PD-1 and PD-L1 expression in HNSCC primary cancer and related lymph node metastasis - impact on clinical outcome.

AIMS: Expression profiles and clinical impact of programmed cell death ligand 1 (PD-L1) and programmed cell death 1 (PD-1) expressing tumour infiltrating lymphocytes (TILs) in head and neck squamous cell carcinoma (HNSCC) are not elucidated fully. This study evaluates expression patterns in primary HNSCC and related lymph node metastasis and the impact on patients' clinical outcome. METHODS AND RESULTS: Immunohistochemical staining patterns of PD-L1 and PD-1 were evaluated in 129 specimens of primary HNSCC and 77 lymph node metastases. Results were correlated with patients' clinical data. PD-L1 expression was observed in 36% of primary carcinoma and 33% of lymph node metastasis, and correlates significantly with decreased overall survival (OS) (P = 0.01) and disease-free survival (DFS) (P = 0.001) in oral cavity squamous cell carcinoma patients. PD-L1 expression was associated with presence of lymph node metastasis (P = 0.0223). Infiltration of PD-1-expressing lymphocytes correlates significantly with favourable OS (P = 0.001) and DFS (P = 0.001) in oropharyngeal cancer and hypopharyngeal cancer patients OS (P = 0.007) and DFS (P = 0.001). Presence of PD-1 TILs also correlates significantly with better OS (P = 0.005) and DFS (P = 0) in the human papilloma virus (HPV)-negative cohort. Cox regression multivariate analysis revealed PD-1 TIL expression as an independent prognostic marker for OS (P = 0.004) and DFS (P = 0.001) and T stage was validated as negative prognostic marker for OS (P = 0.011). PD-1-expressing lymphocytes (P = 0.0412) and PD-L1 expression (P = 0.0022) patterns correlate significantly in primary cancers and matched lymph node metastases. CONCLUSIONS: Our results characterise the expression profiles of PD-1 axis proteins in HNSCC which might serve as possible clinical prognostic markers.

The impact of COVID-19 and socioeconomic status on psychological distress in cancer patients.

Objective: We aimed to investigate the impact of the COVID-19 pandemic on psychological symptom burden against the socioeconomic background of cancer patients using data from routine assessments before and during the pandemic. Method: In this cross-sectional study, standardised assessment instruments were applied in N = 1,329 patients to screen for symptoms of anxiety, depression, post-traumatic stress, and fatigue from 2018 to 2022. Two MANOVAs with post-hoc tests were computed. First, only time was included as predictor to examine the isolated impact of the pandemic. Second, income level and education level were included as further predictors to additionally test the predictive power of socioeconomic factors. Results: In the final model, only income had a significant impact on all aspects of psychological symptom burden, with patients with low income being highly burdened (partial η² = .01, p = .023). The highest mean difference was found for depressive symptoms (MD = 0.13, CI = [0.07; 0.19], p < .001). The pandemic had no further influence on psychological distress. Conclusions: Although the pandemic is a major stressor in many respects, poverty may be the more important risk factor for psychological symptom burden in cancer outpatients, outweighing the impact of the pandemic.

Molecularly guided treatment of metastatic parotid gland carcinoma in adults.

BACKGROUND: Advanced therapy-refractory parotid gland carcinomas have a poor prognosis with limited therapy options. We used molecular profiling to offer molecular guided therapies to patients with advanced metastatic parotid gland malignancies. METHODS: In this retrospective analysis we describe the molecular profiling of ten patients diagnosed with therapy-refractory metastatic parotid gland malignancies. RESULTS: We identified seven genetic aberrations in five patients: two mutations in CDKN2A and one mutation in APC, ATM, TP53, SMARCB1 and FGFR1, respectively. No mutations were detected in five patients. The IHC demonstrated frequent expressions of EGFR and p­mTOR, as well as PTEN in eight patients. For four fifths (n = 8) of the patients, a targeted therapy was suggested. Eventually, three patients received the targeted therapy recommendation and one patient achieved stable disease for 14 months. CONCLUSION: A total of eight therapy recommendations were provided. Based on our observations, molecular-guided therapies may be a feasible treatment approach for this rare disease entity.

