Goshen Health

Taxanes (paclitaxel and docetaxel) are one of the most useful classes of anticancer drugs. Taxanes are highly hydrophobic; therefore, these drugs must be dissolved in organic solvents (polysorbate or Cremophor EL), which contribute to their toxicities. To reduce this toxicity and to enhance their efficacy, novel formulations have been developed. Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is an albumin-stabilized, Cremophor-free, and water-soluble nanoparticle formulation of paclitaxel. Nab-paclitaxel has better solubility and less infusion-associated toxicity compared to solvent-based paclitaxel. Additionally, nab-paclitaxel can be given at higher doses and concentrations compared with solvent-based paclitaxel. Based on its superior clinical efficacy and safety profile, nab-paclitaxel received FDA approval for metastatic breast cancer (2008) and NSCLC (2011). Among gastrointestinal cancers, it is now approved in the USA for treating patients with metastatic adenocarcinoma of the pancreas as first-line therapy in combination with gemcitabine. Furthermore, several clinical trials have suggested the potential efficacy of nab-paclitaxel as a single agent or in combination with other agents for the treatment of metastatic esophageal, gastric, bowel, and biliary tract cancers. Nab-paclitaxel has been demonstrated to have greater overall response rates (ORR) with enhanced progression-free survival (PFS), overall survival (OS) and a superior safety profile with fewer adverse effects in patients with gastrointestinal tract cancers. This review summarizes the advantages associated with nab-paclitaxel-based regimens in terms of improving clinical efficacy and the safety profile in upper gastrointestinal cancer.

<div>Abstract<p>There is accumulating evidence that continuous activation of the sympathetic nervous system due to psychosocial stress increases resistance to therapy and accelerates tumor growth via β2-adrenoreceptor signaling (ADRB2). However, the effector mechanisms appear to be specific to tumor type. Here we show that activation of ADRB2 by epinephrine, increased in response to immobilization stress, delays the loss of MCL1 apoptosis regulator (MCL1) protein expression induced by cytotoxic drugs in prostate cancer cells; and thus, increases resistance of prostate cancer xenografts to cytotoxic therapies. The effect of epinephrine on MCL1 protein depended on protein kinase A (PKA) activity, but was independent from androgen receptor expression. Furthermore, elevated blood epinephrine levels correlated positively with an increased MCL1 protein expression in human prostate biopsies. In summary, we demonstrate that stress triggers an androgen-independent antiapoptotic signaling via the ADRB2/PKA/MCL1 pathway in prostate cancer cells.</p>Implications:<p>Presented results justify clinical studies of ADRB2 blockers as therapeutics and of MCL1 protein expression as potential biomarker predicting efficacy of apoptosis-targeting drugs in prostate cancer.</p></div>

Summary Background Perioperative processes have a great impact on the quality of surgery. In a high-risk surrounding, proper planning and communication is of upmost importance. We have identified other professions next to surgery with comparable circumstances and conducted a survey to elaborate on the impact of perioperative processes. Objective To identify standards in preoperative planning in high-risk professions and determine possible shortcomings in surgical practice. Methods Two surveys were constructed and distributed to surgeons, mountain guides, and soldiers. Questions were designed to investigate preoperative planning behavior and compare the different professions. Results Nearly every participant (97%) agreed to the fact that preoperative planning helps to avoid complications. Most surgeons agreed that the preoperative and postoperative phase of care had the greatest ability to improve overall quality of care. The opinions about planning were divided. The minority of surgeons agreed to the importance of sharing a plan preoperatively. Soldiers were the profession with the highest rate of plan sharing. Conclusion The readiness to communicate varies between professions and is lowest for surgeons. Missing standardization of procedures and the surgeon’s ego might be explanations for this behavior. Interventions to overcome this shortcoming, like the preoperative team timeout, have already been implemented but further improvements are needed.

Although this might mistakenly be seen as an issue for the radiation oncology community, all of us who share in the treatment of women with early stage breast cancer should be concerned about the upcoming NRG BR007 trial, a "Phase III Randomized Trial: Evaluating De-escalation of Breast Radiation (DEBRA) for Conservative Treatment of Stage I, HR+, HER2-, RS ≤ 18 Breast Cancer), which is due to open in July.I am very supportive of the concept of using genomic testing to determine which patients between the ages of 50 and 70 with T1 N0 ER and/or PR positive breast cancers following breast conserving surgery with negative margins can be safely treated with endocrine therapy without adjuvant radiation therapy.Conceptually it is an exciting and well needed study.I am deeply concerned about the non-inferiority threshold of 4%.This has never previously been considered to be an acceptable difference in ipsilateral breast tumor recurrence (IBTR) for women between the ages of 50 and 70 with stage I, low risk cancers.

Background Nestin, a class VI intermediate filament protein of the cytoskeleton, and CD34, a transmembrane phosphoglycoprotein, are markers of progenitor cells. This study aimed to evaluate their expression and clinical significance in colorectal cancer. Methods A clinically annotated tissue microarray, including 599 patients with colorectal cancer, was analyzed by immunohistochemistry. Furthermore, nestin and CD34 correlations with HIF-1a and a panel of cytokines and chemokines were assessed using quantitative reverse transcription PCR and The Cancer Genome Atlas dataset. Results Expression of nestin and CD34 was observed only in the tumor stroma. Patients displaying high expression of nestin and CD34 demonstrated higher rates of T1 and T2 tumors (p = .020), lower vascular invasion (p < .001) and improved 5-year overall survival (65%; 95% CI = 55–73 vs 45%; 95% CI = 37–53) after adjusting for clinicopathological characteristics (HR: 0.67; 95% CI = 0.46–0.96). A moderate to strong correlation (r = 0.37–0.78, p < .03) of nestin and CD34 was demonstrated for the following markers; HIF-1α, CD4, CD8, FOXP3, IRF1, GATA3, CCL2, CCL3, CXCL12 and CCL21. Conclusions Combined expression of nestin and CD34 expression is associated with better overall survival possibly by modulating a favorable immune response.

