Paradoxical response in a patient with non-small cell lung cancer who received nivolumab followed by anti-Mycobacterium tuberculosis agents.

Anti-programmed cell death-1 (PD-1) agents enhance the antitumor immunoresponse. A number of reports have indicated that patients with malignancies who receive anti-PD-1 agents are at risk for tuberculosis (TB) infection. In this report, we present a patient with non-small cell lung cancer who developed pulmonary tuberculosis while receiving the anti-PD-1 agent nivolumab, and who subsequently demonstrated a paradoxical response (PR) 10 days after initiation of anti-MTB treatment. We suggest that anti-PD-1 agents not only induce the development of pulmonary TB, but also development of PR after anti-MTB treatment, through upregulation of the immune response. Furthermore, based on their radiological and immunological similarity, we speculate that the schema of development of PR closely resembles that of pseudoprogression in non-small cell lung cancer patients after anti-PD-1 treatment.

Contraction Bands Are Induced by Cardiac Massage Itself.

Pathological contraction bands (CB) are recognized as a type of necrosis pattern found in the myocardium. It is well known that CB are induced by cardiopulmonary resuscitation (CPR) with cardiac massage. However, it is not known whether the reperfusion or massage itself causes the formation of CB. We studied 10 cardiac tissues taken from forensic autopsy cases that had not received CPR. We excluded the cases where the cause of death was a cardiac event. After making sections for forensic research, we massaged the left ventricles for 10 minutes. We found CB in all cases with massage performed within 12 hours after death, which is the time frame for supravital reactions. We did not find CB in any cases where more than 24 hours had elapsed since the time of death. Contraction bands were not observed in any sections that were taken before massage. We suggested here that CB induced by CPR were caused by the cardiac massage itself, and that most CPR-induced CB are not contraction band necrosis but rather artifactual CB.

Autopsy of a patient with alcoholic suffering from cardiopulmonary arrest at the hospital.

A 48-year-old Japanese woman with >10 years history of alcoholic had been falling repeatedly during 1 week before her death. She complained of nausea and did not eat or drink for 2 days. Thereafter, she became drowsy and she was transferred to the hospital. On arrival at the hospital, she had cardiopulmonary arrest and died soon after. Although blood tests showed metabolic ketoacidosis, a hemorrhagic lesion was also found in the brain by computed tomography. To determine the cause of death,. a forensic autopsy was performed on the next day. At autopsy, cerebral contusion, skull fracture, and subdural hemorrhage caused.by the head injury received after falling were found. Histological examination showed fatty changes and Mallory bodies in the liver. There was a marked increase in ketone bodies, especially ß -hydroxybutyrate, in postmortem blood examination. Therefore, the cause of death was diagnosed as alcoholic ketoacidosis. Accurate diagnosis of mild trauma and metabolic disease is difficult by postmortem computed tomography; therefore, autopsy is required for sudden death. In this case, the cause of death and accompanying traumatic lesions that were compatible with her history was clarified by autopsy. Furthermore, because the blood was taken at the time of cardiopulmonary arrest, we.obtained reliable data from the terminal stage of alcoholic ketoacidosis. This case demonstrates the physiological and pathological changes in sudden death of a patient with alcoholic.

Classification of contraction bands using immunohistochemistry.

Pathological contraction bands (CBs) are a type of necrosis pattern found in the myocardium. The composition of CB is not well studied. This is because CBs have diverse forms and can be observed in various causes of death. In pathology fields, CBs are classified artifactual CB and CB necrosis. We have identified different forms of CB by examining the expression and distribution of complement component C9 (CCC9) and Sirtuin1 by immunohistochemistry in the myocardium of patients who died because of different causes of death. We used cardiac tissues with CB from 30 forensic autopsy cases in our department from the last 2 years. We excluded the cases that had very little CB. We found that our CB classification based on expression levels of both CCC9 and Sirtuin1 correlated well with the agonal situation, including high temperature, myocardial infarction, cardiopulmonary resuscitation, and hypothermia. On the basis of these results, we here advocate a classification scheme based on immunohistochemistry. Furthermore, we found that CB necrosis could be detected using immunostaining with CCC9. Using our classification scheme, it will be possible to more accurately research each type of CB and the causative mechanisms.

Impact of pneumonia on hyperactive delirium in end-stage lung cancer patients.