An analysis of distant metastasis cases from HPV-associated oropharyngeal squamous cell carcinoma.

Although mostly associated with good survival outcomes, some patients with HPV-positive oropharyngeal squamous cell carcinoma develop distant metastasis and face dire prognosis. The aim of this study was to analyze distant metastatic patients in regards to survival, clinical staging, therapy approach and p16/HPV status. This retrospective single-centre study assessed patients with HPV-associated oropharyngeal cancer with distant metastasis treated in a tertiary referral center from 2005 to 2019. Overall- (OS) and survival after diagnosis of distant metastasis (OMS), clinical staging and different therapy approaches were assessed. Moreover, the overall mortality was assessed, as well as the association of different therapy approaches and p16/HPV status with the survival outcome. Out of 211 patients with HPV-associated oropharyngeal cancer that were treated in the study period, 15 developed distant metastases (7.1%). Median OS and OMS of the total group were 11 months (range 0.1-32 months) and 3 months (range 0.1-21 months), respectively. The overall mortality rate was 53.3% (n = 8). Significantly better outcome was present in patients treated with primary chemoradiotherapy (median OS 17 months vs. not reached, p = .03, median OMS 8 months vs not reached, p = .05). The OMS was significantly better in patients treated with chemotherapy initially after diagnosis (mean OMS 21 months vs 4 months; P = .001). Surgical resection after initial diagnosis was associated with a significantly shorter OMS (median OMS 3 vs. 21 months, p = .005). Interestingly, postoperative adjuvant therapy was delayed in all of these cases due to surgical site complications. Systemic treatment after initial diagnosis may be beneficial in clinical outcome of HPV associated distant metastases. Furthermore, surgical site complications should be treated with immediate care in order to avoid delay of adjuvant therapy. Further studies are warranted for validation of our results.

Postoperative chemoradiotherapy with cisplatin is superior to radioimmunotherapy with cetuximab and radiotherapy alone : Analysis of the Austrian head and neck cancer registry of the AGMT.

BACKGROUND: The addition of cisplatin or cetuximab to radiotherapy in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN) has significantly improved the outcome. While the superiority of cisplatin over cetuximab in combination with radiotherapy has been shown in a definitive setting, we set out to compare postoperative chemoradiotherapy with cisplatin to radioimmunotherapy with cetuximab and radiotherapy alone within the Austrian head and neck cancer registry of the Working Group on Pharmaceutical Tumor Treatment (AGMT) study group. MATERIAL AND METHODS: In the AGMT head and neck cancer registry, data of 557 patients with SCCHN from five Austrian cancer centers were prospectively collected between 2012 and 2017. Of these patients 120 received postoperative chemoradiotherapy with cisplatin, 26 patients received postoperative radioimmunotherapy with cetuximab and 56 patients were treated with adjuvant radiotherapy only. Patient characteristics, stage of disease, details on treatment as well as survival were analyzed by a chart-based review. RESULTS: In patients treated with postoperative radiotherapy the addition of cisplatin significantly improved progression-free survival (PFS) and overall survival (OS) compared to cetuximab (PFS 84.2 months vs. 17.0 months, p = 0.04, OS not reached vs. 46.0 months, p = 0.02) and PFS compared to radiotherapy alone (PFS 84.2 months vs. 28.5 months, p < 0.01). Patients treated with cetuximab were significantly older and had a worse performance score than patients receiving cisplatin or radiotherapy alone. CONCLUSION: This study confirmed the importance of multimodal treatment concepts in patients with locally advanced SCCHN. Postoperative cetuximab might be an option in patients not eligible for high-dose cisplatin but cisplatin should remain the standard of care.

Docetaxel, cisplatin and 5-FU compared with docetaxel, cisplatin and cetuximab as induction chemotherapy in advanced squamous cell carcinoma of the head and neck: Results of a randomised phase II AGMT trial.

