Neoadjuvant therapy bridging patients with hepatocellular cancer waiting for liver transplant

Introduction. Liver transplant (LT) is a widely accepted treatment for hepatocellular carcinoma (HCC). The role of neoadjuvant (NAT) is still under debate.The aim of the work is to assess the effect of NAT on relapse-free survival (RFS) and overall survival (OS) in patients with HCC who underwent LT.Methods and materials. 63 patients diagnosed with HCC were observed at Blokhin National Medical Research Center of Oncology from October 2010 to January 2020. Of these, 28 patients did not receive any type of treatment before transplantation, 35 patients received various types of NAT. Two groups had similar patient and tumour characteristics at baseline. A significant number of patients with decompensated cirrhosis were observed in the non-NAT group (n = 14; 50%), while no patients with CP-C liver cirrhosis were observed in the NAT group (n = 0; 0%; p = 0.000). The average wait for a liver transplant was 10.3 months in the NAT group and 6.8 months in the NAT-free group (p = 0.561).Results. In the bridging subgroup, the tumour progression was detected in 29% of patients, stable disease in 47% of patients, partial response was achieved in 14% of patients, complete tumour response was observed in 5%. For 5% of patients, it was not possible to estimate the effect of the therapy due to the lack of appropriate data archives. In the subgroup of downstaging therapy, the tumour progression was detected in 23% of patients, stable disease in 41% of patients, a partial response was achieved in 12% of patients, a complete tumour response was observed in 6%. The treatment allowed the Milan criteria to be fulfilled in 18% of patients.Conclusion. There was no difference in overall survival (OS) or disease-free survival (DFS) between the NAT and control groups.

ATR inhibition enables complete tumour regression in ALK-driven NB mouse models

High-risk neuroblastoma (NB) often involves MYCN amplification as well as mutations in ALK. Currently, high-risk NB presents significant clinical challenges, and additional therapeutic options are needed. Oncogenes like MYCN and ALK result in increased replication stress in cancer cells, offering therapeutically exploitable options. We have pursued phosphoproteomic analyses highlighting ATR activity in ALK-driven NB cells, identifying the BAY1895344 ATR inhibitor as a potent inhibitor of NB cell growth and proliferation. Using RNA-Seq, proteomics and phosphoproteomics we characterize NB cell and tumour responses to ATR inhibition, identifying key components of the DNA damage response as ATR targets in NB cells. ATR inhibition also produces robust responses in mouse models. Remarkably, a 2-week combined ATR/ALK inhibition protocol leads to complete tumor regression in two independent genetically modified mouse NB models. These results suggest that NB patients, particularly in high-risk groups with oncogene-induced replication stress, may benefit from ATR inhibition as therapeutic intervention.

Influenza virus vector iNS1 expressing bovine papillomavirus 1 (BPV1) antigens efficiently induces tumour regression in equine sarcoid patients

Bovine papillomaviruses types 1 and 2 (BPV1, BPV2) commonly induce skin tumours termed sarcoids in horses and other equids. Sarcoids seriously compromise the health and welfare of affected individuals due to their propensity to resist treatment and reoccur in a more severe form. We have developed influenza (Flu) A and B virus vectors that harbour a truncated NS1 gene (iNS) assuring interferon induction and co-express shuffled BPV1 E6 and E7 antigens for sarcoid immunotherapy. In a safety trial involving 12 healthy horses, intradermal administration of iNSA/E6E7equ and iNSB/E6E7equ was well tolerated, with the only transient side effect being mild fever in four horses. Repeated screening of secretions and faeces by RT-PCR and plaque assay revealed no virus shedding, thus also confirming biological safety. In a patient trial involving 29 horses bearing BPV1-induced single or multiple sarcoids, at least one lesion per horse was intratumourally injected and then boosted with iNSA/E6E7equ and/or iNSB/E6E7equ. The treatment induced a systemic antitumour response as reflected by the synchronous regression of injected and non-injected lesions. Irrespective of vaccination schemes, complete tumour regression was achieved in 10/29 horses. In 10/29 horses, regression is still ongoing (May 2021). Intriguingly, scrapings collected from former tumour sites in two patients tested negative by BPV1 PCR. Nine severely affected individuals with a history of unsuccessful therapeutic attempts did not (6/29) or only transiently (3/29) respond to the treatment. INSA/E6E7equ and iNSB/E6E7equ proved safe and effective in significantly reducing the tumour burden even in severe cases.

