PIK3CA Mutations in Diffuse Gliomas: An Update on Molecular Stratification, Prognosis, Recurrence, and Aggressiveness

Introduction: PIK3CA is one of the most mutated oncogenes in solid tumors. In breast cancer (ER-positive, HER2-negative), these events represent a predictive biomarker of response to alpelisib. In glioblastomas (GBM), PIK3CA mutations were described as early constitutive events. Here, we investigated PIK3CA mutational profile across glioma molecular subgroups and its relevance during glioma recurrence. Furthermore, PIK3CA mutations’ effect in PI3K pathway, prognosis, and response to therapy was also explored. Material and Methods: Exons 10 and 21 of PIK3CA mutations were evaluated in 394 gliomas and 19 glioma recurrences from Instituto Português de Oncologia Lisboa Francisco Gentil (IPOLFG) and compared with The Cancer Genome Atlas (TCGA) data. TIMER2.0 and NetMHCpan4.1 were used to assess the immune-microenvironment contribution. Results: PIK3CA mutations were identified among all glioma subgroups, although with no impact on their stratification or prognosis. In both cohorts (IPOLFG and TCGA), PIK3CA mutation frequencies in IDH-mutant and IDH-wild-type GBM were similar (IPOLFG: 9% and 3%; TCGA: 8% and 2%). These mutations were not mutually exclusive with PTEN deletion and EGFR amplification. Despite their reduced frequency, we discovered PIK3CA mutations were maintained during glioma recurrence regardless of administered therapies. The immune microenvironment might not contribute to this phenotype as PIK3CA mutations did not influence immune cell infiltration. Conclusions: Despite the absence of a predominant effect in glioma stratification, PIK3CA mutations were maintained during glioma recurrence, possibly contributing to glioma cell survival, representing promising therapeutic targets in recurrent glioma. Nevertheless, understanding the potential synergistic effects between PIK3CA mutations, PTEN deletion, and EGFR amplification is pivotal to targeted therapies’ efficiency.

Advances and Controversies With Checkpoint Inhibitors in Bladder Cancer

Immune checkpoint inhibitors have revolutionized the treatment of bladder urothelial cancers and have wide application in almost all disease states. Although several drugs have initially been shown to be beneficial in the second-line metastatic setting, there are still ongoing controversies and debate, including voluntary withdrawals of durvalumab and atezolizumab, along with the approval of agents in the first-line setting in the cisplatin-ineligible state based on inconsistent confirmatory phase III trials. As novel immunotherapy drugs are discovered and studied in various phases of clinical trials, these agents will continue to change the treatment landscape for bladder cancer patients. This review will discuss current available evidence and information and key pivotal trials using checkpoint inhibitors in bladder cancer.

Is Cytoreductive Surgery Possible in Cervical Cancer Peritoneal Carcinomatosis?

Background: The number of cases of cervical cancer with recurrence and peritoneal carcinomatosis is limited. In our study, we aimed to present the results of cytoreductive surgery hyperthermic intraperitoneal chemotherapy treatment and its 3-year early period results in patients with peritoneal metastases due to cervical cancer. Methods: Data of 306 patients who had undergone cytoreductive surgery hyperthermic intraperitoneal chemotherapy between May 2016 and 2021 because of intra-abdominal metastases were collected prospectively and evaluated retrospectively. Ten cases who had undergone cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy due to cervical peritoneal carcinomatosis were included in this study. Results: Average time of operation was 5 (range = 3-6) hours, mean average of peritoneal carcinomatosis index score was 12.3 (range = 7-36), and mean average of completeness of cytoreduction score was 1 in 2 patients and 0 in 8 patients. No mortality was recorded in 30 days postoperatively. Four patients relapsed and died because of pneumonia, coronavirus disease, pulmonary embolism, and terminal illness. These patients died at 2, 5, 6, and 12 months, respectively. Six patients are still alive and early period tumor relapse has not been reported during their follow-ups. Conclusions: This study has a limited number of patients and the results are early period results. The follow-up of patients were not long term. Therefore, it is hard to say that cytoreductive surgery hyperthermic intraperitoneal chemotherapy could be of any benefit looking at the results. Long-term results should be waited. Also, multicentered randomized cohort study with large sample size is required to evaluate this invasive procedure.

