Raltegravir 1200 mg once daily as maintenance therapy in virologically suppressed HIV-1 infected adults: QDISS open-label trial

Background Raltegravir (RAL) has favorable tolerability and safety profile, with few and manageable drug interactions. The use of RAL 1200 mg once daily (qd) for first-line therapy is well established. We assessed efficacy and safety of RAL 1200 mg qd, as part of triple combined antiretroviral therapy (cART), for maintenance strategy. Methods The QDISS trial (NCT03195452) was a 48-week multicenter, single-arm, open-label study designed to evaluate the ability of 2 NRTIs + RAL 1200 mg qd to maintain virological suppression in HIV-1 infected subjects on a stable cART with 2 NRTIs and a third agent for at least 6 months. The primary endpoint was the proportion of participants with HIV-1 RNA < 50 copies/mL at week 24, by the FDA snapshot algorithm. Results Of 100 participants 91% maintained viral suppression (95% CI: 83.6–95.8) at week 24 and 89% (81.2–94.4) at week 48. At week 24, there was one virological failure, without emergence of resistance-associated mutation and 10 participants had discontinued, 4 because of adverse events (AEs). Over 48 weeks, 7 AEs of grade 3–4 were reported, one possibly study-drug related (spontaneous abortion). BMI remained stable regardless of previous therapy or baseline BMI category. Over 48 weeks, total cholesterol (p = 0.023) and LDL-cholesterol (p = 0.009) decreased, lifestyle and ease subscale significantly improved (p = 0.04). The quality of life and Patients Reported Outcomes (PROs) also improved at W12 (p = 0.007). Conclusion RAL 1200 mg qd as part of a maintenance triple therapy showed a high efficacy in virologically suppressed HIV-1 infected subjects, with good safety profile and improved lipid profile and patient reported outcomes. Trial registration: Clinical trials.gov NCT03195452 and EudraCT 2016-003702-13.

Sirolimus plus prednisolone vs sirolimus monotherapy for kaposiform hemangioendothelioma: a randomized clinical trial

The Kasabach-Merritt phenomenon (KMP) in kaposiform hemangioendothelioma (KHE) is characterized by life-threatening thrombocytopenia and consumptive coagulopathy. This study compared the efficacy and safety of sirolimus plus prednisolone versus sirolimus monotherapy as treatment strategies for KHE with KMP in the largest cohort to date. Participants were randomized to receive either sirolimus in combination with a short course of prednisolone or sirolimus monotherapy for at least 12 months. The primary outcome was defined as achievement of a durable platelet response (platelet count &gt;100×109/L) at week 4. Participants completed efficacy assessments 2 years after the initial treatment. At week 4, a durable platelet response was achieved by 35 of 37 patients given sirolimus and prednisolone compared with 24 of 36 patients given sirolimus monotherapy (difference 27.9%; 95% CI, 10.0% to 44.7%). Compared with the sirolimus monotherapy group, the combination treatment group showed improvements in terms of measures of durable platelet responses at all points during the initial 3-week treatment period, median platelet counts during weeks 1 to 4, increased numbers of patients achieving fibrinogen stabilization at week 4, and objective lesion responses at month 12. Patients receiving combination therapy had fewer blood transfusions and a lower total incidence of disease sequelae than patients receiving sirolimus alone. The frequencies of total adverse events and grade 3-4 adverse events during treatment were similar in both groups. The responses seen in patients with KHE with KMP were profound and encouraging, suggesting that sirolimus plus prednisolone should be considered a valid treatment for KHE with KMP. ClinicalTrial.gov, number NCT03188068

Efficacy, safety and prognostic factors in patients with refractory metastatic colorectal cancer treated with trifluridine/tipiracil plus bevacizumab in a real-world setting