Cross-HLA targeting of intracellular oncoproteins with peptide-centric CARs

The majority of oncogenic drivers are intracellular proteins, thus constraining their immunotherapeutic targeting to mutated peptides (neoantigens) presented by individual human leukocyte antigen (HLA) allotypes1. However, most cancers have a modest mutational burden that is insufficient to generate responses using neoantigen-based therapies2,3. Neuroblastoma is a paediatric cancer that harbours few mutations and is instead driven by epigenetically deregulated transcriptional networks4. Here we show that the neuroblastoma immunopeptidome is enriched with peptides derived from proteins that are essential for tumourigenesis and focus on targeting the unmutated peptide QYNPIRTTF, discovered on HLA-A*24:02, which is derived from the neuroblastoma dependency gene and master transcriptional regulator PHOX2B. To target QYNPIRTTF, we developed peptide-centric chimeric antigen receptors (CARs) using a counter-panning strategy with predicted potentially cross-reactive peptides. We further hypothesized that peptide-centric CARs could recognize peptides on additional HLA allotypes when presented in a similar manner. Informed by computational modelling, we showed that PHOX2B peptide-centric CARs also recognize QYNPIRTTF presented by HLA-A*23:01 and the highly divergent HLA-B*14:02. Finally, we demonstrated potent and specific killing of neuroblastoma cells expressing these HLAs in vitro and complete tumour regression in mice. These data suggest that peptide-centric CARs have the potential to vastly expand the pool of immunotherapeutic targets to include non-immunogenic intracellular oncoproteins and widen the population of patients who would benefit from such therapy by breaking conventional HLA restriction.

Vascular Resection for Intrahepatic Cholangiocarcinoma: Current Considerations

Intrahepatic cholangiocarcinoma (iCCA) accounts for approximately 10% of all primary liver cancers. Surgery is the only potentially curative treatment, even in cases of macrovascular invasion. Since resection offers the only curative chance, even extended liver resection combined with complex vascular or biliary reconstruction of the surrounding organs seems justified to achieve complete tumour removal. In selected cases, the major vascular resection is the only change to try getting the cure. The best results are achieved by the referral centre with a wide experience in complex liver surgery, such as ALPPS procedure, IVC resection, and ante-situ and ex-situ resections. However, despite aggressive surgery, tumour recurrence occurs frequently and long-term oncological results are very poor. This suggests that significant progress in prognosis cannot be expected by surgery alone. Instead, multimodal treatment including neoadjuvant chemotherapy, radiotherapy, and subsequent adjuvant treatment for iCCA seem to be necessary to improve results.

Treatment strategies for inverted papillomas with intracranial or intraorbital involvement

Objective Sinonasal inverted papillomas are challenging benign tumours of the nasal cavity because of their high recurrence rates and the lifetime malignant transformation risk of 10 per cent as well as their locally aggressive behaviour. This study aimed to describe treatment strategies for inverted papillomas with intracranial or intraorbital involvement. Method This was a prospective case series study of 18 patients with inverted papilloma with intracranial or intraorbital involvement. Patient demographic data, imaging, pathology, surgical technique and recurrences were recorded prospectively over a period of seven years. Results A total of 83 per cent of the patients in this study had been previously operated on, consisting of 8 cases with intracranial involvement, 1 case with intraorbital involvement and 9 with both. During follow up with a medium of 37 months (range, 13–115 months) there were two recurrences. Conclusion It was postulated that intracranial or intraorbital involvement observed in this series was the result of multiple revisions. However, using accurate imaging protocols and the pedicle-oriented approach for tumour excision, complete tumour removal was achieved in most cases with minimal post-operative complications.

