Evolution and Progress of mRNA Vaccines in the Treatment of Melanoma: Future Prospects.

mRNA vaccines encoding tumor antigens may be able to sensitize the immune system of the host against cancer cells, enhancing antigen presentation and immune response. Since the breakout of the COVID19 pandemic, interest in mRNA vaccines has been accelerating, as vaccination against the virus served as a measure to limit disease spread. Given that immunotherapy has been the cornerstone of melanoma treatment over the last several decades, further innate immunity enhancement by targeted mRNA vaccines could be the next pivotal achievement in melanoma treatment. Preclinical data coming from murine cancer models have already provided evidence of mRNA vaccines' ability to induce host immune responses against cancer. Moreover, specific immune responses have been observed in melanoma patients receiving mRNA vaccines, while the recent KEYNOTE-942 trial may establish the incorporation of the mRNA-4157/V940 vaccine into the melanoma treatment algorithm, in combination with immune checkpoint inhibition. As the existing data are further tested and reviewed, investigators are already gaining enthusiasm about this novel, promising pathway in cancer therapy.

Bilateral Spontaneous Supraspinatus Tendon Rupture Under Prolonged BRAF/MEK Targeting Treatment in a Melanoma Patient.

The B-Raf proto-oncogene, serine/threonine kinase (BRAF)/ mitogen-activated protein kinase kinase (MEK) targeting agents have become the treatment of choice for BRAF-mutated melanoma during the last decade. However, it is possible that some long-term adverse events of these drugs have not yet been reported. A case of bilateral spontaneous, non-traumatic, supraspinatus tendon rupture in a 65-year-old Caucasian male suffering metastatic melanoma under prolonged and successful combination treatment with dabrafenib plus trametinib is presented. These damages could not be attributed to some other probable cause. The ruptured tendons were promptly restored arthroscopically. Oncologists should remain vigilant for the early detection of potential side effects of BRAF/MEK targeting agents that have not been systematically recorded yet but may appear and affect patients in the long run.

Next-Generation Sequencing of Circulating Tumor DNA Can Optimize Second-Line Treatment in RAS Wild-Type Metastatic Colorectal Cancer after Progression on anti-EGFR Therapy: Time to Rethink Our Approach.

BACKGROUND: Management of Ras wild-type colorectal cancer (CRC) patients upon disease progression after the successful use of targeted treatment with anti-EGFR monoclonal antibodies and backbone chemotherapy remains a clinical challenge. SUMMARY: Development of treatment resistance with prevalence of preexisting RAS mutated clones, RAS mutation conversion, truncation of extracellular receptor domains as well as HER2 and MET amplification are molecular events that can be difficult to follow without the use of sophisticated laboratory techniques. The clinical hurdle of re-biopsy and tumor heterogeneity can be overcome by the implementation of next-generation sequencing (NGS) to analyze circulating tumor DNA (ctDNA) and identify druggable mutations or recovery of RAS-wildness. In this opinion paper, we summarize with critical thinking the clinical approach to be followed after the failure of first-line treatment in Ras wild-type CRC tumors with the use of NGS. Rechallenge with anti-EGFR inhibitors, in case of persistent or recovery of RAS-wildness, and targeted approach of specific mutations (BRAF inhibitors), amplifications (anti-Her2 treatment), or fusion proteins (NTRK inhibitors) can by guided by the use of NGS. The use of NGS platforms for serial analysis of ctDNA is an important step to better understand the molecular landscape of metastatic CRC and guide clinical decisions. KEY MESSAGES: NGS should be considered a mainstay in clinical practice for the management of CRC patients and health authorities should consider reimbursing its use in the appropriate clinical settings.

COVID-19 Vaccinations: Summary Guidance for Cancer Patients in 28 Languages: Breaking Barriers to Cancer Patient Information.

BACKGROUND: Covid-19 vaccination has started in the majority of the countries at the global level. Cancer patients are at high risk for infection, serious illness, and death from COVID-19 and need vaccination guidance and support. Guidance availability in the English language only is a major limit for recommendations' delivery and their application in the world's population and generates information inequalities across the different populations. METHODS: Most of the available COVID-19 vaccination guidance for cancer patients was screened and scrutinized by the European Cancer Patients Coalition (ECPC) and an international oncology panel of 52 physicians from 33 countries. RESULTS: A summary guidance was developed and provided in 28 languages in order to reach more than 70 percent of the global population. CONCLUSION: Language barrier and e-guidance availability in the native language are the most important barriers when communicating with patients. E-guidance availability in various native languages should be considered a major priority by international medical and health organizations that are communicating with patients at the global level.

