The value of virtual molecular tumor boards for informed clinical decision-making.

Genomic profiling and other new technologies have increased the volume and complexity of information available for guiding clinical decision-making in precision oncology. Consequently, there is a need for multidisciplinary expert teams, in the form of molecular tumor boards (MTBs), who can translate this information into a therapeutic plan, including matching patients to suitable clinical trials. Virtual MTBs (vMTBs) can help to overcome many of the challenges associated with in-person MTBs, such as limited time availability, access to appropriate experts or datasets, or interactions between institutions. However, real-world experience from vMTBs is lacking. Here, we describe oncologists' vMTB experiences and the value of working with multicenter and/or multinational vMTBs. We also address knowledge gaps and barriers that could affect the implementation of vMTBs in routine clinical practice. Case studies from Argentina, Turkey, and Portugal illustrate the value of informed clinical decision-making by vMTBs, including expansion of therapeutic options for patients, faster time to treatment, and the resulting improvement in patient outcomes or impact of vMTB discussions on patients. With the uptake of comprehensive genomic profiling and the evolution of some cancers now being conceptualized as a collection of rare diseases with small patient populations based on molecular profiling, the importance of MTBs has increased in modern cancer management. However, an adjustment in clinical decision-making by healthcare professionals is required and evidence of the added value of vMTBs is lacking. Existing vMTBs and recommendations from participating oncologists could point toward a structured evaluation and analysis of this new platform.

A cross-sectional survey of the diagnosis and management of bone metastasis in breast cancer patients in Turkey.

PURPOSE: This study aimed to report the practice of managing breast cancer with bone metastasis in Turkey and to determine the adherence to the British Association of Surgical Oncology (BASO) guidelines. METHODS: This multicenter, cross-sectional epidemiological survey was conducted in 38 centers across Turkey. Data from 1,026 breast cancer patients with bone metastases (mean age 54.0 ± 11.9 years) were analyzed. RESULTS: Over 30 % of patients had a diagnosis of metastatic breast cancer (stage IV) at the time of primary diagnosis. The imaging modalities used for diagnosing bone metastases were bone scintigraphy (57.8 %), radiography (22.8 %), and bone survey (4.4 %). Tumor markers were detected in 94.9 %, and markers of bone metabolism were measured in 90.4 % of patients. A total of 3.5 % of patients underwent surgery for bone metastasis, 26.4 % underwent palliative chemotherapy (most commonly docetaxel + capecitabine), and 56.5 % endured radiotherapy. Most patients (96 %) also received bisphosphonate. Radiography, bone scintigraphy, and CT were the main imaging tools used for postoperative follow-up of bone metastasis. Our results were >95 % in line with the BASO guidelines for the management of bone metastasis, except that interventional procedures, such as biopsy, were applied less frequently in our survey. CONCLUSIONS: The diagnosis and management practices of breast cancer with bone metastasis in Turkey were generally compatible with international guidelines. However, the awareness and knowledge of physicians on the current guidelines should be increased, and equipment for the appropriate interventional procedures should be provided in every clinic to obtain optimal and standard management of bone metastases.

Navigating uncharted territory: a case report and literature review on the remarkable response to personalized crizotinib containing combinational therapy in a pazopanib refractory patient with novel alterations.

This paper presents a patient with a novel Ig-like-III domain fibroblast growth factor receptor (FGFR2) alteration (W290_P307>C) along with CDKN2A/B alterations and a cadherin 1 (CDH1) alteration. Initial responsiveness to pazopanib monotherapy was encouraging, yet progression occurred after 7.5 months. Following progression, the molecular tumor board recommended a combination therapy approach comprising pazopanib, crizotinib, and palbociclib to target all of the changed pathways at the same time. Pazopanib was chosen to specifically target the FGFR2 alteration, while crizotinib was selected due to its potential synthetic lethality with the CDH1 alteration. In addition, the CDK4/6 inhibitor palbociclib was administered to address the CDKN2A/B alterations. The patient exhibited a remarkable and sustained response to this innovative combination. This case not only underscores the potential of tyrosine kinase inhibitors, exemplified by pazopanib, as a viable alternative for patients without access to pan-FGFR inhibitors, but it also emphasizes their efficacy beyond commonly detected point mutations and rearrangements. Notably, the outstanding response to combination therapy, including crizotinib, in a patient with a CDH1 alteration, further substantiates the preclinical evidence of synthetic lethality between crizotinib and CDH1 alterations. To our knowledge, this represents the first clinical evidence demonstrating the efficacy of crizotinib in a patient with a CDH1 alteration. Through careful dosage adjustments and consideration of individualized genomic information, this case exemplifies the power of personalized medicine in achieving favorable treatment outcomes.

