Immunohistochemical Evaluation of Renal Biopsy with Anti-PD1 and p53 to Solve the Dilemma between Platinum- and Pembrolizumab-Induced AKI: Case Report and Review.

Introduction: The combination therapy of platinum and pembrolizumab looks like a promising treatment in advanced non-small-cell lung cancer. However, both platinum-based chemotherapy and pembrolizumab can lead to AKI. AKI can occur due to acute tubular necrosis or interstitial nephritis. It is essential to identify the drug responsible for renal damage. For this purpose, we used new immunohistochemistry markers (p53 and anti-PD1 analysis). Case Description: A 77-year-old female patient with advanced non-small-cell lung cancer received the PD-1 inhibitor pembrolizumab and platinum-based chemotherapy carboplatin. The patient, after 60 days, experienced AKI. A kidney biopsy was performed, and two new immunohistochemical techniques for p53 (experimental markers of ATN from platinum) and anti-PDL1 (experimental markers of PD-1 inhibitors nephritis) were employed. Renal biopsies revealed severe tubular damage. No infiltration was detected, and the immunohistochemical assessment of PDL-1 was negative. The expression of p53 was positive. The renal biopsy suggested platinum-induced acute tubular necrosis. After discontinuing steroids and reducing carboplatin, the patient continued with pembrolizumab, and their renal function returned to normal within two months. Discussion: Combining checkpoint inhibitors and platinum-based therapies may result in AKI. The standard method of examining kidney tissue may not provide sufficient information about the effects of these drugs on the kidneys. To address this issue, we recommend incorporating an assessment of the analysis of the expression of PDL1 and p53. This personalized approach will help identify the best treatment option for the patient while ensuring the best possible cancer treatment plan.

First-Line Pharmacotherapies and Survival among Patients Diagnosed with Non-Resectable NSCLC: A Real-Life Setting Study with Gender Prospective.

(1) Purpose: To describe first-line pharmacotherapy and overall survival in non-resectable non-small cell lung cancer (nrNSCLC) patients by gender. (2) Methods: Incident cases of nrNSCLC recorded between 2009 and 2019 (cohort entry) in the pathology registry of the regional administrative healthcare database of Tuscany were identified. Records of antineoplastic therapies delivered up to 4 months following cohort entry were classified as chemotherapy, target therapies, immunotherapies, and undefined monoclonal antibodies. First-line treatment and survival of patients receiving drug treatment was described. Analyses were stratified according to histology, gender, and cohort entry year. (3) Results: 4393 incident cases of nrNSCLC were included. Women with non-squamous-NSCLC received target-therapy more frequently than men (14.9% vs. 6.5%). Immunotherapy incidence of use varied between 3.8% (2017) and 9.1% (2019). The 2-year survival rate increased over time: for non-squamous-NSCLC, it was 22.3% (2009-2011) and 30.6% (2018-2019), while for squamous-NSCLC, it was 13.5% and 22.5%, respectively. After multivariate analysis, a low reduction in mortality risk in 2018-2019 vs. 2009-2011 was found (non-squamous: HR: 0.95 CI95%: 0.92-0.98; squamous: HR: 0.94 CI95%: 0.90-0.98). Among non-squamous NSCLC, median survival was longer in women than in men (389 vs. 276 days). (4) Conclusion: In light of sex-related biomolecular differences, among non-squamous NSCLC, women received target-therapy more frequently than men. Survival seemed to slightly improve over the study period for both histologies, despite a poor reduction in mortality risk was still observed.

CEA and CA19.9 as early predictors of progression in advanced/metastatic colorectal cancer patients receiving oxaliplatin-based chemotherapy and bevacizumab.

We evaluated the changes of the tumor markers CEA and CA19.9 as early predictors of progression in metastatic colorectal cancer (mCRC) patients participating in a clinical study and receiving chemotherapy and bevacizumab (Bev). Seventy-two patients had high baseline CEA or CA19.9 serum levels. By ROC analyses, the areas under the curves were 0.83 for variable CEA cutoff values for distinguishing progressive disease (PD) versus stable disease (SD)/partial remission (PR)/complete remission (CR), and 0.80 for variable CA19.9 cutoff values for distinguishing PD versus SD/PR/CR. Rises in CEA and CA19.9 may early signal the occurrence of progression in mCRC patients receiving chemotherapy and Bev.

