Cancer-of-Unknown-Primary-Origin: A SEER-Medicare Study of Patterns of Care and Outcomes among Elderly Patients in Clinical Practice.

Knowledge of contemporary patterns of cancer-of-unknown-primary-origin (CUP) diagnostic work-up, treatment, and outcomes in routine healthcare is limited. Thus, we examined data from elderly patients diagnosed with CUP in real-world US clinical practice. From the Surveillance, Epidemiology, and End Results-Medicare-linked database, we included patients ≥ 66 years old with CUP diagnosed between 1 January 2013 and 31 December 2015. We analyzed baseline demographics, clinical characteristics, methods of diagnostic work-up (biopsy, immunohistochemistry, imaging), treatment-related factors, and survival. CUP diagnosis was histologically confirmed in 2813/4562 patients (61.7%). Overall, 621/4562 (13.6%) patients received anticancer pharmacotherapy; among these, 97.3% had a histologically confirmed tumor and 83.1% received all three procedures. Among those with a histologically confirmed tumor, increasing age, increasing comorbidity score, not receiving all three diagnostic measures, and having a not-further specified histologic finding of only 'malignant neoplasm' were all negatively associated with receipt of anticancer pharmacotherapy. Median overall survival was 1.2 months for all patients. Median time between CUP diagnosis and treatment initiation was 41 days. Limited diagnostic work-up was common and most patients did not receive anticancer pharmacotherapy. The poor outcomes highlight a substantial unmet need for further research into improving diagnostic work-up and treatment effectiveness in CUP.

A Challenging Task: Identifying Patients with Cancer of Unknown Primary (CUP) According to ESMO Guidelines: The CUPISCO Trial Experience.

BACKGROUND: CUPISCO is an ongoing randomized phase II trial (NCT03498521) comparing molecularly guided therapy versus platinum-based chemotherapy in patients newly diagnosed with "unfavorable" cancer of unknown primary (CUP). MATERIALS AND METHODS: Patients with an unfavorable CUP diagnosis, as defined by the European Society of Medical Oncology (ESMO), and available cancer tissue for molecular sequencing are generally eligible. Potential patients with CUP entering screening undergo a review involving reference histopathology and clinical work-up by a central eligibility review team (ERT). Patients with "favorable" CUP, a strongly suspected primary site of origin, lack of tissue, or unmet inclusion criteria are excluded. RESULTS: As of April 30, 2020, 628 patients had entered screening and 346 (55.1%) were screen failed. Screen fails were due to technical reasons (n = 89), failure to meet inclusion and exclusion criteria not directly related to CUP diagnosis (n = 89), and other reasons (n = 33). A total of 124 (35.8%) patients were excluded because unfavorable adeno- or poorly differentiated CUP could not be confirmed by the ERT. These cases were classified into three groups ineligible because of (a) histologic subtype, such as squamous and neuroendocrine, or favorable CUP; (b) evidence of a possible primary tumor; or (c) noncarcinoma histology. CONCLUSION: Experience with CUPISCO has highlighted challenges with standardized screening in an international clinical trial and the difficulties in diagnosing unfavorable CUP. Reconfirmation of unfavorable CUP by an ERT in a clinical trial can result in many reasons for screen failures. By sharing this experience, we aim to foster understanding of diagnostic challenges and improve diagnostic pathology and clinical CUP algorithms. IMPLICATIONS FOR PRACTICE: A high unmet need exists for improved treatment of cancer of unknown primary (CUP); however, study in a trial setting is faced with the significant challenge of definitively distinguishing CUP from other cancer types. This article reports the authors' experience of this challenge so far in the ongoing CUPISCO trial, which compares treatments guided by patients' unique genetic signatures versus standard chemotherapy. The data presented will aid future decision-making regarding diagnosing true CUP cases; this will have far-reaching implications in the design, execution, and interpretation of not only CUPISCO but also future clinical studies aiming to find much-needed treatment strategies.

Comprehensive Genomic Profiling of Carcinoma of Unknown Primary Origin: Retrospective Molecular Classification Considering the CUPISCO Study Design.