We evaluated the efficacy and safety of trifluridine/tipiracil (TAS-102) plus bevacizumab in treating refractory metastatic colorectal cancer (mCRC) in a retrospective, observational study. Patients refractory or intolerant to standard therapies received TAS-102 (30–35 mg/m2 twice daily on days 1–5 and days 8–12 every 28 days) plus bevacizumab 5 mg/kg on days 1 and 15. Clinical and pathological characteristics, overall response rate (ORR) and disease control rate (DCR), overall survival (OS) and progression-free survival (PFS) data were collected and analysed. Thirty-five patients were treated from July 2019 to October 2021 (median age 64 years). The majority of patients (68.6%) were receiving TAS-102 plus bevacizumab as third-line treatment. Patients received a median of 4 (range 2–15) cycles of treatment. Among 31 patients evaluable for response (88.6%), ORR and DCR were 3.2% and 51.6%, respectively. After a median 11.6 months’ follow-up, median PFS was 4.3 (95% confidence interval [CI] 3.4–5.1) months and median OS was 9.3 (95% CI 6.6–12.1) months. The most common grade 3–4 toxicities were neutropenia, asthenia and nausea/vomiting, and there were no treatment-related deaths. This real-world study confirms the efficacy and safety of TAS-102 plus bevacizumab in patients with refractory mCRC.

Bone Infarct Associated Osteosarcoma: Epidemiologic and Survival Trends

Background Bone tumors are not a frequent occurrence and bone-infarct-associated sarcomas are even rarer. The prognosis of this disease is poor and its treatment remains a challenge. Nevertheless, hardly any analyses in literature report on secondary osteosarcoma (SO) on bone infarct and most of the data available do not provide sufficient details. We evaluated whether this condition could be further characterized and if prognosis could be influenced by the chemotherapy treatment. In particular, we sought to determine (1) the main features of this rare disease; (2) the overall survival (OS) rate; (3) the OS rate associated to chemotherapy treatment; (4) the correspondence between our results and published data in terms of survival. Methods We retrospectively reviewed patients admitted at Rizzoli Orthopedic Institute of Bologna between 1992 and 2018 (1465 total cases of osteosarcoma). We identified a list of 11 cases of SO on bone infarct (cohort 1). We conferred about the epidemiology, surgical and chemotherapy (ChT) treatment and surveillance of infarct-associated osteosarcoma showing the correlation to data present in literature, corresponding to 15 case reports published within 1962-2018 (cohort 2). Results (1) cohort 1 was made of 11 patients: six females and five males, median age was 55 years. Nine (81%) were grade 4, two (19%) grade 3. Tumor predominantly arise on distal femur (64%). Most of patients had localized osteosarcoma at the diagnosis (81%); resection surgery was the elective treatment (73%) followed by amputation (18%). Of 11 patients, seven received also ChT (64%). (2) Five-years OS was 62% (95% CI: 28-84). Median OS was 74 months (95% CI: 12-not reached). The cumulative incidence of cancer-related deaths (CICRD) was 37.7% (95% CI: 11.4-64.5) at 120 months. (3) In the group treated with only surgery OS was 50% at 5 years. For patients treated with any form of ChT, OS was 71% at 5 years (p=0.4773) and hazard ratio (HR) 0.56. The CICRD was 29% (at 2 years of follow-up. Instead, it was of 50% for patients treated only with surgery. (4) Median survival was 74 months and 19 months for cohort 1 and cohort 2 respectively (p=0.09). Data analysis showed a decreased HR for cohort 1 compared to cohort 2 (HR 0.378). Results confirmed also stratifying for age and ChT administration (HR 0.355). Conclusions Based on this work, our opinion is that the choice to undergo the patients to ChT combined to surgery could improve their prognosis.

Neoadjuvant PD-1 Blockade Combined With Chemotherapy Followed by Concurrent Immunoradiotherapy in Locally Advanced Anal Canal Squamous Cell Carcinoma Patients: Antitumor Efficacy, Safety and Biomarker Analysis

