Photodynamic Therapy—Current Limitations and Novel Approaches

Photodynamic therapy (PDT) mostly relies on the generation of singlet oxygen, via the excitation of a photosensitizer, so that target tumor cells can be destroyed. PDT can be applied in the settings of several malignant diseases. In fact, the earliest preclinical applications date back to 1900’s. Dougherty reported the treatment of skin tumors by PDT in 1978. Several further studies around 1980 demonstrated the effectiveness of PDT. Thus, the technique has attracted the attention of numerous researchers since then. Hematoporphyrin derivative received the FDA approval as a clinical application of PDT in 1995. We have indeed witnessed a considerable progress in the field over the last century. Given the fact that PDT has a favorable adverse event profile and can enhance anti-tumor immune responses as well as demonstrating minimally invasive characteristics, it is disappointing that PDT is not broadly utilized in the clinical setting for the treatment of malignant and/or non-malignant diseases. Several issues still hinder the development of PDT, such as those related with light, tissue oxygenation and inherent properties of the photosensitizers. Various photosensitizers have been designed/synthesized in order to overcome the limitations. In this Review, we provide a general overview of the mechanisms of action in terms of PDT in cancer, including the effects on immune system and vasculature as well as mechanisms related with tumor cell destruction. We will also briefly mention the application of PDT for non-malignant diseases. The current limitations of PDT utilization in cancer will be reviewed, since identifying problems associated with design/synthesis of photosensitizers as well as application of light and tissue oxygenation might pave the way for more effective PDT approaches. Furthermore, novel promising approaches to improve outcome in PDT such as selectivity, bioengineering, subcellular/organelle targeting, etc. will also be discussed in detail, since the potential of pioneering and exceptional approaches that aim to overcome the limitations and reveal the full potential of PDT in terms of clinical translation are undoubtedly exciting. A better understanding of novel concepts in the field (e.g. enhanced, two-stage, fractional PDT) will most likely prove to be very useful for pursuing and improving effective PDT strategies.

Active Hexose Correlated Compound For Patients With Resectable/Borderline Resectable Pancreatic Cancer Treated By Neoadjuvant Therapy: A Study Protocol For A Double-Blind Randomized Phase II Trial

Background: The prognosis of pancreatic ductal adenocarcinoma remains very poor. One possible reason for the short survival of patients with this disease is malnutrition, which can be present at the initial diagnosis, and continue after pancreatectomy. Then, it is important to improve nutritional status and to decrease adverse events during neoadjuvant and adjuvant chemotherapy. Active hexose correlated compound (AHCC) is a standardized extract of cultured Lentinula edodes mycelia, and is considered a potent biological response modifier in the treatment of cancer. To evaluate the survival impact of AHCC on the patients with pancreatic ductal adenocarcinoma, we plan to perform this trial.Methods: This is a prospective multicenter phase II trial in patients with resectable/borderline resectable pancreatic ductal adenocarcinoma to investigate the efficacy of AHCC regarding survival. Patients will begin taking AHCC or placebo on the first day of neoadjuvant therapy. AHCC or placebo will be continued until 2 years after surgery. The primary endpoint will be 2-year disease-free survival. The secondary endpoints are the completion rate, dose intensity, and adverse event profile of preoperative chemotherapy; response rate to preoperative chemotherapy; rate of decrease in tumor marker (carbohydrate antigen 19-9, carcinoembryonic antigen) concentrations during preoperative chemotherapy; entry rate, completion rate, dose intensity, and adverse event profile of adjuvant chemotherapy; safety of the protocol therapy (adverse effect of AHCC); 2-year overall survival rate; and nutrition score before and after preoperative chemotherapy, and before and after adjuvant chemotherapy. We will enroll 230 patients, and the study involves eight leading Japanese institutions that are all high-volume centers in pancreatic surgery.Discussion: AHCC is expected to function as a supportive food in patients with pancreatic ductal adenocarcinoma, and to reduce the proportion of severe adverse events related to neoadjuvant chemotherapy and to increase the completion proportion of multimodal treatments, resulting in improved survival. Trial registration: The trial protocol has been registered in the protocol registration system at the Japan Registry of Clinical Trials (Trial ID: jRCTs051200029). At the time of the submission of this paper (October 2020), the protocol version is 2.0. The completion date is estimated to be November 2024.

Descriptive analysis of the unwarranted continuation of antipsychotics for the management of ICU delirium during transitions of care: A multicenter evaluation across New Jersey

Disclaimer In an effort to expedite the publication of articles related to the COVID-19 pandemic, AJHP is posting these manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. Purpose Nearly half of intensive care unit (ICU) patients will develop delirium. Antipsychotics are used routinely for the management of ICU delirium despite limited reliable data supporting this approach. The unwarranted continuation of antipsychotics initiated for ICU delirium is an emerging transitions of care concern, especially considering the adverse event profile of these agents. We sought to evaluate the magnitude of this issue across 6 centers in New Jersey and describe risk factors for continuation. Methods This multicenter, retrospective study examined adult ICU patients who developed ICU delirium from June 2016 to June 2018. Patients were included in the study if they received at least 3 doses of antipsychotics while in the ICU with presence of either a clinical diagnosis of delirium or a positive Confusion Assessment Method score. Patients were excluded if they were on an antipsychotic before ICU admission. Results Of the 300 patients included and initiated on antipsychotics for ICU delirium, 157 (52.3%) were continued on therapy upon transfer from the ICU to another level of inpatient care. The number of patients continued on newly initiated antipsychotics further increased to 183 (61%) upon discharge from the hospital. Conclusion The continuation of antipsychotics for the management of delirium during transitions of care was a common practice across ICUs in New Jersey. Several risk factors for continuation of antipsychotics were identified. Efforts to reduce unnecessary continuation of antipsychotics at transitions of care are warranted.

Dilemma of seizure prophylaxis in sub-arachnoid haemorrhage

There is around 10% risk of developing seizures in post subarachnoid hemorrhage (SAH) period. This is considered to be linked to decreased oxygenation of brain due to increase in intra-cranial pressure obviating use of anti-epileptic drugs (AED) as a prophylactic measure. This review was done to study the effect and changes of blood brain barrier permeability in subarachnoid hemorrhage with regard to the present knowledge available and how it could be utilized to open arenas for future research for the rationalization of therapy for such patients. There is no consensus till date on the etiopathogenesis due to which no established guidelines are present for the management of such patients. It is safer to approach the patient on a case by case basis and assess whether to give prophylaxis or not based on the risk of development of seizures and adverse event profile of drugs. Also, there is a need to conduct prospective studies in this arena so as to get some meaningful interpretations which could be of some use to the future therapeutic guidelines.