Bevacizumab and weekly docetaxel in patients with metastatic castrate-resistant prostate cancer previously exposed to docetaxel.

Background. The aim of this paper was to evaluate the activity and tolerability of docetaxel (D) and bevacizumab (Bev) in patients with metastatic castrate-resistant prostate cancer (CRPC) previously exposed to D. Methods. Treatment consisted of D 30 mg/m(2) i.v. for four consecutive weekly administrations followed by a 2-week rest interval, in addition to Bev 5 mg/kg i.v. every 2 weeks. Results. Forty-three patients were enrolled: a PSA response was observed in 27 patients (62.7%, 95% CI: 0.41 to 0.91), and a palliative response was achieved in 31 patients (72.1%, 95%CI: 0.48 to 1.02). After a median followup of 11.3 months, only five patients had died. The regimen was generally well tolerated. Conclusion. Weekly D + biweekly Bev seems to be an effective and well-tolerated treatment option for patients with metastatic CRPC previously exposed to D-based chemotherapy.

Osteonecrosis of the jaw in patients with cancer who received zoledronic acid and bevacizumab.

BACKGROUND: The authors investigated the incidence of and risk factors for osteonecrosis of the jaw (ONJ) in patients with metastases to the bone who received the bisphosphonate agent zoledronic acid (ZOL) and chemotherapy combined with the antiangiogenic agent bevacizumab (BEV). METHODS: The authors evaluated 59 participants (34 with breast cancer and 25 with nonsmall-cell lung cancer). All of the participants received 4 milligrams of ZOL via intravenous (IV) infusion every four weeks and 15 mg per kilogram of BEV every three weeks. They conducted a dental examination in participants at baseline and every three months until the patients died or were lost to follow-up. If needed, participants received periodontal disease treatment and underwent tooth extraction before they started receiving ZOL and BEV. RESULTS: The median time the participants received ZOL therapy was 18.8 months (range, 3.1-28.9 months); 36 participants (61.0 percent) received ZOL therapy for more than one year. The median time participants received BEV therapy was 16.7 months (range, 2.8-29.6 months). None of the participants required dentoalveolar surgery while undergoing cancer treatment. After a median follow-up period of 19.7 months, none of the participants developed bisphosphonate-related ONJ. CONCLUSIONS AND CLINICAL IMPLICATIONS: ZOL combined with BEV did not predispose to ONJ participants with cancer that had metastasized to the bone who underwent a baseline dental examination and preventive dental measures. The study results must be considered in the context of the study's protocols and the follow-up period.

Effects of intravenous zoledronic acid and oral ibandronate on early changes in markers of bone turnover in patients with bone metastases from non-small cell lung cancer.

BACKGROUND: The aim of this study was to assess the early effects of zoledronic acid (ZOL) and oral ibandronate (IBA) on the bone resorption marker s-CTX (serum C-telopeptide of collagen type I) and the bone formation marker B-ALP (bone-alkaline phosphatase) in patients with bone metastases from non-small cell lung cancer (NSCLC). METHODS: Fifty-five patients with at least one site of bone metastasis secondary to NSCLC were randomly assigned to receive intravenous ZOL 4 mg every 4 weeks, or oral IBA 50 mg/day. RESULTS: At 1 month of treatment, s-CTX was reduced by 54.8% (95% CI 40.4-59.8%) in the ZOL group (26 evaluable patients) compared with 38.2% (95% CI 29.8-48.7%) in the oral IBA group (27 evaluable patients) (p = 0.03). At 3 months, s-CTX was reduced by 72.6% (95% CI 58.6-71.3%) in the ZOL group, compared with 66.4% (95% CI 54.3-79.5%) in the oral IBA group (p = 0.22). Both bisphosphonates similarly decreased the bone marker B-ALP at 1 month (ZOL 24.7%, 95% CI 3.6-39.5%, and IBA 24.2%, 95% CI 2.8-43.4%) and 3 months (ZOL 28.6%, 95% CI +2.8-43.3%, and IBA 24.2%, 95% CI 3.2-47.4%). Both bisphosphonates were well tolerated. CONCLUSION: Considering the changes in bone markers, ZOL and oral IBA show comparable efficacy in patients with NSCLC and bone metastases.

