Reirradiation with radiosurgery or stereotactic fractionated radiotherapy in association with regorafenib in recurrent glioblastoma.

PURPOSE: No standard treatment has yet been established for recurrent glioblastoma (GBM). In this context, the aim of the current study was to evaluate safety and efficacy of reirradiation (re-RT) by radiosurgery or fractionated stereotactic radiotherapy (SRS/FSRT) in association with regorafenib. METHODS: Patients with a histological or radiological diagnosis of recurrent GBM who received re-RT by SRS/FSRT and regorafenib as second-line systemic therapy were included in the analysis. RESULTS: From January 2020 to December 2022, 21 patients were evaluated. The median time between primary/adjuvant RT and disease recurrence was 8 months (range 5-20). Median re-RT dose was 24 Gy (range 18-36 Gy) for a median number of 5 fractions (range 1-6). Median regorafenib treatment duration was 12 weeks (range 3-26). Re-RT was administered before starting regorafenib or in the week off regorafenib during the course of chemotherapy. The median and the 6­month overall survival (OS) from recurrence were 8.4 months (95% confidence interval [CI] 6.9-12.7 months) and 75% (95% CI 50.9-89.1%), respectively. The median progression-free survival (PFS) from recurrence was 6 months (95% CI 3.7-8.5 months). The most frequent side effects were asthenia that occurred in 10 patients (8 cases of grade 2 and 2 cases of grade 3), and hand-foot skin reaction (2 patients grade 3, 3 patients grade 2). Adverse events led to permanent regorafenib discontinuation in 2 cases, while in 5/21 cases (23.8%), a dose reduction was administered. One patient experienced dehiscence of the surgical wound after reintervention and during regorafenib treatment, while another patient reported intestinal perforation that required hospitalization. CONCLUSION: For recurrent GBM, re-RT with SRT/FSRT plus regorafenib is a safe treatment. Prospective trials are necessary.

Radiosurgery and Stereotactic Brain Radiotherapy with Systemic Therapy in Recurrent High-Grade Gliomas: Is It Feasible? Therapeutic Strategies in Recurrent High-Grade Gliomas.

PURPOSE: For recurrent high-grade gliomas (HGG), no standard therapeutic approach has been reported; thus, surgery, chemotherapy, and re-irradiation (re-RT) may all be proposed. The aim of the study was to evaluate safety and efficacy of re-RT by radiosurgery or fractionated stereotactic radiotherapy (SRS/FSRT) in association to chemotherapy in patients with recurrent HGG. MATERIAL/METHODS: All patients with histological diagnosis of HGG that suffered by recurrent disease diagnosed by magnetic resonance imaging (MRI), according to Response Assessment in Neuro-Oncology (RANO) criteria, after primary/adjuvant chemo-radiotherapy treatment and underwent to re-RT by SRS/FSRT were included in the analysis. Second-line chemotherapy was administered. Outcomes were evaluated by neurological examination and brain MRI performed 1 month after re-RT and then every 2-3 months. RESULTS: From November 2019 to September 2021, 30 patients presenting recurrent HGG underwent re-RT. Median dose was 24 Gy (range 15-36 Gy), and median fractions was 5 (range 1-6). Twenty-one patients (70%) had RPA class ≤ IV. One patient had a histological diagnosis of anaplastic oligodendroglioma, 24 patients (80%) were affected by glioblastoma (GBM) including 3 cases of multifocal form, and 5 patients (17%) by anaplastic astrocytoma. Median time between primary/adjuvant RT and disease recurrence was 8 months. In six cases (20%) re-operation was performed, and in most cases (87%), a second line of systemic therapy was administrated. At a median follow-up time from recurrence of 13 months (range 6-56 months), 10 patients (33%) were alive: 2 patients with partial response disease, 7 patients with stable disease, and 1 patient with out-field progression disease. Of the 20 patients who died (67%), 15 (75%) died for progression disease and 5 (25%) for other causes (3 due to septic event, 1 due to thrombo-embolic event, and 1 due to car accident). Median OS and PFS after recurrence were 12.1 and 11.2 months. Six-month and one-year OS were, respectively, 81% and 51%. No acute or late neurological side effects grade ≥ 2 and no case of radio-necrosis were reported. One patient experienced, after reintervention and during Regorafenib treatment (administered 40 days after surgery), dehiscence of the surgical wound. In three cases, grade 2 distal paresthesia was reported. Grade 3-4 hematologic toxicity occurred in seven cases. Three case of grade 5 toxicities during chemotherapy were reported: three septic events and one thrombo-embolic event. CONCLUSION: Re-RT with SRT/FSRT in association with second-line systemic therapy is a safe and feasible treatment for patients with HGG recurrence. Validation of these results by prospective studies is needed.

