Δευτέρα 18 Ιανουαρίου 2021

Bioinformatic analysis of dysregulated proteins in prostate cancer patients reveals putative urinary biomarkers and key biological pathways

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Abstract

Prostate cancer (PCa) is one of the most common cancer types among men. The quantification of prostate-specific antigen used for PCa detection has revealed limited applicability. Thus, it is crucial to identify new minimally invasive biomarkers for PCa. It is believed that the integration of proteomics data from different studies is vital for identifying new biomarkers for PCa, but studies carried out in this regard have few converging results. Using a different approach, this study aimed to unveil molecular features consistently dysregulated in PCa and potential urinary biomarkers for PCa. The novelty of this analysis relies on the comparison of urinary and tissue proteomes from PCa patients and consequent exclusion of kidney and bladder cancer interference. The conducted bioinformatic analysis revealed molecular processes dysregulated in urine from PCa patients that mirror the alterations in prostate tumor tissue. To identify putative urinary biomarkers, prot eins previously detected in kidney and bladder tissues were eliminated from the final list of potential urinary biomarkers for PCa. After a detailed analysis, MSMB, KLK3, ITIH4, ITIH2, HPX, GP2, APOA2 and AZU1 proteins stood out as candidate urinary biomarkers for PCa.

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Identifying and Meeting the Needs of Adolescents and Young Adults with Cancer

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Abstract

Purpose of Review

Adolescents and young adults (AYAs) with cancer are a vulnerable population with unique needs that are under-recognized and often overlooked by healthcare providers. This review focuses on identifying and meeting some of those needs including adherence to treatment, financial implications, impact on fertility and intimacy, issues with work/school, isolation, challenges with re-entry, and long-term side effects and survivorship.

Recent Findings

Survival rates have not improved in adolescents and young adults with cancer at the same rate as in children and older adults (the so called "AYA gap"). Restricted or delayed access to care and inconsistent cancer treatment and follow-up care contribute to this. Importantly, fertility preservation options have broadened and efforts to provide age appropriate counseling prior to treatment have improved. Additionally, AYAs face a variety of psychosocial issues while dealing with a cancer diagnosis during critical developmental years, and yet data pertaining to the successful identification and management of these issues is lacking. As a result, there has been recent increasing awareness that this patient population warrants strong advocates, additional research, and requires age group specific resources to be successful in navigating their cancer experience during treatment and into survivorship care.

Summary

Members of the healthcare team should familiarize themselves with the unique needs of AYA cancer patients to provide optimal patient care. In order to build upon early progress, this group calls for additional study particularly when it comes to barriers to enrollment for AYA-specific research (including clinical trials), recognizing psychosocial needs (both during and after treatment), transition planning for returning to life after cancer, and managing long-term effects of treatment (including neuro cognitive changes). In addition, access to financial resources and appropriate mental health support needs to be improved.

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Therapeutic vaccination targeting CD40 and TLR3 controls melanoma growth through existing intratumoral CD8 T cells without new T cell infiltration

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Abstract

Dendritic cells are potently activated by the synergistic action of CD40 stimulation in conjunction with signaling through toll like receptors, subsequently priming T cells. Cancer vaccines targeting the activation of dendritic cells in this manner show promise in murine models and are being developed for human patients. While the efficacy of vaccines based on CD40 and toll like receptor stimulation has been established, further investigation is needed to understand the mechanism of tumor control and how vaccination alters tumor infiltrating immune cells. In this study we vaccinated mice bearing established murine melanoma tumors with agonistic anti-CD40, polyI:C, and tumor antigen. Vaccination led to increased intratumoral T cell numbers and delayed tumor growth, yet did not require trafficking of T cells from the periphery. Pre-existing intratumoral T cells exhibited an acute burst in proliferation but became less functional in response to vaccination. However, the increased intratumoral T cell numbers yielded increased numbers of effector T cells per tumor. Together, our data indicate that the existing T cell response and intratumoral dendritic cells are critical for vaccination efficacy. It also suggests that circulating T cells responding to vaccination may not be an appropriate biomarker for vaccine efficacy.

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Local control and patterns of failure for “Radioresistant” spinal metastases following stereotactic body radiotherapy compared to a “Radiosensitive” reference

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Abstract

Purpose

The concept of a radioresistant (RR) phenotype has been challenged with use of stereotactic body radiotherapy (SBRT). We compared outcomes following SBRT to RR spinal metastases to a radiosensitive cohort.

Methods

Renal cell, melanoma, sarcoma, gastro-intestinal, and thyroid spinal metastases were identified as RR and prostate cancer (PCA) as radiosensitive. The primary endpoint was MRI-based local failure (LF). Secondary endpoints included overall survival (OS) and vertebral compression fracture (VCF).