Clinical Impact of COVID-19 Outbreak on Cancer Patients: A Retrospective Study

Background: Coronavirus disease (COVID-19), an acute respiratory syndrome caused by a novel severe acute respiratory syndrome coronavirus (SARS-CoV-2), has rapidly spread worldwide, significantly affecting the outcome of a highly vulnerable group such as cancer patients. The aim of the present study was to evaluate the clinical impact of COVID-19 infection on outcome and oncologic treatment of cancer patients. Patient and methods: We retrospectively enrolled cancer patients with laboratory and/or radiologic confirmed SARS-CoV-2 infection, admitted to our center from February to April 2020. Descriptive statistics were used to summarize the clinical data and univariate analyses were performed to investigate the impact of anticancer treatment modifications due to COVID-19 outbreak on the short-term overall survival (OS). Results: Among 61 patients enrolled, 49 (80%) were undergoing anticancer treatment and 41 (67%) had metastatic disease. Most patients were men; median age was 68 years. Median OS was 46.6 days (40% of deaths occurred within 20 days from COVID-19 diagnosis). Among 59 patients with available data on therapeutic course, 46 experienced consequences on their anticancer treatment schedule. Interruption or a starting failure of the oncologic therapy correlated with significant shorter OS. Anticancer treatment delays did not negatively affect the OS. Lymphocytopenia development after COVID was significantly associated with worst outcome. Conclusions: COVID-19 diagnosis in cancer patients may affect their short-term OS, especially in case of interruption/starting failure of cancer therapy. Maintaining/delaying cancer therapy seems not to influence the outcome in selected patients with recent COVID-19 diagnosis.

Detection of EGFR Activating and Resistance Mutations by Droplet Digital PCR in Sputum of EGFR-Mutated NSCLC Patients

Background: Proof of the T790M resistance mutation is mandatory if patients with EGFR-mutated non-small cell lung cancer (NSCLC) progress under first- or second-generation tyrosine kinase inhibitor therapy. In addition to rebiopsy, analysis of plasma circulating tumor DNA is used to detect T790M resistance mutation. We studied whether sputum is another feasible specimen for detection of EGFR mutations. Methods: Twenty-eight patients with advanced EGFR-mutated NSCLC were included during stable and/or progressive disease. The initial activating EGFR mutations (exon 19 deletions or L858R mutations) at stable disease and at progressive disease (together with T790M) were assessed in simultaneously collected plasma and sputum samples and detected by droplet digital polymerase chain reaction (ddPCR). Results: Activating EGFR mutations were detected in 47% of the plasma samples and 41% of sputum samples during stable disease, and in 57% of plasma samples and 64% of sputum samples during progressive disease. T790M was detected in 44% of the plasma samples and 66% of the sputum samples at progressive disease. In ddPCR T790M-negative results for both specimens (plasma and sputum), negativity was confirmed by rebiopsy in 5 samples. Concordance rate of plasma and sputum for T790M was 0.86, with a positive percent agreement of 1.0 and a negative percent agreement of 0.80. Conclusions: We demonstrated that EGFR mutation analysis with ddPCR is feasible in sputum samples. Combination of plasma and sputum analyses for detection of T790M in NSCLC patients with progressive disease increases the diagnostic yield compared with molecular plasma analysis alone.

Targeting MDSC for Immune-Checkpoint Blockade in Cancer Immunotherapy: Current Progress and New Prospects

Immune-checkpoint blockade (ICB) demonstrated inspiring effect and great promise in anti-cancer therapy. However, many obstacles, such as drug resistance and difficulty in patient selection, limited the efficacy of ICB therapy and awaited to be overcome. By timely identification and intervention of the key immune-suppressive promotors in the tumor microenvironment (TME), we may better understand the mechanisms of cancer immune-escape and use novel strategies to enhance the therapeutic effect of ICB. Myeloid-derived suppressor cell (MDSC) is recognized as a major immune suppressor in the TME. In this review, we summarized the roles MDSC played in the cancer context, focusing on its negative biologic functions in ICB therapy, discussed the strategies targeted on MDSC to optimize the diagnosis and therapy process of ICB and improve the efficacy of ICB therapy against malignancies.

The Role and Clinical Effectiveness of Multiline Chemotherapy in Advanced Desmoplastic Small Round Cell Tumor

Background: A multimodal approach is the standard treatment for desmoplastic small round cell tumor (DSRCT); however, many patients are diagnosed with inoperable disease, which leaves chemotherapy as the only treatment option. There are limited data on the effectiveness of palliative chemotherapy, especially when used after first-line treatment. Here, we evaluated the clinical outcomes of patients with DSRCT treated with multiple lines of chemotherapy. Methods: We reviewed medical records of 14 patients with pathologically confirmed DSRCT at Asan Medical Center between 2004 and 2018. Results: The median age at diagnosis was 25, with males comprising 92.9% of patients. All patients had inoperable disease at presentation and received chemotherapy as the initial treatment. Four patients (28.6%) were treated with surgery, and complete resection was achieved in 1 patient. Median overall survival (OS) was 23.9 months, and 1-, 2-, and 3-year survival rates were 92.9%, 48.6%, and 19.5%, respectively. In patients receiving first- (N = 14), second- (N = 10), and third-line (N = 8) chemotherapy, median time-to-progression was 9.9, 3.5, and 2.5 months, respectively, and the disease control rates were 100%, 88.9%, and 75.0%, respectively. Factors associated with longer OS in the univariable analysis were ⩽2 metastatic sites at presentation (27.0 vs 14.7 months; P = .024) and surgery with intended complete resection (43.5 vs 20.1 months; P = .027). Conclusions: Although advanced DSRCT may initially respond to chemotherapy after first-line treatment, the response becomes less durable as the disease progresses. Individualized treatment decisions focused on palliation should be made.