PURPOSE: Induction chemotherapy (ICT) with cisplatin (P), 5-FU (F) and taxanes (T) is a therapeutical option in patients suffering from locally advanced or unresectable stage III or IV squamous cell carcinoma of the head and neck (SCCHN). The role of ICT is controversial, and toxicity and/or delay of radiotherapy (RT) may reduce the potential benefit of this treatment regimen. Here, we report the results of a randomised phase II trial comparing TPF with TP + cetuximab (C). PATIENTS AND METHODS: In this trial, 100 patients with locally advanced stage III or IV SCCHN were included in the analysis. Patients were randomly assigned to either TPF-ICT (N = 49) or TPC-ICT (N = 51), both followed by RT + C. The primary end-point of the study was overall response rate (ORR) three months after RT + C was finished. RESULTS: On an intention-to-treat basis, the ORR (complete remission + partial remission) was 74.5% in the TPC arm compared with 63.3% in the TPF arm (p = 0.109). OS was similar in both arms 400 days after treatment was initiated (86.1% [95% confidence interval {CI}, 73.0-93.1%] in the TPC arm and 78.5% [95% CI, 63.7-87.8%] in the TPF arm). TPC resulted in slightly less serious adverse events and in less haematological, but more skin toxicities. Two patients randomised in the TPC arm died during ICT and RT. Four patients in the TPF arm died after completion of RT. No delay from the end of ICT to RT + C was observed. A total of 83.1% of patients (80% in the TPC arm; 86% in the TPF arm) received RT without dose reduction and/or modification. CONCLUSION: TPC-containing ICT for patients with locally advanced SCCHN was found to be an effective and tolerable one-day regimen. Further prospective evidence from larger trials is warranted.

Systemic Therapy, Palliation and Supportive Care of Patients with Hypopharyngeal Cancer.

Hypopharyngeal cancer patients have a very poor prognosis and limited therapeutic options. Seventy to eighty per cent of all hypopharyngeal cancer patients will require palliative and/or end-of-life care for incurable end-stage disease during the course of their illness. The overall proportion of hypopharyngeal cancer patients not qualifying for initial curative treatment, or requiring palliation and supportive care over time is higher than for any other subsite of the head and neck. Surgery and radiotherapy usually have a very limited role in this setting, while systemic therapy will usually compete with supportive care as the best approach. Advances in medicine and oncological treatments for the management of patients with recurrent head and neck cancer have given physicians the opportunity to prolong life where possible. However, this increase in survival might not be clinically meaningful if patients do not simultaneously experience palliative benefits, such as a reduction in symptoms and an improvement in their overall quality of life (QoL). The optimal outcome of palliative treatment is the control of symptoms with minimal treatment toxicities while improving QoL. It remains unclear if current palliative treatment options are better at improving QoL than the best supportive care. An intervention that results in insufficient or unacceptable functional status to the extent that the patient cannot achieve treatment goals - even in the course of prolonging life - is questionable. When used for palliative care purposes, surgery, chemotherapy and radiotherapy commonly have limited effectiveness in improving QoL. Moreover, if these treatments are not congruent with a patient's end-of-life goals, they could constitute low-value care.

Review of cancer treatment with immune checkpoint inhibitors : Current concepts, expectations, limitations and pitfalls.

Immunotherapy by checkpoint inhibition is about to profoundly change cancer therapy. The number of indications are growing at an unprecedented speed. Clinical studies have demonstrated efficacy in a variety of solid tumors and in hematologic malignancies, although some clinical trials have produced negative results. Thus, it is fair to assume that there are obvious limitations and pitfalls in immunotherapy. Future concepts for combination treatment of immune checkpoint inhibitors have to be developed, but there is also urgent need for better and standardized biomarkers to identify those cancer patients who will benefit from treatment by checkpoint inhibition. The current overview summarizes current knowledge on immune checkpoint inhibitor treatment in malignancies, its outlook and limitations, diagnostic means and, finally, side effect management.