Results

From a prospectively maintained database of 1394 spinal segments in 605 patients treated with spine SBRT, 173 patients/395 RR spinal segments were compared to 94 patients/185 PCA segments. Most received 24–28 Gy in 2 fractions (68.9%) and median follow-up was 15.5 months (range, 1.4–84.2 months). 1- and 2-year LF rates were 19.2% and 22.4% for RR metastases, respectively, which were significantly greater (p < 0.001) than PCA (3.2% and 8.4%, respectively). Epidural disease (HR: 2.47, 95% CI 1.65–3.71, p < 0.001) and RR histology (HR: 2.41, 95% CI 1.45–3.99, p < 0.001) predicted for greater LF. Median OS was 17.4 and 61.0 months for RR and PCA cohorts, respectively. Lung/liver metastases, polymetastatic disease and epidural disease predicted for worse OS. 2-year VCF rates were ~ 13% in both cohorts. Coverage of the CTV V90 (clinical target volume receiving 90% of prescription dose) by ≥ 87% (HR: 2.32, 95% CI 1.29–4.18, p = 0.005), no prior spine radiotherapy (HR: 1.96, 95% CI 1.09–3.55, p = 0.025), and a greater Spinal Instability Neoplasia Score (p = 0.013) predicted for VCF.

Conclusions

Higher rates of LF were observed after spine SBRT in RR metastases. Optimization strategies include dose escalation and aggressive management of epidural disease.

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Coronavirus Disease (COVID-19) and Peritoneal Malignancies

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Coronavirus Disease (COVID-19) and Peritoneal Malignancies
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Letter to the Editor
Published: 16 January 2021
Coronavirus Disease (COVID-19) and Peritoneal Malignancies
Sohan Lal Solanki, Mrida AK Jhingan & Avanish P Saklani
Indian Journal of Surgical Oncology (2021)Cite this article

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To the Editor,

As the number of coronavirus disease 2019 (COVID-19) cases are rapidly increasing, hospitals are finding it progressively difficult to accommodate an increased patient load and provide services, both emergent and elective in nature. During this pandemic, it has become essential to ensure adequate allocation of resources for the management of both COVID-19 patients and non-COVID-19 patients, and in particular, patients with cancer. Delayed cancer treatment may lead to an increased risk of disease progression and subsequent, worsening prognosis [1].

The Lancet reported an estimated 59.7% cancer surgeries being postponed in India during the peak 12 weeks of disruption due to the COVID-19 pandemic and lockdown, translating to about 51,100 cancer patients being denied of treatment. This delay in treatment could have led to disastrous consequences, such as increase in the tumor load leading to increased morbidity, inoperability, and eventual palliative intent of treatment [2].

Early studies have demonstrated that cancer patients are more likely to develop a severe form of COVID-19 [3, 4] with a fatality rate up to eight times as high as compared to non-cancer patients [3]. Peri-operative infection with SARS-CoV2 has been associated with high mortality with more than half patients developing post-operative pulmonary complications in the form of pneumonia, requirement of post-operative mechanical ventilation, and acute respiratory distress syndrome [5]. However, no association has been found between chemotherapy and mortality related to COVID-19 [4].

Peritoneal malignancies, both of primary and metastatic origin, benefit greatly from cytoreductive surgeries (CRS) with or without hyperthermic intraperitoneal chemotherapy (HIPEC) [6]. The performance of these potential life-saving surgeries in the current health crisis poses a significant dilemma to treating physicians. Another treatment offered for these malignancies is pressurized intraperitoneal aerosolized chemotherapy (PIPAC). Though its efficacy has not yet been proven, it is hypothesized to increase patient lifespan [3, 7].

Benefits of CRS-HIPEC are well established in peritoneal malignancies with a median disease-free survival of 98 months being achieved in high volume centers for pseudomyxoma peritonei and median survival of more than 50 months after CRS-HIPEC for peritoneal mesotheliomas. On the other hand, median survival of 1 year has been achieved with isolated systemic chemotherapy in peritoneal mesotheliomas [3]. Thus, despite higher complication risks, improved survival benefits with surgery can justify the need to target curative intent with surgical procedures and thus improve the overall outcome of the patients.

These procedures can, however, lead to exhaustion of resources, such as intensive care unit (ICU) beds and ventilators in the post-operative period along with the increased need for blood and blood products in the peri-operative period besides being labor exhaustive with requirement of large teams for peri-operative management [8]. This puts both the healthcare professionals and the patients, at an increased risk of infection with the SARS-CoV2 virus.