Durable radiologic and molecular complete response following nivolumab in an HNSCC patient with UV signature and HIV.

Cancer patients living with HIV (CPLWH) may experience increased mortality risk. Furthermore, they have been historically excluded from clinical trials due to safety concerns. Our patient with squamous cell carcinoma of the lower lip received radiotherapy and platinum-based chemotherapy but declined by multiple centers due to his accidental HIV status. Genomic profiling revealed CDKN2A/B, PBRM1, TP53, and TERT alterations corresponding to UV signature, and high tumor mutational burden with positive PD-L1 staining. Accordingly, we report a durable radiologic and molecular complete response upon nivolumab plus IVC and antiretroviral therapy (ART). We demonstrated the safety and efficacy of ICIs, and feasibility of managing adverse events caused by antitumor, antiviral, and integrative therapies.

PARP inhibitor combinations with high-dose vitamin C in the treatment of Ewing sarcoma: two case reports and mechanistic overview.

Ewing's sarcoma (ES) is a bone and soft tissue tumor that mainly occurs at a young age. The underlying cause of Ewing's sarcoma is the formation of fusion proteins between FET family genes and ETS family genes. Tumors with FET/ETS fusion genes can have defects in the DNA damage response and are sensitive to PARP inhibitors (PARPi). However, several studies have shown that PARPi alone is not sufficient to induce a meaningful antitumor response and that combinations of DNA-damaging agents with PARPi are required to achieve efficacy. Accordingly, preclinical studies have reported dramatic responses to PARPi treatment in combination with DNA-damaging agents such as temozolomide or irinotecan. Similarly, it has been previously reported that by generating reactive oxygen species, high-dose intravenous vitamin C (IVC) can induce DNA damage. This suggests that the combination of IVC with PARPi may increase genotoxic stress and enhance the antitumor response. In addition, unlike chemotherapeutic agents, IVC induces DNA damage selectively in cancer cells, and the side effects are significantly milder than those of chemotherapy. As ETS fusion-positive ES is deficient in faithful DNA repair, partly due to the interaction between ETS fusion products and PARP1, a PARPi plus IVC seems to be a logical and effective combination for the treatment of ETS fusion-positive ES. This paper reports significant responses to IVC (1-1.5 g/kg) in combination with PARPi (olaparib 300 mg BID or talazoparib 1 mg/day) in two patients with metastatic Ewing's sarcoma. The observations highlight an unmet therapeutic need for patients with advanced metastatic ES. The combination of PARPi with a selective DNA-damaging agent was effective in these cases. This case experience suggests that IVC may be incorporated into PARPi-based therapeutic strategies. Further studies are needed to confirm the efficacy of this combination in the treatment of Ewing sarcoma with ETS fusions.

Combining vitamin C with PARP inhibitors for Ewing sarcoma treatment: mechanistic insights and 2 case studies Ewing's sarcoma is a type of bone and soft tissue tumor that commonly affects young people and it is often resistant to conventional therapy. In this study, clinical cancer scientists and oncologists investigated a new approach to treating this cancer by combining high-dose vitamin C with PARP inhibitors. High-dose vitamin C can damage the DNA of cancer cells and PARP inhibitors block the damaged DNA sites so they can't be repaired and eventually this leads to cancer cells dying. The researchers found that when these two treatments were used together, there were significant improvements in two patients with advanced Ewing's sarcoma. Importantly, the combination led to fewer side effects compared to standard chemotherapy, suggesting it might be a more tolerable treatment option. These findings suggest that combining high-dose intravenous vitamin C with PARP inhibitors could be a promising treatment for Ewing's sarcoma. More research is needed to confirm these results, but this approach shows potential for helping patients with advanced forms of this type of cancer. This is the first clinical report demonstrating the benefits of using high-dose vitamin C with PARP inhibitors and the study emphasizes the importance of exploring more treatment options for this aggressive type of cancer and suggests that further investigations into this combined approach could lead to more effective and tolerable treatments for Ewing's sarcoma.