Thymidine phosphorylase expression in metastatic sites is predictive for response in patients with colorectal cancer treated with continuous oral capecitabine and biweekly oxaliplatin.

The primary objective of this study was to determine the activity and safety profile of biweekly oxaliplatin combined with continuous oral capecitabine in the first-line treatment of metastatic colorectal cancer. A secondary endpoint was to investigate the correlation between thymidylate synthase and thymidine phosphorylase (TP) expression in metastatic tissues and tumor response. Forty-one patients received oral capecitabine 1331 mg/m every day combined with intravenous oxaliplatin 85 mg/m every 2 weeks. The overall response rate was 58.5% [95% confidence interval (CI): 43.3-73.6%], the median progression-free survival 9.4 months (95% CI: 7.7-11.2 months) and the median survival 22.3 months (95% CI: 16.1-27.5 months). There were no grade 4 toxicities, and grade 3 toxicity was also uncommon. High TP expression in metastatic tissue was significantly associated with response to treatment (P=0.019), and also with a trend towards a better median progression-free survival and overall survival compared with patients expressing low TP (P=0.056; P=0.073). This study suggests that biweekly oxaliplatin and continuous oral capecitabine is an active and well-tolerated chemotherapy regimen in the first-line treatment of metastatic colorectal cancer. Moreover, these findings add to a growing body of evidence that patients with high levels of intratumoral TP expression are the ideal candidates for capecitabine-based chemotherapy.

The role of doxorubicin and epirubicin in the treatment of patients with metastatic hormone-refractory prostate cancer.

Advanced hormone-refractory prostate cancer (HRPC) is characterized by prevalently osteoblastic bone metastases which are what mostly affect these patients' quality of life and make the assessment of response to treatment particularly difficult by commonly used criteria. HRPC cannot be cured by any available therapeutic option, and chemotherapy has to be still considered as a palliative treatment. The anthracyclines doxorubicin (Dox) and epirubicin (Epi), alone or in combination with other agents, have been extensively used in the treatment of HRPC, but controversial results have been reported. The majority of reviewed studies reported a pain reduction in >50% of patients receiving Dox or Epi, suggesting a substantial palliative effect by their use in metastatic HRPC. The weekly schedule of anthracyclines seemed to achieve similar results to the 3-weekly schedule but with a better toxicity profile. Although the toxic adverse effects were usually manageable when anthracyclines were combined with other agents, toxicity was severe by a number of aggressive regimens. Docetaxel is today approved for the treatment of HRPC, and must be considered the standard platform on which new agents may be combined. Given that HRPC includes a heterogeneous group of patients with variable rates of tumour growth, the combination of docetaxel with active agents such as anthracyclines may deserve further clinical investigation.

Neurotoxicity of FOLFOX-4 as adjuvant treatment for patients with colon and gastric cancer: a randomized study of two different schedules of oxaliplatin.

PURPOSE: The dose limiting toxicity of oxaliplatin (l-HOP) is neurotoxicity, which is characterized by an acute neuropathy and a clinically distinct chronic neuropathy. This randomized study evaluated if prolonged l-HOP infusion over the conventional l-HOP schedule was useful in reducing acute and possibly chronic l-HOP induced neurotoxicity in colon and gastric cancer patients receiving l-HOP-based regimen as adjuvant chemotherapy. METHODS: Sixty-four patients were randomly assigned to group A (26 colon and 6 gastric cancer) and to group B (23 colon and 9 gastric cancer). Chemotherapy in both groups consisted of l-HOP 85 mg/m(2) i.v. only on day 1, with leucovorin 100 mg/m(2) i.v. as a 2-h infusion followed by bolus 5-fluorouracil (5-FU) 400 mg/m(2)/day and a 22-h infusion of 5-FU 600 mg/m(2)/day, repeated for two consecutive days every 2 weeks for a maximum of 12 cycles. Patients in group A received l-HOP as a continuous 6-h i.v. infusion, and patients in group B received l-HOP as the conventional 2-h i.v. infusion. RESULTS: The percentage of patients presenting with grade >/=2 neurotoxicity was statistically lower in group A than in group B (28.1% vs. 59.3%: P = 0.02). There was a statistically lower percentage of cycles with grade >/=2 neurotoxicity in group A (6.1%) than in group B (18.5%) (P < 0.001). CONCLUSIONS: This study suggests that l-HOP as a continuous 6-h infusion is useful in preventing and reducing acute l-HOP induced neurotoxicity in patients with colon and gastric cancer receiving FOLFOX-4 regimen as adjuvant treatment.