PURPOSE: Patients with incurable lung cancer often receive palliative care. Hyperactive delirium is a burden not only for the patient's family but also for caregivers. There are no reports describing the risk factors for delirium among lung cancer patients. The present study investigated the frequency of incidence and risk factors for hyperactive delirium among end-stage lung cancer patients. METHODS: Patients who died of lung cancer in our institute from January 2010 to December 2010 were retrospectively investigated. Information was obtained from medical records, and patients who developed hyperactive delirium (delirium group, group D) were compared with patients who did not (control group, group C) based on clinical and laboratory data. RESULTS: A total of 146 patients (median age, 70 years; 80 % male) died of lung cancer. Thirty-one (21.2 %) patients developed hyperactive delirium. Sex (P = 0.0093) and pneumonia (P = 0.023) were statistically significant variables in univariate analysis. Pneumonia occurred in 27.4 % of all patients. The incidence of pneumonia was 45.2 % in group D and 22 % in group C. Only pneumonia (odds ratio, 2.89; 95 % confidence interval, 1.22-6.85; P = 0.016) was identified as a significant factor for predicting hyperactive delirium in multivariate analysis. CONCLUSIONS: Pneumonia was identified as a significant risk factor for the development of hyperactive delirium among end-stage lung cancer patients.

Tubular nephrotoxicity induced by docetaxel in non-small-cell lung cancer patients.

Renal dysfunction is a characteristic of many patients with cancer; however, a standard therapy has not been established for stage III or IV non-small-cell lung cancer (NSCLC) complicated with chronic renal failure. Docetaxel has a proven significant activity against NSCLC. This agent is predominantly eliminated by hepatobiliary extraction and is safe in patients with renal failure, including dialysis patients. Docetaxel is, thus, a therapeutic option in that patient population. Here, we report acute tubular nephrotoxicity secondary to docetaxel in NSCLC patients, even in patients with normal renal function. Little is known about tubular nephrotoxicity induced by docetaxel; however, oncologists should be aware of its possibility.

[A case of locally advanced non-small-cell lung cancer complicated with chronic renal failure and gastric cancer, successfully treated with weekly docetaxel and concurrent thoracic radiotherapy].

A standard therapy is not established for locally advanced non-small-cell lung cancer(NSCLC)complicated with chronic renal failure, although some cases of the disease have been reported. We report a case of a locally advanced squamous cell carcinoma of the lung, complicated with chronic renal failure. He was successfully treated with weekly docetaxel(DOC)and concurrent thoracic radiotherapy, and no deterioration of renal function was observed. In locally advanced NSCLC complicated with renal dysfunction, treatment with weekly DOC and concurrent thoracic radiotherapy is considered to be a therapeutic option. Since radiation pneumonitis occurred in the present case, the accumulation and precise analysis of applicable cases is an important subject for future consideration.

A case of successful concurrent anti-cancer treatment in a patient who developed follicular lymphoma during treatment with afatinib for advanced lung adenocarcinoma.

The present report describes the case of a 64-year-old woman with advanced lung adenocarcinoma expressing mutant epidermal growth factor receptor (EGFR). The patient developed follicular lymphoma during treatment with the EGFR-tyrosine kinase inhibitor afatinib. Standard immunochemotherapy for follicular lymphoma was introduced in addition to continuing treatment with afatinib for lung cancer. Immunochemotherapy was effective and improved the patient's performance status while afatinib controlled the progression of lung cancer. Our case study suggests that it is safe to introduce standard immunochemotherapy for patients who develop malignant lymphoma while continuing treatment with tyrosine kinase inhibitors for lung adenocarcinoma expressing mutant EGFR.

Re-challenge chemotherapy in patients with sensitive relapse small-cell lung cancer and interstitial lung disease.

BACKGROUND: Treatment modalities for small-cell lung cancer (SCLC) with pre-existing interstitial lung disease (ILD) are limited. Although re-challenge with first-line chemotherapy can be effective for sensitive relapse SCLC, its safety and efficacy are uncertain in cases with ILD. This study aimed to investigate both the efficacy and safety of re-challenge chemotherapy in patients with sensitive relapse SCLC with ILD. METHODS: Patients with sensitive relapse SCLC with ILD who received re-challenge chemotherapy were studied retrospectively. Sensitive relapse was defined as a treatment-free interval (TFI) of more than 60 days after first-line platinum-based treatment. The endpoints were progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Re-challenge platinum and etoposide were administered in 11 patients, with the median re-challenge cycle of 3. The overall response rate was 55%. The median PFS and OS from the time of re-challenge treatment were 4 months (95% CI, 2.9-NA) and 9.2 months (95% CI, 8.0-NA), respectively. One patient developed acute exacerbation of ILD 173 days after the last course of re-challenge treatment. CONCLUSIONS: Re-challenge chemotherapy can be effective and considered in SCLC patients with pre-existing ILD.