BackgroundAnal canal squamous cell carcinoma (ACSCC) is an exceedingly rare malignant neoplasm with challenges in sphincter preservation, treatment toxicities and long-term survival. Little is known concerning the activity of PD-1 antibodies in locally advanced ACSCC. This study reports on the efficacy and toxicities of a neoadjuvant PD-1 blockade combined with chemotherapy followed by concurrent immunoradiotherapy in ACSCC patients, and describes biomarkers expression and mutation signatures.MethodsIn this cohort study, patients were treated as planned, including four cycles of neoadjuvant PD-1 antibody toripalimab combined with docetaxol and cisplatin, followed by radiotherapy and two cycles of concurrent toripalimab. Multiplex immunofluorescence staining (mIHC) with PD-L1, CD8, CD163, Pan-Keratin and DAPI was performed with the pretreatment tumor tissue. Whole exome sequencing was performed for the primary tumor and peripheral blood mononuclear cells. The primary endpoint was the complete clinical response (cCR) rate at 3 months after overall treatment. Acute and late toxicities graded were assessed prospectively.ResultsFive female patients with a median age of 50 years old (range, 43-65 years old), finished treatment as planned. One patient had grade 3 immune related dermatitis. Two patients had grade 3 myelosuppression during neoadjuvant treatment. No severe radiation-related toxicities were noted. Four patients with PD-L1 expression &gt;1% achieved a cCR after neoadjuvant treatment. and the other patient with negative PD-L1 expression also achieved a cCR at 3 months after radiotherapy. All the patients were alive and free from disease and had a normal quality of life, with 19.6-24 months follow up. Inconsistent expression of PD-L1 and CD163 was detected in 3 and 5 patients, respectively. TTN, POLE, MGAM2 were the top mutation frequencies, and 80 significant driver genes were identified. Pathway analysis showed enrichment of apoptosis, Rap1, Ras, and pathways in cancer signaling pathways. Eight significantly deleted regions were identified.ConclusionsThis small cohort of locally advanced ACSCC patients had quite satisfactory cCR and sphincter preservation rate, after neoadjuvant PD-1 antibody toripalimab combined with chemotherapy followed by concurrent immunoradiotherapy, with mild acute and long-term toxicities.

Cisplatin and Irinotecan as First-Line Chemotherapy for Previously Untreated Metastatic Thymic Carcinoma: Updated Analysis

Platinum-based chemotherapy is the de facto standard treatment for metastatic or unresectable thymic carcinoma. The optimal chemotherapy regimen has not yet been determined, including whether this should be combined with a second- or third-generation anti-cancer agent. We retrospectively evaluated the data of patients with metastatic or unresectable thymic carcinoma who were treated with a combination of cisplatin and irinotecan as first-line chemotherapy between 2002 and 2021 (trial registration UMIN000012175). The primary endpoint was response rate according to the RECIST criteria version 1.1. Secondary endpoints were disease control rate, progression-free survival (PFS), overall survival (OS), and toxicity (adverse events). Some patients analyzed in this study were also included in the previous trial, which was terminated early. For this analysis, we included 18 patients with a median age of 56 years and an Eastern Cooperative Oncology Group performance status of 0 or 1. All patients had clinical stage IVa or IVb thymic carcinoma according to the Masaoka-Koga staging system. The response rate was 44% and the disease control rate was 89%. The median PFS was 8.4 months (95% confidence interval (CI): 2.7–11.6 months) and the median OS was 45.6 months (95% CI: 15.7–69.1 months). Grade 3 or worse hematological toxicity was observed in 5 patients and grade 3 or worse non-hematological toxicity was observed in 3 patients. None of the patients developed febrile neutropenia, and no treatment-related deaths occurred. Thus, the combination of cisplatin and irinotecan as first-line chemotherapy for metastatic thymic carcinoma showed efficacy and acceptable toxicity.

Immune-related adverse events caused by combined immune checkpoint inhibitor therapy with nivolumab and ipilimumab for lung cancer

It has been less than a decade since immune checkpoint inhibitors became the mainstay of lung cancer treatment, and 2020 saw the advent of the era of complex immune checkpoint inhibitors. Although clinical trials have shown that the therapeutic effects of complex immune checkpoint inhibitors are favorable, they are associated with an increase in adverse events. The use of combined immune checkpoint inhibitors in clinical practice has progressed slowly, and the frequency and types of adverse events they cause remain unclear. Here we report the adverse events of six patients with lung cancer treated with regimens containing nivolumab and ipilimumab in 2021. Four of the six patients had grade 3 or higher adverse events, including one patient with lung injury and one patient with skin injury, both of whom died. The timing and nature of the adverse events were difficult to predict.