Levan enhanced the NF-κB suppression activity of an oral nano PLGA-curcumin formulation in breast cancer treatment.

Chemoresistance (CR) is one of the reasons why chemotherapy agents like Gemcitabine (GMC) remain insufficient in healing breast cancer. Activation of Nuclear Factor-kappa B (NF-κB) during chemotherapy is known as an important factor in the development of CR. The hydrophobic polyphenol curcumin is shown to inhibit NF-κB and hence CR. The aim of this work was to increase the poor bioavailability of curcumin by loading it into the nano-micelles made of Poly (Lactide-co-Glycolide) (PLGA) and levan, where levan as a natural fructose homopolymer makes the nano-micelle more stable and increases its uptake using the fructose moieties. In this study, a PLGA-levan-curcumin formulation (PLC) was designed and characterized. The size was measured as 154.16 ± 1.45 nm with a 67.68% encapsulation efficiency (EE%). The incorporation between the components was approved. Levan made the nano-micelles stable for at least three months, increased their uptake, and led to a 10,000-fold increase in the solubility of curcumin. The enhanced bioavailability of curcumin reduced the NF-κB levels elevated by GMC, both in vitro and in vivo. The PLC showed a complete tumor treatment, while GMC only showed a rate of 52%. These point to the great potential of the PLC to be used simultaneously with chemotherapy.

Combinatorial Therapy of High Dose Vitamin C and PARP Inhibitors in DNA Repair Deficiency: A Series of 8 Patients.

BACKGROUND: Tumor-specific DNA repair defects are ubiquitous in cancerous tissue, which offers a potential for clinical gain to build on these perturbations. Intravenous high-dose vitamin C (IVC) triggers the formation of hydrogen peroxide (H2O2), which contributes to Fenton chemistry producing hydroxyl radicals (-OH), causing selective damage to DNA. Herein, we evaluated the therapeutic response to IVC and PARP inhibitors (PARPi) in combination in 8 patients with a deficiency of homologous recombination repair system (dHRR) in a 3-year period. MATERIAL AND METHODS: Eight patients with progressive stage IV malignancy, who were pre-treated with conventional methods, were admitted to our clinic. Subsequent therapy has included IVC at a dose that was set to be in the range of 1 to 1.5 g/kg, although 1.25 g/kg was dominantly administered. Furthermore, following genomic evaluation, PARPi (niraparib or olaparib or talazoparib) was chosen to be used in combination with IVC which was administered 2 to 4 times a week. RESULTS: In the present study, we achieved partial response in 5 patients and complete response in 3 patients. Grade 2 anemia and fatigue toxicities were observed in some cases, while grade 3 toxicity was not found in any of the patients. CONCLUSION: Our 8 patient case study shows that IVC could be a plausible additional therapy for HRR deficiency. Although the single agent PARPi therapy is effective for metastatic disease, an overall survival (OS) advantage has not been demonstrated. Our results suggest that adding IVC can improve PARPi therapy outcomes. To fully endorse the results stated above, combinatorial therapy of intravenous high dose vitamin C and PARP inhibitors needs to be reviewed in broader cohorts of patients.

Prognostic value of nm23 in gastrointestinal stromal tumors.

AIM/BACKGROUND: nm23 is suggested to represent a new class of metastasis suppressor genes. An inverse correlation between nm23 expression level and metastatic potential has been demonstrated in different malignancies. This study evaluated the prognostic value of nm23 in gastrointestinal stromal tumors (GISTs). METHODS: Immunohistochemical expression level of nm23 was studied in a total of 32 patients with localized GISTs. The relationship between the expression level of nm23 and patient outcome was investigated. RESULTS: A tumor size of 10 cm or more and a mitotic rate of 10 or more per 50 high-power fields were not significantly associated with the metastasis risk (p = 0.60 and 0.55, respectively). Tumors with high expression of nm23 tended to have significantly lower metastatic potential (p = 0.02). The median survival was significantly longer in patients with high expression of nm23 (p = 0.007). CONCLUSION: These results suggest that expression level of nm23 may be considered as a prognostic predictor in GISTs. Future studies with larger patient numbers will be essential to confirm the prognostic significance of nm23 in patients with GIST.