The impact of COVID-19 and socioeconomic status on psychological distress in cancer patients

Objective: We aimed to investigate the impact of the COVID-19 pandemic on psychological symptom burden against the socioeconomic background of cancer patients using data from routine assessments before and during the pandemic Method: In this cross-sectional study, standardised assessment instruments were applied in N = 1,329 patients to screen for symptoms of anxiety, depression, post-traumatic stress, and fatigue from 2018 to 2022. Two MANOVAs with post-hoc tests were computed. First, only time was included as predictor to examine the isolated impact of the pandemic. Second, income level and education level were included as further predictors to additionally test the predictive power of socioeconomic factors Results: In the final model, only income had a significant impact on all aspects of psychological symptom burden, with patients with low income being highly burdened (partial η² = .01, p = .023). The highest mean difference was found for depressive symptoms (MD = 0.13, CI = [0.07; 0.19], p < .001). The pandemic had no further influence on psychological distress Conclusions: Although the pandemic is a major stressor in many respects, poverty may be the more important risk factor for psychological symptom burden in cancer outpatients, outweighing the impact of the pandemic. (AU)

A Cross-Sectional Study of Patients' Satisfaction With Totally Implanted Access Ports.

BACKGROUND: Totally implanted access ports (PACs) are valuable tools for the treatment of patients with cancer because they ease the administration of chemotherapy, stem cells, and supportive care by reducing the rate of peripheral vein punctures. OBJECTIVES: The purpose of this study was to evaluate the satisfaction and impairments of activities of daily living of ambulatory patients with PAC systems receiving chemotherapy. METHODS: This cross-sectional, questionnaire-based study evaluated 202 patients with PAC systems in a comprehensive cancer center and cancer rehabilitation center. From November 2012 to August 2013, patients were invited to answer a questionnaire concerning quality of life and satisfaction with their PAC devices. Data regarding PAC-related complications were collected retrospectively by searching patients' medical history. FINDINGS: A total of 202 patients with 230 PAC devices were included. Median time from PAC implantation to inclusion in the study was nine months. Surgical complications occurred in some cases, with bleeding and hematoma being the most frequently observed events. Late complications consisted of infections, drug extravasation, PAC malposition, PAC malfunction, and thrombosis. A third of the patients reported that their PAC interfered with activities of daily living. However, most agreed that PAC systems alleviated the burden of chemotherapy administration, and the vast majority said they would choose the implantation of a PAC system for chemotherapy administration again.

Safety and feasibility of every-other-week maintenance cetuximab after first-line chemotherapy in patients with recurrent or metastatic head and neck squamous cell cancer.

BACKGROUND: In patients with recurrent and/or metastatic head and neck squamous cell cancer (HNSCC), there are no data about an every-other-week cetuximab maintenance schedule after chemotherapy plus cetuximab as first-line treatment. METHODS: We reviewed the safety and feasibility of every-other-week maintenance cetuximab administered at 3 different European centers. RESULTS: Thirty-one patients with recurrent or metastatic HNSCC were treated from 2006 to 2010. Mean cetuximab dose intensity in the maintenance phase was 93%. The major toxicities reported during every-other-week maintenance cetuximab were skin rash (grade 3, 16%; grade 2, 23%), fatigue (grade 3, 3%; grade 2, 16%), diarrhea (grade 3, 7%; grade 2, 13%), hypomagnesemia (grade 4, 3%; grade 3, 3%; grade 2, 19%), and mucositis (grade 3, 3%; grade 2, 23%). CONCLUSIONS: Every-other-week maintenance cetuximab schedule was well tolerated and did not worsen toxicity that occurred during chemotherapy. In daily practice, this simplified schedule could improve compliance and possibly improve quality of life in patients with recurrent or metastatic HNSCC that showed no progression during first-line chemotherapy.

[Therapy of castration-resistant prostate cancer]. / Therapie des kastrationsrefraktären Prostatakarzinoms.

Within the last two years the therapy of castration resistant prostate cancer (CRPC) has made major advances. Both the COU-AA-301 phase III trial and the TROPIC trial showed a survival benefit for patients after docetaxel failure treated with abiraterone or cabazitaxel, respectively. With rising interest for chemotherapeutic options and novel drugs, our goal was to review within the context of a multidisciplinary team the available evidence and explore the standards for medical treatment of prostate cancer outside of clinical trials. From this background, we are carefully evaluating the current treatment recommendations, based on the available evidence, and highlight potential future treatment options but also discuss important clinical topics like treatment until progression versus the advantage of chemo holidays and definition of particular patient subgroups. Additionally, we focus on novel molecular entities, which will most likely be available in the near future, such as MDV3100 and Sipuleucel T. The role and importance of palliation with radiotherapy and proactive medical management of pain is also discussed, as well as new options for bone directed therapy. The multitude of treatment options for patients with advanced prostate cancer clearly asks for a close collaboration between urologists, medical oncologists and radiation therapists.