Continuous oral capecitabine at fixed dose in patients older than 75 years with metastatic colorectal and gastric cancer: a study of the Multidisciplinary Oncology Group on Gastrointestinal Tumors.

The aim of this study was to investigate the safety profile of continuous oral capecitabine at fixed dose in patients older than 75 years, having metastatic colorectal and gastric cancer. Capecitabine was administered at a fixed dose of 2000 mg daily without interruptions. Thirty-four patients were considered evaluable for toxicity and efficacy. The median age was 81 years (range 76-85). The median duration of treatment was 113 days (range 24-238 days). No grade 4 toxicity was observed. One patient had grade 3 nausea and vomiting, and one had grade 3 diarrhea. Partial responses were observed in six patients with colorectal cancer, and in one patient with gastric cancer. This study suggests that continuous oral capecitabine at a fixed daily dose of 2000 mg is well tolerated, and that it allows for the simplification and ease of dosing in elderly patients with metastatic colorectal and gastric cancer.

Capecitabine as third-line treatment in patients with metastatic renal cell carcinoma after failing immunotherapy.

The aim of this study was to evaluate the activity and toxicity of capecitabine as third-line treatment in patients with advanced renal cell carcinoma for whom immunotherapy had failed. Twenty-one patients with metastatic clear renal cell carcinoma were enrolled. Capecitabine was administered orally twice daily at a dosage of 2500 mg/m(2) for 14 days, followed by 7 days of rest. The median number of administered cycles was five (1-13). One patient (4.8%) achieved a remission after eight treatment cycles. Stable disease was observed in nine patients (42.8%), whereas 11 progressed (52.4%). The estimated median time to progression was 3.6 months (confidence interval: 1.4 to 5.2). The estimated median overall survival was 7.2 months (confidence interval: 4.6 to 8.8). The regimen was well tolerated and no unexpected toxic effects were observed. Capecitabine as third-line treatment showed a favourable toxicity profile, but exhibited low activity in patients with advanced renal cell carcinoma after failing immunotherapy.

Weekly high-dose calcitriol and docetaxel in patients with metastatic hormone-refractory prostate cancer previously exposed to docetaxel.

OBJECTIVE: To evaluate the activity and tolerability of weekly high-dose calcitriol and docetaxel in patients with metastatic hormone-refractory prostate cancer (HRPC) previously exposed to docetaxel, as patients who progress after docetaxel treatment might be considered for second-line chemotherapy, but with no standard salvage therapy available we hypothesised that high-dose calcitriol might restore sensitivity to chemotherapy. PATIENTS AND METHODS: The study comprised 26 patients who had progressed after first-line treatment with docetaxel-based chemotherapy had failed. Treatment cycles consisted of calcitriol (32 microg orally as 0.5 microg tablets) on day 1 and docetaxel (30 mg/m(2) intravenous) on day 2, administered for six consecutive weeks followed by a 2-week rest interval for a maximum of 24 cycles. RESULTS: There was a response in prostate-specific antigen (PSA) level in eight patients (31%); seven (27%) had a stable PSA level for >/= 12 weeks. The median time to PSA progression was 4.2 months and the median survival was 9.3 months. The regimen was generally well tolerated; there was grade 2 hypercalcaemia, probably related to calcitriol, in one patient after six treatment cycles. CONCLUSION: Weekly high-dose calcitriol and docetaxel seems to be an effective and well-tolerated treatment option for patients with metastatic HRPC previously exposed to docetaxel-based chemotherapy.