Protective effect of amifostine against toxicity of paclitaxel and carboplatin in non-small cell lung cancer: a single center randomized study.

AIM: In this study we determined the protective role of amifostine against the side effects of the combination of paclitaxel and carboplatin in patients with non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Chemo-naive patients with NSCLC were eligible. Thirty-eight patients were randomized to receive paclitaxel 175 mg/m2 and carboplatin AUC = 6 with amifostine 910 mg/m2 (group B) or chemotherapy alone (group A). The occurrences of hematologic, neurologic, cardiologic toxicities, and ototoxicity were evaluated. RESULTS: All patients completed the six scheduled cycles of therapy. A total of 114 cycles of chemotherapy was given in both groups. Neutropenia grade 3-4 was observed in 11 cycles (9.6%) in group A and 19 cycles (16.6%) in group B (p = 0.16). Paresthesia grade 1 or 2 was observed in 18 of 19 patients of group A and in 8 of 19 patients of group B, following the sixth cycle of chemotherapy (p = 0.018). Two patients of group B and nine patients of group A suffered from sensory motor impairment grade 2 (p = 0.029). There was no clinical evidence in any patient for deterioration in cardiac function. Asymptomatic and transient sinus bradycardia or ventricular premature beats developed in four patients. None of the patients reported vertigo, tinnitus, or hearing loss. CONCLUSION: The addition of the amifostine to the combination of paclitaxel and carboplatin may prevent or reduce the incidence of neurotoxicity in the treatment of NSCLC. Amifostine does not appear to have a preventive role in neutropenia.

Evaluation of the effects of Helicobacter pylori eradication therapy on gastric antral epithelial hyperproliferation: a prospective six-month follow-up study.

BACKGROUND/AIMS: H. pylori-induced hyperproliferation of the gastric epithelium may have a critical role in gastric carcinogenesis. H. pylori-related hyperproliferation and reversibility of hyperproliferation after eradication therapy is still controversial. Therefore, we have evaluated the effects of H. pylori and its eradication on gastric antral epithelial proliferation. METHODOLOGY: A total of 32 H. pylori-positive and 22 H. pylori-negative subjects were enrolled into the study. Triple eradication therapy was given to the H. pylori-positive group. Upper endoscopy was repeated one month after the therapy and six months later, antral biopsy specimens were taken in each endoscopy. Biopsy specimens from H. pylori-negative subject were taken at the beginning of the study and sixth months later also. RESULTS: Proliferative index was 40.2% in H. pylori-positive state; it regressed to 27.6% after eradication and six months later the proliferative index was 30.7%. H. pylori-negative group's proliferative index was 25.5% initially and six months later it was 25.6%. The difference between the H. pylori-positive and -negative group was statistically significant (p<0.0001). The difference between H. pylori-positive group's values at the beginning of the study and one month after the eradication was significant (p<0.0001). In addition, the difference between H. pylori-positive group's initial values and those six months after eradication was also significant (p<0.0001). CONCLUSIONS: H. pylori increased the gastric epithelial proliferation and after the eradication therapy proliferative index decreased to control values. H. pylori and the related factors inducing gastric antral hyperproliferation may have an important role in H. pylori-related gastric malignancies.

Comparison of clinical outcomes of different erythropoietin usage strategies.

AIM: There is no comprehensive study that compares the different usage strategies of recombinant human erythropoietin (rHuEPO) in platinum-induced anemia. In order to clarify this issue, we conducted a prospective clinical study. MATERIAL AND METHODS: Seventy-seven patients were studied in three main groups. Group 1 (n = 17) consisted of cancer patients without anemia. These patients received rHuEPO starting from the first chemotherapy cycle. Group 2 (n = 26) consisted of patients whose hemoglobin (Hb) values decreased by at least 1 g/dL after the first cycle of chemotherapy. Group 3 (n = 34) consisted of patients whose Hb values dropped below 10.5 g/dL after the second chemotherapy cycle. Groups 2 and 3 were each divided into two subgroups. In groups 1, 2A and 3A rHuEPO (5000 U/day subcutaneously three times a week) treatment was continued until three weeks after the completion of chemotherapy. In groups 2B and 3B, rHuEPO was given for 12 weeks only. RESULTS: There were no prominent differences between the Hb values of these groups throughout the chemotherapy cycles. Transfusion rates and the number of patients who became anemic were also not different between groups. CONCLUSION: No rHuEPO usage strategies are superior to others in terms of Hb levels and transfusion requirements. The decision as to when rHuEPO is to be added to platinum-containing therapy should be tailored to the health conditions of individual patients.