An Italian Model for the Management of Cancer Patients during COVID-19 Pandemic: The Regional Center for Oncological Orientation (COrO) of Taranto (ROP).

OBJECTIVE: The recent outbreak of COVID-19 limited the resources of the National Health System necessitating the formulation of novel practice recommendations for oncological care. To date, management guidelines for cancer patients in case of pandemic are not available. Each center tried to manage its own needs and requests independently, often reducing access to treatment and diagnostic exams to patients. Here, we have described the management of cancer patients during COVID-19 infection with suggestions of some practical approaches applied by our Regional Center for Oncological Orientation (COrO) in S.G. Moscati Hospital (Taranto, Italy). SUBJECTS AND METHODS: Our strategy was to minimize any interruption of cancer treatment through the extension of Taranto's Health Regional (COrO). The extension of the oncological network, assisted by the General Management of Taranto ASL through agreements with private structures in Taranto's area, allowed cancer patients to receive up to 11 different types of services, according to their needs (first investigation or follow-up), and represents an exclusive organization on the entire Italian territory. RESULTS: Thanks to the organization of the COrO in 2020, 1,406 first oncological visits and 566 preparatory treatments were carried out, 372 of exemption for oncological pathology (free health care) were activated, and 1,742 instrumental investigations and 7 cases of civil invalidity were performed (certificate of disability). CONCLUSIONS: We have overcome barriers to care of oncology patients leading to a reduction of waiting lists representing a practical application model that can be extended to other healthcare settings.

Poor-Prognosis Patients Affected by Glioblastoma: Retrospective Study of Hypofractionated Radiotherapy with Simultaneous Integrated Boost and Concurrent/Adjuvant Temozolomide.

BACKGROUND: Glioblastoma (GBM) is a very poor-prognosis brain tumor. To date, maximal excision followed by radiochemotherapy, in 30 fractions, is the standard approach. Limited data are present in the literature about hypofractionated radiotherapy (hypo-RT) in GBM poor prognosis patients. Thus, this retrospective study was conducted to evaluate efficacy and toxicity of hypo-RT with simultaneous integrated boost (SIB) in association with temozolomide (TMZ) in this patient setting. METHODS: Poor-prognosis GBM patients underwent surgery (complete, subtotal or biopsy) followed by SIB-hypo-RT and concomitant/adjuvant TMZ. The prescription dose was 40.05 Gy (15 fractions) with a SIB of 52.5 Gy (3.5 Gy/fraction) on surgical cavity/residual/macroscopic disease. Volumetric modulated arc therapy was performed. RESULTS: From July 2019 to July 2021, 30 poor-prognosis patients affected by GBM were treated by SIB-hypo-RT; 25 were evaluated in the present analysis due to a minimum follow up of 6 months. The median age and KPS were 65 years and 60%, respectively. At the median follow-up time of 15 months (range 7-24), median and 1-year overall survival and progression-free survival were 13 months and 54%, and 8.4 months and 23%, respectively. No acute or late neurological side effects of grade ≥ 2 were reported. Grade 3-4 hematologic toxicity occurred in three cases. CONCLUSION: SIB-hypo-RT associated with TMZ in poor-prognosis patients affected by GBM is an effective and safe treatment. Prospective studies could be warranted.

Differential Glycosylation Levels in Saliva from Patients with Lung or Breast Cancer: A Preliminary Assessment for Early Diagnostic Purposes.

