers to be performed in a comfortable way. Twenty-eight patients were examined stereotactically in the Signa SP interventional 0.5 Tesla MRI (General Electric Medical Systems, USA), including 15 patients with malignant intracerebral tumors and poor general medical conditions (8 gliomas, 7 metastases) who were treated by laser-induced interstitial thermotherapy (LITT) after definite intraoperative neuropathological diagnosis. As a special stereotactic holding device, the NEUROGATE was favored as a reliable tool for stereotaxy and minimally invasive procedures.

[Cryotherapy of the brain--a new methodologic approach]. / Kryotherapie am Hirn--ein neuer methodischer Ansatz.

Cryodestruction of tissue is influenced by cooling and thawing rates, absolute tissue temperature, number of freeze-thaw cycles, and type of tissue. However, under clinical conditions a MRT visualization of the temperature distribution during cryo-procedures is not possible. Thus, the extent of necrotic areas within the cryo-influenced regions are not precisely predictable. This limitation is particularly relevant for the application of cryoablation in the brain. The present paper proposes the concept of a local, cryo-induced ischemic necrosis. The basic concept is that the MRT-observable and surgically well-manageable frozen region is ischemic. This cryo-induced ischemia causes a necrosis. The extent of the necrotic region is exclusively determined by the ischemia tolerance of the tissue. The effectiveness of this method is demonstrated on sheep brain in vivo. Compared to the freeze-thaw method, histological examinations show a sharper demarcation between regions of necrosis and healthy tissue. In conclusion, the method of MR-controlled local, cryo-induced ischemia enables an exact definition of the region of necrosis in the brain.

Historical perspective on neurosurgery in Germany after World War II.

AFTER THE COLLAPSE of the Third Reich, the specialty of neurosurgery in Germany, although well developed in the late 1930s, had to start anew, and for decades to come, had to deal with the physical and political consequences of World War II. Because of the division of the country, neurosurgery developed separately in the two independent states. In West Germany, the evolution was promoted by a few personalities who represented different schools according to their own training: these "surgical neurologists" emphasized the neurological basis of neurosurgery and were represented by Traugott Riechert and the students of Otfrid Foerster, such as Arist Stender and Hans Kuhlendahl. In contrast, the "neurological surgeons" stressed their origins in general surgery. Their main proponent was Wilhelm Tönnis, who gained particular merit for promoting neurosurgical teaching, the development of new neurosurgical units, and the recognition of neurosurgery as an autonomous specialty. In East Germany, progress was delayed by a weak economy and a repressive political system. Yet several excellent neurosurgeons won international recognition, predominantly Georg Merrem, who came from the school of Fedor Krause. Following a worldwide trend, the number of neurosurgical units in West Germany increased dramatically from 18 in 1950 to 85 in 1988. In 2006, in the unified nation, 1200 certified neurosurgeons in 138 hospital departments and 75 private practices served 82 million people. Since its founding in 1949, the German Neurosurgical Society has promoted the idea of reconciliation and has focused on international collaboration in both science and education. This idea, shared by other European nations, eventually gave rise to the European Association of Neurosurgical Societies. At present, escalating costs in the health sector pose a problem to neurosurgical services and have led to reconsiderations about their structure and financing.

Effects of temporary clips on somatosensory evoked potentials in aneurysm surgery.

INTRODUCTION: Changes in somatosensory evoked potentials (SEPs) were used to identify cerebral ischemia and to predict neurological outcome during the application of temporary clips in aneurysm surgery. METHODS: SEPs were recorded intra-operatively in 76 patients with 79 aneurysms (8 in the posterior fossa). Twenty aneurysms ruptured during surgery, and 37 temporary clips were applied over an average of 8.1 minutes (range: 2-25 minutes). RESULTS: Of 17 cases with complete loss of potential, 14 were associated with temporary clips. Two losses were persistent with postoperative neurological deficit after 10 minutes of clipping. Six showed incomplete recovery after a mean loss of 19.2 minutes following clipping of 9.3 minutes, resulting in a new deficit in four patients. Despite complete recovery of potential in six patients after a 1 loss over 18.8 minutes following clipping of 10.7 minutes, four patients developed neurological deficits. The sensitivity of SEPs in determining permanent neurological deficits was 57%, and the was specificity 88%. The duration of temporary clipping was significantly shorter in patients without resulting new neurological deficit (Mann-Whitney Test; p < 0.01). The risk of a new deficit was 30.7% in cases where less than 8 minutes of clipping was performed, and the risk was 80.9% when clipping exceeded 8 minutes. The extent of recovery of potentials and the duration of SEP changes was strongly associated with the postoperative deficits (Kolmogorov-Smirnov Test, p = 0.009; p = 0.001, Mann-Whitney Test). Pathological p(ti)O2 measurements were obtained in 6 of 12 patients. In four patients, temporary occlusion was followed by a parallel alteration of SEPs and p(ti)O2 below 10 mmHg. CONCLUSION: There is no genuinely safe permissible occlusion time. Despite complete recovery of SEPs after a loss of potential, the patient may develop new deficits.