Treatment of metastatic pancreatic cancer with a combination of gemcitabine and 5-fluorouracil: a single center phase II study.

AIM: To determine the activity and toxicity of a combination of weekly gemcitabine and 5-fluorouracil bolus intravenously in patients with metastatic pancreatic cancer. PATIENTS AND METHODS: Twenty-one patients with previously untreated metastatic pancreatic cancer were included in this phase II study. The schedule was gemcitabine (1000 mg/m2 i.v.) and 5-fluorouracil (500 mg/m2 bolus i.v.) weekly for 3 weeks every month. RESULTS: Four patients (19%) achieved a partial response and three stable disease. A clinical benefit was obtained in 7 patients (33%). Median survival for all the patients was 6 months. The treatment was well tolerated and toxicity was mild. WHO grade 3 leukopenia occurred in 2 (9.5%) patients, grade 3 anemia in 4 (19%) patients, grade 3-4 thrombocytopenia in 4 (19%) patients, grade 1 diarrhea in 1 (4.7%) patient and grade 1 mucositis in 3 (14.2%) patients. CONCLUSION: The weekly administration of gemcitabine combined with 5-fluorouracil bolus i.v. is an active and well-tolerated regimen in metastatic pancreatic cancer. However, its efficacy is relatively limited.

Single-agent irinotecan as second-line treatment for advanced gastric cancer.

AIM: To investigate the activity and toxicity of irinotecan (CPT-11) as a single agent in patients with advanced gastric cancer after failure of previous 5-fluorouracil-based combination chemotherapy. PATIENTS AND METHODS: Sixteen patients with advanced gastric received CPT-11, 350 mg/m2 every 21 days. The median age of the patients was 54.6 years; ECOG performance status was 0-1 in 14 patients and 2 in 2 patients. Dominant metastatic sites included liver, lung, lymph nodes and peritoneum. RESULTS: No complete response was observed. Two patients (12.5%) achieved a partial response to treatment. One patient (6.25%) had a minor response. Ten patients (62.5%) had progressive disease on therapy, and 3 patients (18.75%) had stable disease. The median survival of all 16 patients was 5 months. Grade 3 neutropenia was observed in 3 patients (18.75%), grade 4 thrombocytopenia in 1 patient (6.25%), and grade 3 anemia in 1 patient (6.25%). Three patients (18.75%) suffered from grade 3 diarrhea. CONCLUSIONS: CPT-11 is moderately active and a well-tolerated regimen for selected advanced gastric cancer patients who experience disease progression after receiving first-line treatment.

Small cell carcinoma of the urinary bladder. A clinicopathologic study of five cases.

AIMS AND BACKGROUND: Small cell carcinoma of the bladder (SCCB) is a rare entity characterized clinically by an aggressive behavior with a high incidence of systemic metastases. We report the clinicopathologic findings of five cases. METHODS: We reviewed five consecutive patients with SCCB treated at our institute. In each case the following clinical data were recorded: age, sex, presenting symptoms, endoscopically determined location of the tumor, clinical staging, node involvement (if any), site of metastases (if any), treatment, follow-up and outcome. RESULTS: There were four male and one female patients, age range 42 to 68 years, mean 57.6 years. The clinical presentation was not different from conventional transitional cell carcinoma, with hematuria being the most frequent complaint (four cases). Microscopic examination revealed oat cells in three cases and an intermediate variant in one. At the time of diagnosis the tumors were staged as T3bN2M0, T2N2M0, T4N0M0, T3aN0M0, and T2N0M0. Primary therapy consisted of radical cystectomy alone (one case), transurethral resection (TUR) alone (one case), TUR with chemotherapy (two cases), or TUR with chemotherapy and radiotherapy (one case). Four patients died of progressive disease, with survival from the time of diagnosis ranging from 7 to 16 months (mean, 12.2 months). One patient died of myocardial infarction (unrelated to the primary disease) one month after diagnosis. CONCLUSION: Our study indicates that primary small cell carcinoma of the urinary bladder is as aggressive as its pulmonary counterpart and the overall prognosis of this tumor is very poor.