BACKGROUND: Carcinoma of unknown primary origin (CUP) accounts for 2%-5% of newly diagnosed advanced malignancies, with chemotherapy as the standard of care. CUPISCO (NCT03498521) is an ongoing randomized trial using comprehensive genomic profiling (CGP) to assign patients with CUP to targeted or immunotherapy treatment arms based on genomic profiling. We performed a retrospective analysis of CUP cases referred for CGP to determine how many were potentially eligible for enrollment into an experimental CUPISCO arm. MATERIALS AND METHODS: Centrally reviewed adenocarcinoma and undifferentiated CUP specimens in the FoundationCore database were analyzed using the hybrid capture-based FoundationOne CDx assay (mean coverage, >600×). Presence of genomic alterations, microsatellite instability (MSI), tumor mutational burden (TMB), genomic loss of heterozygosity (gLOH), and programmed death-ligand 1 (PD-L1) positivity were determined. RESULTS: A total of 96 of 303 patients (31.7%) could be matched to an experimental CUPISCO arm. Key genomic alterations included ERBB2 (7.3%), PIK3CA (6.3%), NF1 (5.6%), NF2 (4.6%), BRAF (4.3%), IDH1 (3.3%), PTEN, FGFR2, EGFR (3.6% each), MET (4.3%), CDK6 (3.0%), FBXW7, CDK4 (2.3% each), IDH2, RET, ROS1, NTRK (1.0% each), and ALK (0.7%). Median TMB was 3.75 mutations per megabase of DNA; 34 patients (11.6%) had a TMB ≥16 mutations per megabase. Three patients (1%) had high MSI, and 42 (14%) displayed high PD-L1 expression (tumor proportion score ≥50%). gLOH could be assessed in 199 of 303 specimens; 19.6% had a score of >16%. CONCLUSIONS: Thirty-two percent of patients would have been eligible for targeted therapy in CUPISCO. Future studies, including additional biomarkers such as PD-L1 positivity and gLOH, may identify a greater proportion potentially benefiting from CGP-informed treatment. Clinical trial identification number. NCT03498521 IMPLICATIONS FOR PRACTICE: The findings of this retrospective analysis of carcinoma of unknown primary origin (CUP) cases validate the experimental treatment arms being used in the CUPISCO study (NCT03498521), an ongoing randomized trial using comprehensive genomic profiling to assign patients with CUP to targeted or immunotherapy treatment arms based on the presence of pathogenic genomic alterations. The findings also suggest that future studies including additional biomarkers and treatment arms, such as programmed death-ligand 1 positivity and genomic loss of heterozygosity, may identify a greater proportion of patients with CUP potentially benefiting from comprehensive genomic profiling-informed treatment.

Correlation of skin rash and overall survival in patients with pancreatic cancer treated with gemcitabine and erlotinib - results from a non-interventional multi-center study.

BACKGROUND: Gemcitabine/erlotinib treatment offers limited benefit in unselected patients with pancreatic ductal adenocarcinoma (PDAC). Development of skin rash has been associated with favorable outcomes in patients treated with gemcitabine/erlotinib. This study aimed to extend knowledge on the effectiveness of gemcitabine/erlotinib in metastatic PDAC in the context of clinical practice and with focus on skin rash. METHODS: This multicenter, non-interventional study enrolled 376 patients with metastatic PDAC receiving gemcitabine/erlotinib. The primary endpoint was overall survival (OS) in patients with skin rash versus no skin rash. Secondary endpoints included progression-free survival (PFS), treatment satisfaction and safety. All data were analyzed using descriptive statistics. Survival time and time to disease progression were estimated using the Kaplan-Meier method. Effectiveness endpoints were analyzed for subgroups by skin rash grade (no rash, rash grade 1, rash grade ≥ 2), duration of erlotinib treatment (≤8 weeks, > 8 weeks), Eastern Cooperative Oncology Group (ECOG) performance status at baseline (0-1, 2) and age (≤65 years, > 65 years). RESULTS: Within the full analysis set (FAS; N = 270), 48 patients (17.8%) developed grade 1 rash, 51 patients (18.9%) grade ≥ 2 rash, while 171 patients (63.3%) did not develop a rash. Median OS of all patients was 9.11 months with an OS of 9.93 months in rash-positive and 8.68 months in rash-negative patients. Median PFS was 5.06 months for rash-positive and 4.11 months for rash-negative patients. PFS was longer in patients with rash grade ≥ 2 and in older patients (> 65 years). Examination using a multivariate Cox proportional model revealed that an age > 65 years was associated with longer OS (hazard ratio 0.640; p = 0.0327) and PFS (hazard ratio 0.642; p = 0.0026). Out of the 338 patients in the SAF, 310 patients (91.7%) experienced at least one AE, and 176 patients (52.1%) experienced skin-related side effects, all of which were CTC grade 1 to 3. CONCLUSIONS: Comparing rash-positive with rash-negative patients showed no significant difference in survival. While patients with rash grade ≥ 2 and older patients (independent of skin reactions) showed longer PFS, this did not translate into prolonged OS. The study did not reveal new safety signals. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01782690, retrospectively registered on 4 February 2013.