Immunotherapy Efficacy in the Initial Lines of Treatment in Advanced Upper Gastrointestinal Malignancies: A Systematic Review of the Literature.

Background: The therapeutic role of immune checkpoint inhibitors (ICIs) has represented the cutting edge of clinical research in upper gastrointestinal (GI) malignancies, with these agents now included in the armamentarium of treatment options for advanced gastric and esophageal cancers. Methods: We performed a systematic literature review and pooled analysis to map out the currently available robust clinical evidence for the use of ICIs in upper GI cancers. Immunotherapy (IO), either as monotherapy or in combination with chemotherapy, and its role in first-line, maintenance, and second-line settings, as well as in specific clinical and biological subgroups, were critically appraised. All statistical tests were 2-sided. Results: ICIs, in combination with chemotherapy, have provided statistically significant overall survival benefit in the first-line setting in gastric and gastro-esophageal adenocarcinomas (hazard ratio [HR] = 0.83, 95% confidence interval [CI] = 0.76 to 0.90, P < .001; based on 4 studies) and esophageal squamous cell carcinoma (HR = 0.72, 95% CI = 0.64 to 0.81, P < .001; based on 3 studies), albeit with heterogeneous efficacy according to biomarker expression. Patients with esophageal squamous cell carcinoma, and in particular high programmed cell death ligand-1 expression, derive survival benefit when treated with IO in the second-line setting (HR = 0.74, 95% CI = 0.68 to 0.82, P < .001; for any level of programmed cell death ligand-1 expression). Clinical trials interrogating the combination of IO with chemotherapy in second-line treatment should be seriously considered in upper GI adenocarcinomas. The role of maintenance IO after initial disease control is still unclear and cannot be recommended. Impressive response rates and survival benefit from IO have been reported in patients with microsatellite instability-high tumors (HR = 0.33, 95% CI = 0.19 to 0.57, P < .001), and this warrants further prospective biomarker-driven studies. Conclusions: IO is changing the treatment landscape in upper GI malignancies. The rapidly developing evidence in the field needs to be critically appraised while further validation of the existing information from ongoing trials is awaited.

Advanced germ cell tumors and chemotherapy in G6PD deficient patients: Yes to chemotherapy but no to rasburicase and some premedications.

PURPOSE: Glucose-6 phosphate dehydrogenase (G6PD) deficiency has an estimated prevalence of 5 -7.5% of the global population. Administration of some drugs in G6PD deficient patients may result in clinical conditions of varying severity, including potentially fatal sequels. For these reasons, in case of G6PD deficiency, the use of high dose toxic chemotherapy regimens in potentially curable malignancies with associated risk of tumor lysis syndrome, such as in advanced germ cell tumors, raises both physicians' preoccupations and issues for safeguard patients' health. Nonetheless no systematic information is actually available for safety in premedication to be administered, chemotherapy regimens adopted, and supportive care drugs needed to be provided in some particular situations. METHODS: We present a case of a patient with metastatic testicular cancer and known g6pd deficiency, admitted in our department. We also performed a literature review in tree medical libraries searching for articles addressing the overmentioned security issues. RESULTS: Available literature is particularly scant. nonetheless, there is no evidence contradicting the administration of cytotoxic chemotherapy to G6PD deficient individuals. Our patient was able to complete the preplaned chemotherapy cycles, without any complications. CONCLUSION: Given the absence of data supporting the limitation of chemotherapy to G6PD deficient patients, the latter should not be deprived of the indicated antineoplastic treatment. However, certain premedication agents must be avoided. Continuous patient monitoring during treatment may alleviate physicians' and patients' anxiety and preoccupations.

Is there a role for Gallium-67 SPECT in distinguishing progression and pseudoprogresion in oncologic patients receiving immunotherapy?