Acquired lymphangiectasis after breast conservation treatment for breast cancer: report of a case.

Acquired lymphangiectasis is a dilatation of lymphatic vessels that can result as a complication of surgical intervention and radiation therapy for malignancy. Acquired lymphangiectasis shares clinical and histological features with the congenital lesion, lymphangioma circumscriptum. Diagnosis and treatment of these vesiculobullous lesions is important because they may be associated with pain, chronic drainage, and cellulitis. We describe patient who had these lesions after treatment for cancer. Although a number of treatment options are available, we have found cryosurgery and electrocautery to be particularly effective.

Response to neoadjuvant chemotherapy in breast cancer could be predictable by measuring a novel serum apoptosis product, caspase-cleaved cytokeratin 18: a prospective pilot study.

The M30-monoclonal antibody recognizes a neo-epitope of cytokeratin 18 which is formed after caspase-cleavage during apoptosis. Caspase-cleaved cytokeratin 18 is released from apoptotic cells into circulation. The aim of this study was to evaluate the relationship between M30-antigen level and chemotherapy response in neoadjuvant treatment of breast cancer. Forty-two patients with invasive breast carcinoma received 4 cycles of anthracycline based neoadjuvant chemotherapy. Serum samples were obtained for assessment of M30-antigen levels before the administration of first chemotherapy cycle (baseline), and then after 24 and 48 hours for determination of chemotherapy induced apoptosis. M30-antigen levels at 24 and 48 hours were found to be significantly higher than baseline (p < 0.001, p = 0.003, respectively). M30-antigen levels in responders showed statistically significant increases at 24 and 48 hours (p < 0.001; p = 0.004, respectively), while statistically significant increases were not observed in nonresponders. Percentage change of M30-antigen levels was significantly higher in responders than nonresponders at 24 hours (p = 0.020). In conclusion, our study revealed a significant relationship between increases of M30-antigen levels in serum and overall response to therapy.

Phase II study of gemcitabine plus paclitaxel in metastatic breast cancer patients with prior anthracycline exposure.

UNLABELLED: Chemotherapy provides palliation and modest prolongation of symptom-free survival in metastatic breast cancer. Taxane containing regimens are commonly considered to be among the initials in metastatic setting due to earlier use of anthracyclines in the course of breast cancer. Therefore, we conducted this Phase II study to assess efficacy and safety of gemcitabine plus paclitaxel (GT) combination therapy in anthracycline pretreated metastatic first-line setting. PATIENTS AND METHODS: The study enrolled 26 women with pathologically confirmed and measurable metastatic breast cancer who were previously treated with anthracycline but no prior chemotherapy for metastatic disease. Twenty six and twenty four patients were eligible for toxicity and efficacy evaluations respectively. Mean age was 47.3 years and median ECOG performance status was 0. Twenty patients (76.9 percent) had visceral metastases, most commonly located in liver and lung. Treatment schedule was as follows: paclitaxel 175 mg/m2 was administered intravenously in 3 hours on Day 1 and gemcitabine 1000 mg/m2 was administered intravenously in 30 minutes on Day 1 after paclitaxel application, and on Day 8 every 21 days. RESULTS: Objective response rate was 41.7 percent (95 percent CI: 21.9-61.4) with 16.7 percent (95 percent CI: 1.7-31.6 percent) CR, and 25.0 percent (95 percent CI: 7.6-42.3 percent) PR. Median time to progression and overall survival were 9.6 and 14.5 months, respectively. Grade 3-4 toxicity was observed in 34.6 percent (9) patients. Treatment of two patients was discontinued due to toxicity, consisting of Grade 3 hypersensitivity reactions and Grade 4 infections in one patient each. Dose reductions due to myelotoxicity were performed in 4 (15.3 percent) patients. Hematologic toxicities were generally manageable with appropriate dose modifications and supportive care. CONCLUSION: Gemcitabine and paclitaxel combination regimen is effective and has manageable toxicity profile as first line metastatic setting.