[Erlotinib plus Gemcitabine in metastatic pancreatic cancer: Results from a non-interventional trial]. / Erlotinib plus Gemcitabin als Therapie bei Patienten mit metastasiertem Pankreaskarzinom: Ergebnisse einer nicht-interventionellen Studie.

Metastatic pancreatic cancer has the worst prognosis of all cancers. With nab-Paclitaxel/gemcitabine, FOLFIRINOX, and gemcitabine/erlotinib, several treatment options are available which improve the patient's overall survival. Especially for patients who develop rash under erlotinib treatment can benefit from gemcitabine/erlotinib combination therapy. This non-interventional study (NIS ML21284) investigated the effectiveness and tolerability of gemcitabine/erlotinib therapy in the treatment routine of metastatic pancreatic cancer, in particular, in the context of the occurrence of a rash.Between 2007 and 2010, the treatment data of 433 patients in 98 centres were documented. All parameters recorded were assessed descriptively.Treatment with gemcitabine/erlotinib resulted in both a significant increased median overall survival of the patient subgroup with rash grade ≥ 1 (9.90; 95 % confidence interval [CI], 8.19 to 11.05 vs. 6.48 months; 95 % CI, 5.66 to 7.40, p = 0.0010) and median progression-free survival (5.43, 95 % CI, 4.90 to 6.12 vs. 3.98 months, 95 % CI, 3.52 to 5.03, p = 0.0131). The overall response rate of patients treated with gemcitabine/erlotinib, who had developed rash grade ≥ 1, was 5.9 % higher compared to patients without rash (31.7 % vs. 25.8 %).In conclusion, these results from the daily treatment routine of metastatic pancreatic cancer underline the importance of combined gemcitabine/erlotinib therapy for a subgroup of patients who develop a rash in the course of erlotinib treatment.

Polyamide/PEG Blends as Biocompatible Biomaterials for the Convenient Regulation of Cell Adhesion and Growth.

In addition to their established usage in textiles, commodities, and automotives, classical polyamides (nylons) are recently becoming increasingly interesting for applications in (bio)medicine. This fact relies on many prosperous properties of these polymers, which are toughness, resistance, biocompatibility, low immunogenicity, tunable biodegradability, and their similarity to natural peptides (amide bonds). Some nylon-based medical products do already exist for wound treatment applications, implants, and biomolecule-interacting membranes, but the systematic use of these polymers for tissue engineering is-although desired-still to be accomplished. Inspired by this, the suitability of nylon 6 and of a related biobased and more hydrophobic terpene-derived polyamide as surfaces for the controlled interaction with HaCat cells (human keratinocytes) are investigated herein with regard to possible applications for regenerative skin replacement. The nylons are applied as neat polymers and as hydrophilized blends/composites with polyethylene glycol and confirm their excellent suitability as biomaterials.

Multicenter pilot study of radiochemotherapy as first-line treatment for adults with medulloblastoma (NOA-07).