Immuno-oncology (IO) with immune checkpoint inhibitors (ICIs) is the new landmark in cancer treatment. However, due to its economical-related burden and the possibility of tumor pseudoprogression with late response patterns, it is imperative to find new ways for early discrimination of patients with IO-sensitive versus IO-resistant disease. ICI-mediated antitumor responses depend on tumor immune infiltration by T-cells capable of recognizing and killing tumor cells. Nevertheless, patients may experience different responses to immunotherapy according to their tumor microenvironment and inflammatory infiltration. T-cell infiltrated tumors are referred to as 'hot' and are potential candidates for a good response to ICIs, whereas 'cold' are those tumors lacking T-cell infiltration and exhibit a narrow likelihood of response to IO therapy. Gallium-67 (67Ga) scintigraphy may hold potential for separating 'hot' from 'cold' tumors, thus providing an imaging tool to distinguish 'hot' ICI-induced pseudoprogression from real early 'cold' progression. Even so, various tumors (lymphomas, lung cancer, breast cancer, hepatoma, malignant melanoma) exhibit an inherent affinity for 67Ga that is independent of the ICI-induced immune infiltration, and this raises issues about false positivity. For that reason, future investigational studies to evaluate the prospective role of this radiotracer in the early prediction of ICI response should be confined to tumors with an inherently low 67Ga affinity (thyroid carcinoma, gastrointestinal and genitourinary tract tumors). We describe our experience with a patient with recurrent metastatic lung adenocarcinoma under ICI therapy that was submitted to 67Ga scanning for a fever of unknown origin and we discuss the aforementioned topics, alongside current imaging trends and future perspectives in the field.

Ureteral carcinoma metastasizing to the testicle: Can misdiagnosis of orchiepididymitis be avoided?

Testicular metastases from ureteral carcinoma are rare and they are generally mimic orchiepididymitis. For this reason, these are associated to misleading diagnoses and cancer treatment delay. We believe that both timing and knowledge of genital blood and lymph reverse flow routes may represent two important parameters for avoiding misleading diagnoses and speed proper anticancer treatment. We describe a case and discuss pathophysiological data and relevant literature.

Systematic Review of Recurrent Osteosarcoma Systemic Therapy.

Osteosarcoma is the most frequent primary bone cancer, mainly affecting those of young ages. Although surgery combined with cytotoxic chemotherapy has significantly increased the chances of cure, recurrent and refractory disease still impose a tough therapeutic challenge. We performed a systematic literature review of the available clinical evidence, regarding treatment of recurrent and/or refractory osteosarcoma over the last two decades. Among the 72 eligible studies, there were 56 prospective clinical trials, primarily multicentric, single arm, phase I or II and non-randomized. Evaluated treatment strategies included cytotoxic chemotherapy, tyrosine kinase and mTOR inhibitors and other targeted agents, as well as immunotherapy and combinatorial approaches. Unfortunately, most treatments have failed to induce objective responses, albeit some of them may sustain disease control. No driver mutations have been recognized, to serve as effective treatment targets, and predictive biomarkers of potential treatment effectiveness are lacking. Hopefully, ongoing and future clinical and preclinical research will unlock the underlying biologic mechanisms of recurrent and refractory osteosarcoma, expanding the therapeutic choices available to pre-treated osteosarcoma patients.

Interior Design: A New Perspective in Supportive Care of Patients with Acute Onset of Debilitating Diseases.

Background: Upon the onset of a debilitating rapidly evolving condition (such as cancer or a rapidly progressing myopathy, neuropathy, respiratory disease, or a severe traumatic injury), individuals have limited time to find a new home or make radical structural modifications in their residence. How the affected patients can continue sharing the same house with their families, while meeting their own special requirements, is thus rising as a critical issue. Household and daily routine rearrangements, either temporary or permanent, may be necessary, to ameliorate the life of patients with impairments, lasting for months or even years. Objectives: Interior design may provide a highly efficient "living" palliation for debilitating medical conditions directly at patients' home-site. Methods: Research of relevant literature, using keywords "debilitating conditions," "home care," "end of life care," "care of advanced cancer patients," "care of patients with mental disorders," "home care of covid-19 affected patients," and "care of patients with degenerative illnesses." Results: We found that patients and their relatives may not be aware of the probable interior design solutions to their daily life challenges, imposed by a disease-related impairment. In parallel, interior design experts may equally be unaware of these issues, as well as of who needs the available solutions.Similarly, medical and architectural sciences are not connected, eventually failing to meet patients' everyday needs. Conclusions: Interior architecture and health scientists are called to cooperate, aiming to provide a highly efficient and meaningful support to patients and families affected by unforeseen debilitating medical conditions.