The decision to proceed with surgery must be made keeping in mind both risks and benefits associated with a major definitive surgery versus the risks of a lesser aggressive treatment modality with a higher chance of recurrence and progression. Also, the risk of death due to cancer itself must be weighed against the risk of death due to the infection. Shrikhande et al. reported a post-operative morbidity rate of 5.65% with no mortality in patients posted for elective oncosurgeries during the pandemic, with only 6 out of 494 patients testing positive in the post-operative period, none of whom required intensive care [9].

It is recommended that treatment decision for peritoneal malignancies should be made on a case-to-case basis. The patient's disease status, alternative treatment strategies, and institutional policies play important factors in making this decision. Studies early in the course of the pandemic recommended neoadjuvant systemic chemotherapy in cases of peritoneal metastasis from high-grade appendiceal, gastric, and colorectal cancers, along with high-grade mesotheliomas, ovarian cancers, and desmoplastic small round cell tumors [8, 10]. It was also recommended to continue systemic chemotherapy in patients who were completing neoadjuvant chemotherapy and were responding well in an attempt to delay surgery. The RENAPE and BIG-RENAPE groups [3], however, in their recent treatment proposals, make no recommendations of preferring chemotherapy over surgery in view of the COVID-19 pandemic. In cases where CRS with or without HIPEC would be the gold standard of treatment, such as pseudomyxoma peritonei; resectable, malignant peritoneal mesotheliomas; resectable peritoneal metastasis of colorectal origin not responding to chemotherapy; and limited peritoneal metastasis from ovarian carcinomas, surgery has been recommended, albeit with better patient selection criteria. Chemotherapy has been proposed for these indications only when scheduling of surgeries would prove difficult in the current scenario. Enhanced recovery pathways would serve as an essential component when opting for surgical management and would help reduce hospital stay, complication rates, and thus expedite patient turnover [11].

The decision to proceed for surgery must be made keeping two factors in mind, the possibility of achieving complete cytoreduction and a low to moderate peritoneal carcinomatosis index (PCI) [3]. In cases with low tumor burden, surgical resection involved would be comparatively less, with lesser chances of post-operative complications and hence morbidity and mortality. Besides, efforts for better patient selection must take into account the fact that younger patients having few or no comorbidities with lesser disease burden serve as better candidates for these procedures. Besides routine pre-operative assessment before the procedure, additional screening for COVID-19 infection and any chance of inoperability should be ruled out [3].

In conclusion, for resectable peritoneal malignancies, CRS with or without HIPEC can be carried out, with strict patient selection criteria, adequate availability of resources, and sufficient workforce comprising of adequately trained health personnel while adhering to all safety measures. Decision to delay surgery must be considered carefully, keeping in mind the possibility of disease progression in high-grade tumors and an inadequate response to chemotherapy.

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Affiliations
Department of Anaesthesiology, Critical Care and Pain, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, India

Sohan Lal Solanki & Mrida AK Jhingan

Department of Surgical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, India

Avanish P Saklani

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Correspondence to Sohan Lal Solanki.

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Solanki, S.L., Jhingan, M.A. & Saklani, A.P. Coronavirus Disease (COVID-19) and Peritoneal Malignancies. Indian J Surg Oncol (2021). https://doi.org/10.1007/s13193-020-01270-9

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16 January 2021

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Keywords
Cancer
COVID-19
Cytoreductive surgery
Hyperthermic chemotherapy
Pandemic
Peritoneal malignancies
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Time to Revisit a Low-Cost Alternative? Palpation Assessment Nerve Monitoring (PANM) for Recurrent Laryngeal Nerve to Predict Postoperative Vocal Cord Function—a Validation Study Using an In-House Neuromonitoring Device

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Abstract

Neuromonitoring has proved to be a useful technique in reducing nerve injury during thyroid surgery; however, costs continue to limit its use in resource-constrained settings. This study was done to assess the functional integrity of the recurrent laryngeal nerve (RLN) during thyroid surgery using palpation assessment of posterior cricoarytenoid muscle twitch in response to RLN stimulation. Between August 2016 and July 2017, 24 patients with 47 nerves at risk (NARs) underwent thyroid surgery with visual identification and testing of 44 RLNs. The functional integrity of the RLN was checked by stimulation of the RLN. Intraoperative assessment showed 100% sensitivity and positive predictive value in predicting postoperative vocal cord function. The postoperative vocal cord assessment confirmed all 44 nerves tested to be normally functioning. The mean (standard deviation) peak-to-peak amplitude and latency of the CMAP were 0.889 (0.740)/1.336 (1.660) mV and 2.295 (0. 319)/2.217 (0.393) ms for left/right side NARs, respectively, with no statistically significant difference (P > 0.05). Palpation assessment of the posterior cricoarytenoid muscle provides a simple and reliable technique for confirming integrity of the RLN. Combining palpation assessment with CMAP from the inferior constrictor muscle may help reduce potential false negative results. With the use of our in-house built device which is significantly cheaper than the commercial ones, this could be considered a low-cost alternative to current established techniques.