Background: Medulloblastoma in adult patients is rare, with 0.6 cases per million. Prognosis depends on clinical factors and medulloblastoma entity. No prospective data on the feasibility of radiochemotherapy exist. The German Neuro-Oncology Working Group (NOA) performed a prospective descriptive multicenter single-arm phase II trial to evaluate feasibility and toxicity of radio-polychemotherapy. Methods: The NOA-07 trial combined craniospinal irradiation with vincristine, followed by 8 cycles of cisplatin, lomustine, and vincristine. Adverse events, imaging and progression patterns, histological and genetic markers, health-related quality of life (HRQoL), and cognition were evaluated. Primary endpoint was the rate of toxicity-related treatment terminations after 4 chemotherapy cycles, and the toxicity profile. The feasibility goal was reached if at least 45% of patients received at least 4 cycles of maintenance chemotherapy. Results: Thirty patients were evaluable. Each 50% showed classic and desmoplastic/nodular histology. Sixty-seven percent were classified into the sonic hedgehog (SHH) subgroup without TP53 alterations, 13% in wingless (WNT), and 17% in non-WNT/non-SHH. Four cycles of chemotherapy were feasible in the majority (n = 21; 70.0%). Hematological side effects and polyneuropathy were prevalent toxicities. During the active treatment period, HRQoL and verbal fluency improved significantly. The 3-year event-free survival rate was 66.6% at the time of databank lock. Conclusions: Radio-polychemotherapy did lead to considerable toxicity and a high amount of dose reductions throughout the first 4 chemotherapy cycles that may affect efficacy. Thus, we propose frequent patient surveillance using this regimen. Modifications of the regimen may increase feasibility of radio-polychemotherapy of adult patients with medulloblastoma.

Piezosurgery in Modified Pterional Orbital Decompression Surgery in Graves Disease.

OBJECTIVE: Piezosurgery uses microvibrations to selectively cut bone, preserving the adjacent soft tissue. The present study evaluated the use of piezosurgery for bone removal in orbital decompression surgery in Graves disease via a modified pterional approach. METHODS: A piezosurgical device (Piezosurgery medical) was used in 14 patients (20 orbits) with Graves disease who underwent orbital decompression surgery in additional to drills and rongeurs for bone removal of the lateral orbital wall and orbital roof. The practicability, benefits, and drawbacks of this technique in orbital decompression surgery were recorded. Piezosurgery was evaluated with respect to safety, preciseness of bone cutting, and preservation of the adjacent dura and periorbita. Preoperative and postoperative clinical outcome data were assessed. RESULTS: The orbital decompression surgery was successful in all 20 orbits, with good clinical outcomes and no postoperative complications. Piezosurgery proved to be a safe tool, allowing selective bone cutting with no damage to the surrounding soft tissue structures. However, there were disadvantages concerning the intraoperative handling in the narrow space and the efficiency of bone removal was limited in the orbital decompression surgery compared with drills. CONCLUSIONS: Piezosurgery proved to be a useful tool in bone removal for orbital decompression in Graves disease. It is safe and easy to perform, without any danger of damage to adjacent tissue because of its selective bone-cutting properties. Nonetheless, further development of the device is necessary to overcome the disadvantages in intraoperative handling and the reduced bone removal rate.

Gehirnabszess nach parodontaler Therapie. Ein Fallbericht über einen Gehirnabszess assoziiert mit Fusobacterium nucleatum nach parodontaler Therapie.

Background Nonsurgical periodontal treatment implicates bacteraemia. In rare cases oral pathogens can be found associated with abscesses of brain or liver Case Description A brain abscess was found in a patient after several periodontal treatments causing neurological seizures. In the drain masses of Fusobacterium nucleatum were found. An oral examination revealed a severe periodontally damaged dentition. The woman had been in a generally healthy condition before the event. After neurosurgical treatment and intravenous antibiotic therapy the patient fully recovered. In order to eradicate any possible focus of inflammation, several teeth had to be extracted. Clinical Implications This case report implicates that also patients without particular need for antibiotic prophylaxis can be at risk of developing a brain abscess caused by bacteraemia after periodontal treatments.