Neoadjuvant immunotherapy with nivolumab and ipilimumab induces major pathological responses in patients with head and neck squamous cell carcinoma.

Surgery for locoregionally advanced head and neck squamous cell carcinoma (HNSCC) results in 30‒50% five-year overall survival. In IMCISION (NCT03003637), a non-randomized phase Ib/IIa trial, 32 HNSCC patients are treated with 2 doses (in weeks 1 and 3) of immune checkpoint blockade (ICB) using nivolumab (NIVO MONO, n = 6, phase Ib arm A) or nivolumab plus a single dose of ipilimumab (COMBO, n = 26, 6 in phase Ib arm B, and 20 in phase IIa) prior to surgery. Primary endpoints are feasibility to resect no later than week 6 (phase Ib) and primary tumor pathological response (phase IIa). Surgery is not delayed or suspended for any patient in phase Ib, meeting the primary endpoint. Grade 3‒4 immune-related adverse events are seen in 2 of 6 (33%) NIVO MONO and 10 of 26 (38%) total COMBO patients. Pathological response, defined as the %-change in primary tumor viable tumor cell percentage from baseline biopsy to on-treatment resection, is evaluable in 17/20 phase IIa patients and 29/32 total trial patients (6/6 NIVO MONO, 23/26 COMBO). We observe a major pathological response (MPR, 90‒100% response) in 35% of patients after COMBO ICB, both in phase IIa (6/17) and in the whole trial (8/23), meeting the phase IIa primary endpoint threshold of 10%. NIVO MONO's MPR rate is 17% (1/6). None of the MPR patients develop recurrent HSNCC during 24.0 months median postsurgical follow-up. FDG-PET-based total lesion glycolysis identifies MPR patients prior to surgery. A baseline AID/APOBEC-associated mutational profile and an on-treatment decrease in hypoxia RNA signature are observed in MPR patients. Our data indicate that neoadjuvant COMBO ICB is feasible and encouragingly efficacious in HNSCC.

Publisher Correction: Immune induction strategies in metastatic triple-negative breast cancer to enhance the sensitivity to PD-1 blockade: the TONIC trial.

In the version of this article originally published, there was an error in Fig. 3j. A label on the heatmap read "TGF-α signaling via NF-κB". It should have read "TNF-α signaling via NF-κB". The error has been corrected in the HTML and PDF versions of this article.

Immune induction strategies in metastatic triple-negative breast cancer to enhance the sensitivity to PD-1 blockade: the TONIC trial.

The efficacy of programmed cell death protein 1 (PD-1) blockade in metastatic triple-negative breast cancer (TNBC) is low1-5, highlighting a need for strategies that render the tumor microenvironment more sensitive to PD-1 blockade. Preclinical research has suggested immunomodulatory properties for chemotherapy and irradiation6-13. In the first stage of this adaptive, non-comparative phase 2 trial, 67 patients with metastatic TNBC were randomized to nivolumab (1) without induction or with 2-week low-dose induction, or with (2) irradiation (3 × 8 Gy), (3) cyclophosphamide, (4) cisplatin or (5) doxorubicin, all followed by nivolumab. In the overall cohort, the objective response rate (ORR; iRECIST14) was 20%. The majority of responses were observed in the cisplatin (ORR 23%) and doxorubicin (ORR 35%) cohorts. After doxorubicin and cisplatin induction, we detected an upregulation of immune-related genes involved in PD-1-PD-L1 (programmed death ligand 1) and T cell cytotoxicity pathways. This was further supported by enrichment among upregulated genes related to inflammation, JAK-STAT and TNF-α signaling after doxorubicin. Together, the clinical and translational data of this study indicate that short-term doxorubicin and cisplatin may induce a more favorable tumor microenvironment and increase the likelihood of response to PD-1 blockade in TNBC. These data warrant confirmation in TNBC and exploration of induction treatments prior to PD-1 blockade in other cancer types.

The use of indwelling pleural catheters for the management of malignant pleural effusion--direct costs in a Dutch hospital.

BACKGROUND: Indwelling pleural catheters (IPCs) are increasingly used in the treatment of malignant pleural effusion (MPE). In general, these catheters have been reported to manage MPE efficiently. Unfortunately, insurance companies in the Netherlands do not reimburse these catheters in either first-line treatment or following failed talc pleurodesis. OBJECTIVES: Investigation of direct costs of IPC placement. METHODS: Retrospective analysis of a prospectively collected database. Direct costs for both catheters and vacuum bottles were calculated. Indicators for indirect costs such as adverse events and complications and the need for additional home care for drainage were registered. RESULTS: Mean costs for IPC amounted to EUR 2,173 and were different between tumor types - mesothelioma: EUR 4,028, breast: EUR 2,204, lung: EUR 1,146 and other: EUR 1,841; p = 0.017. Four patients were admitted to hospital for treatment of complications. Mean costs for IPC placement was similar when inserted as frontline treatment and after failed pleurodesis. Approximately 75% of patients did not need any help from specialized home care. CONCLUSION: Direct costs for IPC placement turn out to be acceptable when compared with estimated hospitalization costs for pleurodesis treatment. Randomized controlled trials have to be performed to compare the cost-effectiveness of IPCs compared to pleurodesis.

Clinical outcome of instrumented fusion for the treatment of failed back surgery syndrome: a case series of 100 patients.

OBJECT: Failed back surgery syndrome is defined as persistent chronic low-back pain and/or leg pain lasting more than 1 year, despite of one or more surgical procedures. Instrumented spinal fusion has been offered by surgeons as a potential treatment to recover from pain and functional disability. Factors contributing to good outcome of instrumented spinal fusion have not been investigated extensively. This study evaluated the global perceived recovery and functional status of patients after instrumented fusion for the treatment of failed back surgery syndrome. METHODS: Between January 2004 and September 2007, 100 patients underwent instrumented spinal fusion because of persistent back and/or leg pain lasting more than 1 year despite of one or more previous spine surgeries. The global perceived recovery of the patients was documented on a seven-point Likert scale, in which good outcome was defined as "complete recovery" and "almost complete recovery". Pain was evaluated by the 100-mm visual analogue scale (VAS) of back pain and leg pain, and functional disability measured by the Roland Disability Questionnaire for Sciatica (RDQ) and Oswestry Disability Index (ODI). The Hospital Anxiety and Depression Scale (HADS) evaluated psychological co-morbidity. All patients were sent questionnaires by mail. Pearson's correlation coefficient was calculated between outcome measures and preoperative patient characteristics. RESULTS: Eighty-two patients (82% response rate) returned questionnaires that were useful for analysis. After a mean follow-up period of 15 months, 35% of the patients reported good outcome, whereas 65% had unsatisfactory outcome. The mean (± SD) score of VAS low-back pain and leg pain was 45.7 ± 29 and 37.9 ± 31.9, respectively. The mean (± SD) RDQ and ODI score was 11.8 ± 5.4 and 30.6 ± 20.3, respectively. HADS score indicated a possible anxiety disorder in 28% of the patients and in 30% a possible underlying depression. Of the patients' baseline characteristics, there was only a significantly negative correlation between level of education and outcome. CONCLUSIONS: The present study showed disappointing outcome of instrumented fusion for the treatment of failed back surgery syndrome in terms of perceived recovery, functional disability and pain. Conservative management is probably more beneficial and, therefore, more selective and careful assessment should be done in order to prevent unnecessary surgery.