Prognostic Nomogram for Patients With Pancreatic Ductal Adenocarcinoma of Pancreatic Head After Pancreaticoduodenectomy

Background: The prognosis of patients with pancreatic ductal adenocarcinoma (PDAC) of pancreatic head remains poor, even after potentially curative R0 resection. The aim of this study was to develop an accurate model to predict patients’ prognosis for PDAC of pancreatic head following pancreaticoduodenectomy. Methods: We retrospectively reviewed 112 patients with PDAC of pancreatic head after pancreaticoduodenectomy in Guangdong Provincial People’s Hospital between 2014 and 2018. Results: Five prognostic factors were identified using univariate Cox regression analysis, including age, histologic grade, American Joint Committee on Cancer (AJCC) Stage 8th, total bilirubin (TBIL), CA19-9. Using all subset analysis and multivariate Cox regression analysis, we developed a nomogram consisted of age, AJCC Stage 8th, perineural invasion, TBIL, and CA19-9, which had higher C-indexes for OS (0.73) and RFS (0.69) compared with AJCC Stage 8th alone (OS: 0.66; RFS: 0.67). The area under the curve (AUC) values of the receiver operating characteristic (ROC) curve for the nomogram for OS and RFS were significantly higher than other single parameter, which are AJCC Stage 8th, age, perineural invasion, TBIL, and CA19-9. Importantly, our nomogram displayed higher C-index for OS than previous reported models, indicating a better predictive value of our model. Conclusions: A simple and practical nomogram for patient prognosis in PDAC of pancreatic head following pancreaticoduodenectomy was established, which shows satisfactory predictive efficacy and deserves further evaluation in the future.

Concurrent Chemoradiotherapy With Weekly Low-Dose Cisplatin for Japanese Patients With Head and Neck Squamous Cell Carcinoma

Background: Concurrent chemoradiotherapy (CCRT) with tri-weekly high-dose cisplatin (HDC) is considered the standard regimen. However, due to significant toxicity, various weekly low-dose schedules have been increasingly used. We investigated the tolerability and survival of patients with head and neck squamous cell carcinoma (HNSCC) who underwent CCRT with low-dose weekly cisplatin (LDC) for Japanese population. Methods: A retrospective review was conducted among patients with HNSCC who were treated with CCRT/LDC in our institute. Ninety-five patients who met the criteria were enrolled in this study. We evaluated the cycle and cumulative cisplatin dose, completion rate of radiotherapy, adverse events, and survival outcome. Results: The mean cycles and cumulative cisplatin dose were 4.7 cycles and 187 mg/m2. All patients completed planned dose of radiation without prolonged breaks. Leucopoenia was the most frequent dose-limiting factor and 44% patients developed grade 3 or 4 toxicity. The 2-year overall survival and recurrence-free survival were 93% and 74%, respectively. The significant differences of survival outcomes between the patients with total cisplatin dose (⩾200 mg and <200 mg) or among age distribution (35-55, 56-75, and ⩾76) were not observed. Conclusions: Concurrent chemoradiotherapy/LDC can be safely administered with acceptable toxicity and survival outcome even if the patients with higher age, lower eGFR, and so on.

Nestin Expression as a Diagnostic and Prognostic Marker in Colorectal Cancer and Other Tumors

Lung cancer, colon cancer, breast cancer, and prostate cancer are the leading causes of death in developed countries. Many cancers display non-specific signs in the early stage of the disease, thus making early diagnosis often difficult. We focused on nestin as a new biomarker of possible clinical importance in the early diagnosis and monitoring of cancer. The expression of nestin takes place at an early stage of neural differentiation, but no expression of the nestin gene can be revealed in normal, mature adult tissues. Nestin plays an important role in the development of the central nervous system and contributes to the organization and maintenance of cell shape. Nestin was found to be a marker of microvessel density, which in turn has proven to be a reliable prognostic factor for neoplastic malignancies in patients. Nestin expression correlates with an increased aggressiveness of tumor cells. The role of nestin in cancers of the colon and rectum, liver, central nervous system, lung cancer, breast cancer, melanoma, and other cancers has been reviewed in the literature. Associations between nestin expression and prognosis or drug-resistance may help in disease management. More research is needed to understand the molecular mechanisms of nestin expression and its role in possible targeted therapy.