Abstract Introduction: Intraoperative radiation therapy (IORT) is a convenient treatment option for appropriate women with early stage breast cancer. Some patients undergoing IORT also need adjuvant whole breast radiation therapy due to adverse final pathologic features. Although there are various reports of the complication rates with patients undergoing IORT, comparisons with patients undergoing other forms of radiation therapy such as whole breast or accelerated partial breast radiation are sparse. Methods: A total of 293 patients underwent breast conserving surgery at the study institution between January 2016 and December 2019 for either ductal carcinoma in situ (DCIS) or invasive breast cancer. Three patients had bilateral breast cancer and one patient had a local recurrence having refused adjuvant treatment following breast conserving surgery, for a total of 297 treated breasts. 124 received whole breast radiation therapy, 70 did not receive radiation therapy, 47 received IORT alone, 15 received IORT and whole breast radiation therapy, 30 received accelerated partial breast radiation using external beam radiation (APBI-EB), and 9 received Ir-192 based high dose rate accelerated partial breast radiation (APBI-HDR). One patient with bilateral breast cancer did not complete whole breast radiation therapy to either breast. Complications included cellulitis, wound drainage, symptomatic seroma, delayed wound healing, and wet desquamation. Interventions included observation, antibiotics, wound packing, debridement, fluid aspiration, hydrogel dressings, and wound vacuums. Results: For the entire group, the incidence of wound complications was 20%. The risk of complications was 27.4% for those undergoing IORT (with or without whole breast radiation) compared to 18.3% for those not receiving IORT, which was not statistically different at the 5% significance level. For those who received both IORT and whole breast radiation, however, the proportion having complication was 53.3% versus 18.4% in the other groups. The difference was significant with a p-value 0.0032. Conclusion: Patients who undergo both IORT and whole breast radiation have an increased risk for wound complications. Citation Format: James Wheeler, Houman Vaghefi, Laura Morris, Fang Liu, Irina Sparks, Fiona Denham, Leonard Henry, Ashley Hardy, Meghan Schrock, Vanessa DePue, Leon Coody. Breast complications in patients who received intraoperative radiation therapy compared to other forms of radiation therapy following breast conserving surgery [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS15-03.

Abstract Background: Regular whole-flock treatments and long-term use of similar anthelmintics have led to the development of anthelmintic resistance and widespread epidemics of nematodiasis in sheep. This study was performed to understand the prevalence of gastrointestinal nematodes in Ordos Merino sheep and evaluate the efficacy of currently used anthelmintics. Results: Between March 2017 and April 2019, a total of 4014 fresh fecal samples were collected from sheep, and fecal nematode eggs were qualitatively and quantitatively analyzed to understand the prevalence of sheep nematodiasis. The anthelmintic efficacy of currently used drugs was evaluated in naturally infected sheep. Severe infection by gastrointestinal nematodes was observed in the Ordos Merino sheep. The infection rates of the nematodes in 3 consecutive years were 84.3%, 36.9%, and 42.3%. Haemonchus contortus and Nematodirus sp. were the predominant nematode species, with infection rates of 84.3% and 65.6%, respectively, in 2017. Moreover, these species had acquired high resistance to ivermectin, doramectin, albendazole, and levamisole; the fecal egg count reduction percentages were 6.9%, 1.7%, 3.5%, and 79.0%, respectively, after a single administration. Nitroxynil and closantel showed strong anthelmintic efficacy against the predominant species Haemonchus contortus and other nematodes, but they had almost no effect on Nematodirus sp. Conclusions: The prevalence of gastrointestinal nematodes in Ordos Merino sheep and their resistance to commonly used anthelmintics were comprehensively evaluated, and the drugs with high efficacy against the predominant species were identified. The findings of this study will provide a good foundation for the appropriate use of anthelmintics.

Bruton tyrosine kinase (BTK) inhibition alone leads to incomplete responses in chronic lymphocytic leukemia (CLL). Combination therapy may reduce activation of escape pathways and deepen responses. This open-label, phase Ib, sequential dose-escalation and dose-expansion study evaluated the safety, tolerability, pharmacokinetics, and preliminary efficacy of the selective BTK inhibitor tirabrutinib alone, in combination with the PI3K delta (PI3Kδ) inhibitor idelalisib, or with the spleen tyrosine kinase (SYK) inhibitor entospletinib in patients with relapsed/refractory CLL. Patients received either tirabrutinib monotherapy (80 mg every day) or tirabrutinib 20-150 mg every day in combination with either idelalisib (50 mg twice a day or 100 mg every day) or entospletinib (200 mg or 400 mg every day). Fifty-three patients were included. Systemic tirabrutinib exposure was comparable between monotherapy and combination therapy. No MTD was identified. Across all treatment groups, the most common adverse event was diarrhea (43%, 1 patient grade ≥3); discontinuation due to adverse events was uncommon (13%). Objective response rates were 83%, 93%, and 100%, and complete responses were 7%, 7%, and 10% in patients receiving tirabrutinib, tirabrutinib/idelalisib, and tirabrutinib/entospletinib, respectively. As of February 21, 2019, 46 of 53 patients continue to receive treatment on study. Tirabrutinib in combination with idelalisib or entospletinib was well tolerated in patients with CLL, establishing an acceptable safety profile for concurrent selective inhibition of BTK with either PI3Kδ or SYK. This small study did not establish a superior efficacy of the combinations over tirabrutinib alone. This trial is registered at www.clinicaltrials.gov (NCT02457598).