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Sentinel Lymph Node Biopsy in Early Breast Cancer Using Methylene Blue Dye Alone: a Safe, Simple, and Cost-Effective Procedure in Resource-Constrained Settings

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Sentinel lymph node biopsy (SLNB) is done by different techniques in clinically node-negative patients with early breast cancer. In this study, we aim to estimate the identification rates, positivity rates, cost-effectiveness, and outcomes for patients who underwent sentinel node biopsy using methylene blue dye alone. This was a retrospective review of 172 patients with early breast cancer (cT1–3, N0) who underwent SLNB using methylene blue dye alone between January 2014 and December 2018 including their follow-up details until December 2019. The mean age was 51 ± 10.3 (range: 28 to 76) years. There were 63 (36.6%) patients with cT1 tumor, 108 (62.7%) with cT2, and only 1 patient with cT3 tumor. Breast conservation surgery was performed in 62 (36%) while the remaining 110 (64%) underwent simple mastectomy. Sentinel nodes were successfully identified in 165 (95.9%) with a positivity rate of 23.6%. There was no dye-related adverse reactions intra-operatively . The mean duration of follow-up was 26.68 ± 15.9 months (range: 1–60). Chronic arm pain was present in 7 (4%) while none of the patients had lymphedema or restriction of shoulder joint motion. There were no documented axillary nodal recurrences in this cohort. Eight (4.65%) patients were detected to have systemic metastasis. One patient died of brain metastasis from bilateral breast cancer. The mean disease-free survival was 57 months (95% CI: 55–59). Sentinel lymph node biopsy using methylene dye alone is a safe, simple, and cost-effective alternative to isosulfan blue or radio isotope technique in surgical centers with resource constraints.

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Recent Advances in the Management of Penile Cancer: A Contemporary Review of the Literature

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Penile cancer is a rare condition, which mostly affects men in their sixth decade of life. The most common histology is squamous cell carcinoma (SCC), with about half of the cases linked to human papilloma virus (HPV) infection. The lack of awareness and significant social and psychological stigma associated with penile cancer often leads to delays in presentation, diagnosis and management. Timely multidisciplinary care at experienced centers is therefore critical for improving outcomes. For patients with advanced disease, treatment options are limited and prognosis remains poor. Large international efforts are underway to further define the optimal standards of care. Targeted therapies and immune checkpoint inhibitors could potentially play a role in advanced disease and are under evaluation in clinical trials. In this review, we discuss the current management of penile cancer and future directions.

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Characterization and comparison of innate and adaptive immune responses at vaccine sites in melanoma vaccine clinical trials

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The strength and durability of systemic anti-tumor immune responses induced by cancer vaccines depends on adjuvants to support an immunogenic vaccine site microenvironment (VSME). Adjuvants include water-in-oil emulsions with incomplete Freund's adjuvant (IFA) and combinations of toll-like receptor (TLR) agonists, including a preparation containing TLR4 and TLR9 agonists with QS-21 (AS15). IFA-containing vaccines can promote immune cell accumulation at the VSME, whereas effects of AS15 are largely unexplored. Therefore, we assessed innate and adaptive immune cell accumulation and gene expression at the VSME after vaccination with AS15 and compared to effects with IFA. We hypothesized that AS15 would promote less accumulation of innate and adaptive immune cells at the VSME than IFA vaccines. In two clinical trials, patients with resected high-risk melanoma received either a multipeptide vaccine with IFA or a recombinant MAGE-A3 protein vaccine with AS15. Vaccine site biopsies were obtained after one or multiple vaccines. T cells accumulated early after vaccines with AS15, but this was not durable or of the same magnitude as vaccination in IFA. Vaccines with AS15 increased durable expression of DC- and T cell-related genes, as well as PD-L1 and IDO1, suggesting complex activation and regulation of innate and adaptive immune function with AS15. These changes were generally greater with vaccines containing IFA, but IFA induced reduction in myeloid suppressor cells markers. Evidence of tertiary lymphoid structure (TLS) formation was observed with both adjuvants. Our findings highlight adjuvant-dependent changes in immune features at the VSME that may impact systemic immune responses.

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Anti-cancer strategies targeting the autotaxin-lysophosphatidic acid receptor axis: is there a path forward?

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