Glycans play a fundamental role in several biological processes, such as cell-cell adhesion, signaling, and recognition. Similarly, abnormal glycosylation is involved in many pathological processes, among which include tumor growth and progression. Several highly glycosylated proteins found in blood are currently used in clinical practice as cancer biomarkers (e.g., CA125, PSA, and CA19-9). The development of novel non-invasive diagnostic procedures would greatly simplify the screening and discovery of pathologies at an early stage, thus also allowing for simpler treatment and a higher success rate. In this observational study carried out on 68 subjects diagnosed with either breast or lung cancer and 34 healthy volunteers, we hydrolyzed the glycoproteins in saliva and quantified the obtained free sugars (fucose, mannose, galactose, glucosamine, and galactosamine) by using high-performance anion-exchange chromatography with pulsed-amperometric detection (HPAEC-PAD). The glycosidic profiles were compared by using multivariate statistical analysis, showing differential glycosylation patterns among the three categories. Furthermore, Receiver Operating Characteristics (ROC) analysis allowed obtaining a reliable and minimally invasive protocol able to discriminate between healthy and pathological subjects.

The Role of Laparoscopic Surgery in Localized Pancreatic Neuroendocrine Tumours.

OPINION STATEMENT: Pancreatic neuroendocrine tumours (PNETs) are a rare and heterogeneous group of tumours with various clinical manifestations and biological behaviours. They represent approximately 2-4% of all pancreatic tumours, with an incidence of 2-3 cases per million people. PNETs are classified clinically as non-functional or functional, and pancreatic resection is recommended for lesions greater than 2 cm. The surgical approach can involve "typical" and "atypical" resections depending on the number, size and location of the tumour. Typical resections include pancreaticoduodenectomy, distal pancreatectomy enucleation and, rarely, total pancreatectomy. Atypical resections comprise central pancreatectomies or enucleations. Minimally invasive pancreatic resection has been proven to be technically feasible and safe in high-volume and specialized centres with highly skilled laparoscopic surgeons, with consolidated benefits for patients in the postoperative course. However, open and minimally invasive pancreatic surgery remains to have a high rate of complications; there is no specific technical contraindication to minimally invasive pancreatic surgery, but an appropriate patient selection is crucial to obtain satisfactory clinical and oncological outcomes.

Current status of non-surgical treatment of locally advanced pancreatic cancer.

Pancreatic cancer is the 7th leading cause of death due to cancer in industrialized countries and the 11th most common cancer globally, with 458918 new cases (2.5% of all cancers) and 432242 deaths (4.5% of all cancer deaths) in 2018. Unfortunately, 80% to 90% of the patients present with unresectable disease, and the reported 5-year survival rate range between 10% and 25%, even after successful resection with tumor-free margins. Systemic chemotherapy, radiotherapy, and minimally invasive image-guided procedures that have emerged over the past years, are used for the management of non-operable PC. This review focuses on currently available non-surgical options of locally advanced pancreatic cancer.

KRAS and BRAF Concomitant Mutations in a Patient with Metastatic Colon Adenocarcinoma: An Interesting Case Report.

A 68-year-old female patient with tenesmus and blood in the stool was admitted to the S.G. Moscati Hospital of Taranto. Investigations revealed infiltrative mucinous colon adenocarcinoma accompanied by lymph node metastases. Following surgery and adjuvant chemotherapy, computed tomography (CT) and carcinoembryonic antigen screening were negative. Two years later, CT demonstrated a liver lesion. Histologic and genetic analyses confirmed the diagnosis of metastatic colorectal cancer with the coexistence of KRAS and BRAF mutations in hepatic metastases and the presence of the BRAF V600E in the primary tumour. It is unclear whether the lack of response was due to BRAF mutations, but the data suggest that mutated BRAF confers resistance to anti-epidermal growth factor receptor therapy. In our patient, BRAF mutation turned out to be a negative prognostic factor, and it may have been the cause of clinical implications for disease progression and therapeutic responses.

Pharmacotherapeutic options for patients with refractory breast cancer.

INTRODUCTION: The development of resistance to therapy is a concern in all three subtypes of breast cancer (BC). Yet, outcomes of patients with BC have improved in the past few years thanks to a molecularly targeted approach and a greater understanding of the many mechanisms through which cancer cells adapt to evade drug therapies. Indeed, there have been a number of different and active treatment strategies for hormone receptor positive (HR+ and Her2 positive BC although triple-negative breast cancer treatment remains problematical because of the early onset of resistance to treatments and the limited availability of targeted treatment options. AREAS COVERED: Herein, the authors present the various pharmacotherapeutic options for refractory breast cancer including their perspectives on these options. EXPERT OPINION: In recent years, there has been significant progress in our understanding of the biological mechanisms that cause resistance to BC treatments. The targeted therapeutic approach particularly has improved patient outcomes for those with refractory BC, but some unresolved issues still remain. In particular, we need to identify biomarkers of resistance to better tailor treatments, toxicities, and costs. Moreover, we need to determine the best sequence of treatments in refractory BC patients.