Rare lung cancers—Primary pulmonary leiomyosarcoma: A case report

SummaryPrimary pulmonary sarcomas (PPS) are rare mesenchymal lung cancers, which do not present clinically or radiological different to lung carcinomas. Definite PPS diagnosis can only be made by histological analysis and detailed staging examinations in order to exclude a secondary pulmonary malignancy such as metastatic soft tissue sarcoma or another solid tumour. Here we present the case of a 66-year-old woman with a pulmonary mass infiltrating the diaphragm and the mediastinal adipose tissue, which was identified as leiomyosarcoma. The patient received curative surgery with complete tumour R0 resection. The prognosis of PPS is defined by tumour size, lymph node status and histological grading. Surgery is the mainstay of therapy and there is no definitive indication for adjuvant therapy for R0-resected and lymph-node-negative patients like in our case. However, multimodal therapy approaches such as (neo)adjuvant chemo- and radiotherapy can contribute to improving locoregional tumour control, which is the most important prognostic factor. With our case report we want to raise awareness for pulmonary sarcomas as a relevant proportion of rare lung cancers which have to be kept in mind during the differential diagnosis. Moreover, we aim to discuss the complex and individual interdisciplinary management.

A rare case of polypoid primary anorectal melanoma with subsequent giant stomach metastasis: a gastrointestinal involvement of both primary and metastatic mucosal melanoma

Introduction: Melanoma can involve the gastrointestinal apparatus as both primary and metastatic lesions. Primary anorectal mucosal melanoma (ARMM) and metastatic gastric melanoma are rare entities and usually resulted in a poor prognosis. Case: We presented a case of a 61-year-old man who after the complete excision of an ARMM developed a gastric metastasis after almost three years form the complete tumour excision. Upon esophagogastroduodenoscopy, a giant ulcered mass resulted in melanoma metastasis. The patient underwent a near-total gastrectomy. After five months of follow-up, the patient is disease-free. Conclusion: The incidence of ARMMs is increasing, highlighting the necessity of new prevention and treatment strategies in order to achieve a better prognosis for these patients. There are no known risk factor for ARMMs but surgery, together with the combination of anti-CTLA-4 and anti-PD-1 antibodies, are promising therapeutic options. Early and aggressive treatments are required, together with a strict multidisciplinary approach.

Pineal Region Brain Tumour Treatment Revisited: A Case Report

Pineal region tumours may affect only a relatively small subset of neurosurgical patients, but they present enormous surgical challenge to the neurosurgeon due to their inaccessibly deep locations and compounded by the complex surrounding neurovascular structures. We present a case report of a patient who had combination chemoradiation without histological diagnosis but had complete tumour regression. Cyclical combination chemotherapy with cisplatin, etoposide and bleomycin and radiotherapy followed pre- chemoradiation ventriculo-peritoneal shunt insertion for obstructive hydrocephalus. The patient’s clinical condition improved following the ventriculoperitoneal shunt insertion as walking became re-established. Post – chemoradiotherapy cranial CT scan showed complete tumour regression. Tissue diagnosis may allow for precise, targeted management of pineal region tumours. However, in the absence of facilities which enable safe neurosurgery, resorting to the traditional chemo-radiation is still a viable alternative

Cervical Dumbbell Ganglioneuroma Causing Quadriplegia

Ganglioneuroma is a rare benign tumour that originates from the ganglion cells of the sympathetic nervous system. They are rare in cervical spine region and only 8 % of ganglioneuromas occur in the neck. The common sites of occurrence are in the posterior mediastinum, retroperitoneum and adrenal medulla, and as such, a cervical occurrence presenting with quadriplegia is a reportable event. We present a 26-year old young male with a two-year history of neck pain and progressive quadriplegia. He later became wheelchair-bound. Musculoskeletal examination revealed multiple generalized nodular skin swellings with café au lait macules. Magnetic resonance imaging showed a huge dumbbell tumour of the first two cervical vertebrae, to the right side of the spinal canal causing significant spinal cord compression. He had surgical intervention, aimed at complete tumour resection, postoperatively, power of the limbs improved to normal. Histological examination was consistent with ganglioneuroma. We present this report because the occurrence of ganglioneuroma is rare, secondly a cervical presentation is unusual and thirdly it presented as a rare cause of quadriplegia.