The PI3-kinase/mTOR-targeting drug NVP-BEZ235 inhibits growth and IgE-dependent activation of human mast cells and basophils.

The phosphoinositide 3-kinase (PI3-kinase) and the mammalian target of rapamycin (mTOR) are two major signaling molecules involved in growth and activation of mast cells (MC) and basophils (BA). We examined the effects of the dual PI3-kinase/mTOR blocker NVP-BEZ235 on growth of normal and neoplastic BA and MC as well as immunoglobulin E (IgE)-dependent cell activation. Growth of MC and BA were determined by measuring (3)H-thymidine uptake and apoptosis. Cell activation was determined in histamine release experiments and by measuring upregulation of CD63 and CD203c after challenging with IgE plus anti-IgE or allergen. We found that NVP-BEZ235 exerts profound inhibitory effects on growth of primary and cloned neoplastic MC. In the MC leukemia cell line HMC-1, NVP-BEZ235 showed similar IC(50) values in the HMC-1.1 subclone lacking KIT D816V (0.025 µM) and the HMC-1.2 subclone expressing KIT D816V (0.005 µM). Moreover, NVP-BEZ235 was found to exert strong growth-inhibitory effects on neoplastic MC in a xenotransplant-mouse model employing NMR1-Foxn1(nu) mice. NVP-BEZ235 also exerted inhibitory effects on cytokine-dependent differentiation of normal BA and MC, but did not induce growth inhibition or apoptosis in mature MC or normal bone marrow cells. Finally, NVP-BEZ235 was found to inhibit IgE-dependent histamine release in BA and MC (IC(50) 0.5-1 µM) as well as anti-IgE-induced upregulation of CD203c in BA and IgE-dependent upregulation of CD63 in MC. In summary, NVP-BEZ235 produces growth-inhibitory effects in immature neoplastic MC and inhibits IgE-dependent activation of mature BA and MC. Whether these potentially beneficial drug effects have clinical implications is currently under investigation.

Dose study of the multikinase inhibitor, LY2457546, in patients with relapsed acute myeloid leukemia to assess safety, pharmacokinetics, and pharmacodynamics.

BACKGROUND: Acute myeloid leukemia (AML) is a life-threatening malignancy with limited treatment options in chemotherapy-refractory patients. A first-in-human dose study was designed to investigate a safe and biologically effective dose range for LY2457546, a novel multikinase inhibitor, in patients with relapsed AML. METHODS: In this nonrandomized, open-label, dose escalation Phase I study, LY2457546 was administered orally once a day. Safety, pharmacokinetics, changes in phosphorylation of target kinases in AML blasts, and risk of drug-drug interactions (DDI) were assessed. RESULTS: Five patients were treated at the starting and predicted minimal biologically effective dose of 50 mg/day. The most commonly observed adverse events were febrile neutropenia, epistaxis, petechiae, and headache. The majority of adverse events (81%) were Grade 1 or 2. One patient had generalized muscle weakness (Grade 3), which was deemed to be a dose-limiting toxicity. Notably, the pharmacokinetic profile of LY2457546 showed virtually no elimination of LY2457546 within 24 hours, and thus prevented further dose escalation. No significant DDI were observed. Ex vivo flow cytometry studies showed downregulation of the phosphoproteins, pcKIT, pFLT3, and pS6, in AML blasts after LY2457546 administration. No medically relevant responses were observed in the five treated patients. CONCLUSION: No biologically effective dose could be established for LY2457546 in chemotherapy-resistant AML patients. Lack of drug clearance prevented safe dose escalation, and the study was terminated early. Future efforts should be made to develop derivatives with a more favorable pharmacokinetic profile.