Chemotherapy Associated Ovarian Failure.

As the incidence of malignancies in young adults is increasing, fertility preservation in cancer survivors arises as a major concern. Especially among female cancer patients, pregnancy rates are estimated to be 40% lower compared to women of the same age. Nowadays oncologists are to be preoccupied not only with their patients' successful treatment, but also with the maintenance of the potential of the latter to conceive and obtain children. Chemotherapy associated ovarian failure (COF), refers to disruption of ovarian function both as an endocrine gland and as a reproductive organ, due to previous exposure to chemotherapy agents. Although the underlying mechanism is not fully understood, it is supposed that chemotherapy agents may induce either DNA damage of premature ovarian follicle or early activation and apoptosis of them, resulting into early exhaustion of available follicle deposit. Various chemotherapy agents have been associated with COF with the highest incidence being reported for patients undergoing combination regimens. Although a variety of alternatives in order to maintain ovarian function and fertility in female cancer survivors are available, adequately established practices to do so are lacking. Thus, it is of major importance to investigate further and collect sufficient evidence, aiming to guide patients and physicians in everyday clinical practice.

Old Player-New Tricks: Non Angiogenic Effects of the VEGF/VEGFR Pathway in Cancer.

Angiogenesis has long been considered to facilitate and sustain cancer growth, making the introduction of anti-angiogenic agents that disrupt the vascular endothelial growth factor/receptor (VEGF/VEGFR) pathway an important milestone at the beginning of the 21st century. Originally research on VEGF signaling focused on its survival and mitogenic effects towards endothelial cells, with moderate so far success of anti-angiogenic therapy. However, VEGF can have multiple effects on additional cell types including immune and tumor cells, by directly influencing and promoting tumor cell survival, proliferation and invasion and contributing to an immunosuppressive microenvironment. In this review, we summarize the effects of the VEGF/VEGFR pathway on non-endothelial cells and the resulting implications of anti-angiogenic agents that include direct inhibition of tumor cell growth and immunostimulatory functions. Finally, we present how previously unappreciated studies on VEGF biology, that have demonstrated immunomodulatory properties and tumor regression by disrupting the VEGF/VEGFR pathway, now provide the scientific basis for new combinational treatments of immunotherapy with anti-angiogenic agents.

Behind the numbers and the panic of a viral pandemic: fixed restrictive oncology guidance may jeopardize patients' survival.

To protect cancer patients from COVID-19 exposure, prioritization strategies are being implemented at global level. Measures include use of tele-health services, deferring elective surgeries, delaying non life-saving therapies, interrupting maintenance and supportive care regimens and suspending screening and regular follow-up visits. Nonetheless, the risk of infection may not always outweigh oncology treatment benefit. Lives of most oncology patients depend on their ability to receive medical, surgical and radiotherapy care. Postponing screening, follow-up and radical surgeries increase patients' risk of developing metastatic disease. A viral pandemic lasts long time and exhibits seasonal and geographical variations. Though vaccines will be available only in the 2021, a global, aggressive, all-embracing and protracted slowdown of oncologic activities will severely jeopardize patients' outcomes. A present international oncologists' panel, ECPC and FAVO, strongly suggest that Hospital measures in a specific geographical area/Nation should be in line with the local epidemic, and restrictions adopted should be adapted and stratified over time.

The cancer immunotherapy environment may confound the utility of anti-TIF-1γ in differentiating between paraneoplastic and treatment-related dermatomyositis. Report of a case and review of the literature.