Short-term outcomes associated with temozolomide or PCV chemotherapy for 1p/19q-codeleted WHO grade 3 oligodendrogliomas: a national evaluation

Background The optimal chemotherapy regimen between temozolomide and procarbazine, lomustine, and vincristine (PCV) remains uncertain for W.H.O. grade 3 oligodendroglioma (Olig3) patients. We therefore investigated this question using national data. Methods Patients diagnosed with radiotherapy-treated 1p/19q-codeleted Olig3 between 2010-2018 were identified from the National Cancer Database. The OS associated with first-line single-agent temozolomide vs. multi-agent PCV was estimated by Kaplan-Meier techniques and evaluated by multivariable Cox regression. Results 1,596 radiotherapy-treated 1p/19q-codeleted Olig3 patients were identified: 88.6% (n=1,414) treated with temozolomide and 11.4% (n=182) with PCV (from 5.4% in 2010 to 12.0% in 2018) in the first-line setting. The median follow-up was 35.5 months (interquartile range [IQR] 20.7-60.6 months) with 63.3% of patients alive at time of analysis. There was a significant difference in unadjusted OS between temozolomide (5yr-OS 58.9%, 95%CI: 55.6-62.0) and PCV (5yr-OS 65.1%, 95%CI: 54.8-73.5; p=0.04). However, a significant OS difference between temozolomide and PCV was not observed in the Cox regression analysis adjusted by age and extent of resection (PCV vs. temozolomide HR 0.81, 95%CI: 0.59-1.11, p=0.18). PCV was more frequently used for younger Olig3s, but otherwise was not associated with patient’s insurance status or care setting. Conclusions In a national analysis of Olig3s, first-line PCV chemotherapy was associated with a slightly improved unadjusted short-term OS compared to temozolomide; but not following adjustment by patient age and extent of resection. There has been an increase in PCV utilization since 2010. These findings provide preliminary data while we await the definitive results from the CODEL trial.

Triage by PAX1 and ZNF582 methylation in women with cervical intraepithelial neoplasia grade 3: a multicenter case-control study

Background The colposcopy-conization inconsistency is common in women with cervical intraepithelial neoplasia grade 3 (CIN3). No adequate method has been reported to identify the final pathology of conization. In this study, we explored the ability of PAX1 and ZNF582 methylation to predict the pathological outcome of conization in advance. Methods This was a multicenter study and included 277 histologically confirmed CIN3 women who underwent cold knife conization (CKC) from January 2019 to December 2020. The methylation levels of PAX1 (PAX1m) and ZNF582 (ZNF582 m) were determined by quantitative methylation specific PCR (qMSP) and expressed in ΔCp. Receiver-operating characteristic (ROC) curves were used to evaluate predictive accuracy. Results The final pathological results in 48 (17.33%) patients were inflammation or low-grade squamous intraepithelial lesion (LSIL), 190 (68.59%) were high grade squamous intraepithelial lesion (HSIL) and 39 (14.08%) were squamous cervical cancer (SCC). PAX1 m and ZNF582 m increased as lesions progressed from inflammation/LSIL, HSIL to SCC. PAX1 and ZNF582 methylation yielded better prediction performance compared to common screening strategies, whether individually or combined. ΔCpZNF582 ≥19.18). A 6.53-fold increase in SCC risk was observed in patients with elevated ZNF582 methylation (ΔCpZNF582 &lt; 7.09). Conclusion DNA Methylation would be an alternative screening method to triage and predict the final outcome of conization of the CIN3 cases.

Return to Work Within Four Months of Grade 3 Diffuse Axonal Injury

Neuroprognostication following diffuse axonal injury (DAI) has historically relied on neuroimaging techniques with lower spatial resolution and contrast than techniques currently available in clinical practice. Since the initial studies of DAI classification and prognosis in the 1980s and 1990s, advances in neuroimaging have improved detection of brainstem microbleeds, a hallmark feature of Grade 3 DAI that has traditionally been associated with poor neurologic outcome. Here, we report clinical and radiologic data from two patients with severe traumatic brain injury and grade 3 DAI who recovered functional independence and returned to work within 4 months of injury. Importantly, both patients were scanned using 3 Tesla MRI protocols that included susceptibility-weighted imaging (SWI), a technique that provides enhanced sensitivity for detecting brainstem microbleeds. These observations highlight the importance of developing approaches to DAI classification and prognosis that better align with contemporary neuroimaging capabilities.