An update on first line therapies for metastatic breast cancer.

INTRODUCTION: In recent years, outcomes of patients with metastatic breast cancer (MBC) have improved due to a greater understanding of the mechanisms of carcinogenesis in the development of newer molecularly targeted drugs, especially those as a front-line therapy. Remarkable improvements have been made in the treatment of hormone receptor positive (HR+) and Her2 positive MBC and currently targeted treatment strategies represent a valid first line treatment. AREAS COVERED: Herein, the authors provide an overview of the first-line pharmacotherapies currently available for the treatment of MBC and provide their expert perspectives on the area. EXPERT OPINION: Decisions on the first-line treatment of MBC should consider the clinical features of the disease, but also the biological mechanisms that regulate tumor cell growth. New and effective therapeutic agents have recently been introduced in the first-line therapy of MBC. However, to optimize the treatment of patients with metastatic disease, clinicians need biomarkers of resistance or sensitivity to targeted therapies. Efforts must also be made in developing strategies to personalize treatments of MBC patients and to identify those patients who might gain the most benefit from new treatment interventions, to save costs and limit toxicity.

Dose intensity and efficacy of the combination of everolimus and exemestane (EVE/EXE) in a real-world population of hormone receptor-positive (ER+/PgR+), HER2-negative advanced breast cancer (ABC) patients: a multicenter Italian experience.

AIM: This retrospective analysis focused on the effect of treatment with EVE/EXE in a real-world population outside of clinical trials. We examined the efficacy of this combination in terms of PFS and RR related to dose intensity (5 mg daily versus 10 mg daily) and tolerability. METHODS: 163 HER2-negative ER+/PgR+ ABC patients, treated with EVE/EXE from May 2011 to March 2016, were included in the analysis. The primary endpoints were the correlation between the daily dose and RR and PFS, as well as an evaluation of the tolerability of the combination. Secondary endpoints were RR, PFS, and OS according to the line of treatment. Patients were classified into three different groups, each with a different dose intensity of everolimus (A, B, C). RESULTS: RR was 29.8% (A), 27.8% (B) (p = 0.953), and not evaluable (C). PFS was 9 months (95% CI 7-11) (A), 10 months (95% CI 9-11) (B), and 5 months (95% CI 2-8) (C), p = 0.956. OS was 38 months (95% CI 24-38) (A), median not reached (B), and 13 months (95% CI 10-25) (C), p = 0.002. Adverse events were stomatitis 57.7% (11.0% grade 3-4), asthenia 46.0% (6.1% grade 3-4), hypercholesterolemia 46.0% (0.6% grade 3-4), and hyperglycemia 35.6% (5.5% grade 3-4). The main reason for discontinuation/interruption was grade 2-3 stomatitis. CONCLUSIONS: No correlation was found between dose intensity (5 vs. 10 mg labeled dose) and efficacy in terms of RR and PFS. The tolerability of the higher dose was poor in our experience, although this had no impact on efficacy.

Bone marrow endothelial cells in multiple myeloma secrete CXC-chemokines that mediate interactions with plasma cells.

Bone marrow endothelial cells (EC) from patients with multiple myeloma (MM) were found to express and secrete higher amounts of the CXC-chemokines CXCL8/interleukin (IL)-8, CXCL11/interferon-inducible T-cell alpha chemoattractant (I-TAC), CXCL12/stromal cell-derived factor (SDF)-1alpha, and CCL2/monocyte chemotactic protein(MCP)-1 than EC from human umbilical vein (HUVEC), considered as a healthy counterpart. Paired plasma cells and several MM cell lines expressed cognate receptors of each chemokine to a variable extent. When cells were exposed to chemokines, CXCL8/IL-8 and CXCL12/SDF-1alpha stimulated their proliferation and all chemokines stimulated cell chemotaxis. It is suggested that angiogenesis also favours MM progression through the release of CXC-chemokines.