With the advent of immunotherapy and with the expanding spectrum of malignancies treated with immunomodulatory agents, a new kind of adverse events has come under the spotlight. Clinicians have to be aware of immune-related adverse events and their clinical manifestations. Immunotherapy has been strongly associated with endocrinopathies, gastrointestinal, pulmonary, cutaneous, and renal toxicities but the incidence of rheumatologic adverse events is lower compared to the aforementioned systems. Dermatomyositis is an autoimmune myopathy which has been correlated to underlying evident or occult malignancies. Apart from its characteristic symptoms and signs, the presence of specific antibodies such as anti-transcriptional intermediary factor 1γ (anti-TIF 1γ) usually supports the diagnosis of paraneoplastic nature of the disease. However, a solid distinction between paraneoplastic syndrome and immune-related adverse event is still missing and remains to be elucidated. We here present a case of dermatomyositis in a male patient who underwent four cycles of combined ipilimumab and nivolumab immunotherapy. This is, to our knowledge, the first case of dermatomyositis following combined immune checkpoint inhibition therapy.

Acquired Hemophilia in an Elderly Patient with Carcinoma of the Ampulla of Vater.

Acquired hemophilia is a rare autoimmune bleeding disorder related to the production of autoantibodies that inhibit clotting factor VIII or IX. The underlying cause can be autoimmune disease, malignancy, pregnancy, or medications, but it is most commonly idiopathic. Here we present the case of an 81-year-old patient with locoregionally relapsed periampullary carcinoma who presented with soft tissue hematoma and an abnormally elevated activated partial thromboplastin time (aPTT) in the presence of a normal prothrombin time. A diagnosis of acquired hemophilia was established. The patient was managed with immunosuppressive prednisone and cyclophosphamide plus immunoglobulin G. He also received a cycle of chemotherapy with gemcitabine and oxaliplatin, because the underlying malignancy was the cause of the bleeding disorder. Care was complicated by neutropenia and nosocomial fever, but the patient eventually showed signs of clinical stability, while the aPTT decreased 2-fold. The patient was successfully discharged from the hospital and continued treatment in outpatient care.

An unusual termination of seven veins in the jugulo-subclavian junction / Inusual terminación de siete venas en la unión yugulo-subclavia

During anatomical dissection of a female Caucasian cadaver in our department, we observed an unusual termination of seven veins at the jugulo-subclavian junction. Normally, the jugulo-subclavian junction is formed by the union of the internal jugular vein and the subclavian vein, and gives rise to the brachionocephalic vein. In our case, except from these two, five additional veins, namely the cephalic vein, the transverse cervical vein, the external jugular vein, the anterior jugular vein, and the vertebral vein, were also joined at the level of the jugulo-subclavian junction, in order to form the brachionocephalic vein. Such a variation has not yet been reported in the literature.

Durante la disección anatómica de un cadáver caucásico femenino, se observó una inusual terminación de siete venas en el lugar de unión yúgulo-subclavia. Normalmente, la unión yúgulo-subclavia consiste en la unión de la vena yugular interna y la vena subclavia, que forman la vena braquiocefálica. En nuestro caso, además de estas dos venas, se observaron cinco venas adicionales, la vena cefálica, la vena cervical transversa, la vena yugular externa, la vena yugular anterior y la vena vertebral, la que también se unió en el nivel de la unión yúgulo-subclavia, a fin de formar la vena braquiocefálica. Tal variación no ha sido reportado en la literatura.

A rare variation of the axillary artery combined contralaterally with an unusual high origin of a superficial ulnar artery: description, review of the literature and embryological analysis.

During anatomical dissection of a female Caucasian cadaver in our department we observed a combination of two rare arterial patterns of the upper limb bilaterally; a superficial ulnar artery of high origin in the right upper limb and some rare variations of the left axillary artery: Right arm: The superficial ulnar artery originated from the second part of the axillary artery, before the origin of the subscapular artery. It proceeded superficially in the forearm. The axillary artery continued normally in the arm as brachial artery, and finally divided into the radial and the common interosseous artery. The normal ulnar artery was absent. The presence of the superficial ulnar artery is a rare variation given that its total incidence ranges from 0.67% to 9.38%, with only 0.17% to 2% originating from the axillary artery. Left arm: The second part of the axillary artery gave rise to a first common trunk (named A), lying between the two roots of the median nerve, which divided in two new common trunks (B and C). One of these gave origin to the subscapular and the posterior circumflex humeral artery while the other gave rise to the anterior circumflex humeral artery, two muscle twigs and then continued as profunda brachii artery. The incidence of anatomic variations of the major arteries of the upper extremities ranges from 11% to 24%. Nevertheless a pattern with three common trunks comprising the origin of the profunda brachii has not yet been cited in the literature.