Comparison of the Utilities of Cryobiopsy and Forceps Biopsy for Peripheral Lung Cancer.

BACKGROUND/AIM: This study aimed to compare the efficacies of cryobiopsy and forceps biopsy for peripheral lung cancer detection. PATIENTS AND METHODS: A retrospective review of peripheral lung cancer cases between December 2017 and April 2019 was conducted. Forceps biopsy was performed followed by cryobiopsy using a guide sheath (GS). Diagnostic yields were compared between cryobiopsy and forceps biopsy. RESULTS: A total of 53 lung cancer lesions were evaluated. The diagnostic yields of forceps biopsy and cryobiopsy were 86.8% and 81.1%, respectively. Univariate and multivariate analyses indicated that cryobiopsy with a GS was significantly associated with increased diagnostic yield (odds ratio(OR)=11.6; p=0.044). Among the four patients who tested positive on cryobiopsy and negative on forceps biopsy, one had diffused pulmonary metastases and the others showed intratumoural air bronchograms. CONCLUSION: Cryobiopsy using a GS can significantly increase diagnostic yield and help identify lesions with intratumoural air bronchograms and external wall lesions.

Skin Rash Can Be a Useful Marker for Afatinib Efficacy.

BACKGROUND/AIM: Although afatinib has a strong efficacy, it can be toxic; hence, we aimed to determine markers of response to afatinib in order to assess prognosis. PATIENTS AND METHODS: Information on clinical background, therapeutic effects, and adverse events was collected retrospectively at one Institution from patients treated with afatinib as initial epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI). We examined the relationship between different adverse events and their effects on prognosis. RESULTS: Afatinib was used in 32 patients as the initial EGFR-TKI. Adverse events of grade 3 or higher including diarrhoea (12.5%), paronychia (6.3%), and stomatitis (3.1%) were experienced by patients. The median progression-free survival (PFS) was 15.4 months. A relationship between skin rash severity and PFS was observed. CONCLUSION: Grade 2 or higher skin rash might be a marker for long-term efficacy of afatinib when administered as a first-line treatment.

Successful osimertinib rechallenge after osimertinib-induced pneumonitis in a patient with lung adenocarcinoma.

Pneumonitis is a serious adverse event of EGFR-TKI treatment. Although several cases of EGFR-TKI rechallenge after EGFR-TKI-induced pneumonitis have been reported, little is known about post-pneumonitis osimertinib rechallenge. We describe a 69-year-old never-smoking Japanese woman with postoperative recurrent lung adenocarcinoma retreated with osimertinib after osimertinib-induced pneumonitis. Although osimertinib rechallenge must be carefully chosen based on risk/benefit analysis, osimertinib rechallenge after osimertinib-induced pneumonitis may be an option, with limited alternative therapeutic options.

Osimertinib Treatment Was Unsuccessful for Lung Adenocarcinoma with G719S, S768I, and T790M Mutations.

Epidermal growth factor receptor (EGFR) T790M mutations are the most frequent mechanism of resistance to first- and second-generation tyrosine kinase inhibitors, and osimertinib is an effective treatment for patients with both EGFR-activating mutations and T790M resistance mutations. We describe the case of a 68-year-old woman with lung adenocarcinoma with G719S, S768I, and T790M mutations in which osimertinib treatment was unsuccessful. The patient died of disease progression one month after discontinuing osimertinib treatment. This case suggests that osimertinib may be ineffective for treating patients with uncommon mutations such as G719S when the patient has also acquired a T790M resistance mutation.

Transformation to small cell lung cancer after first-line afatinib treatment.

Acquiring resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) is inevitable. Transformation to small cell lung cancer (SCLC) is reported as a possible mechanism of this acquired resistance. We describe the case of a 35-year-old man with lung adenocarcinoma harboring EGFR exon 19 deletion. After 7 months of successful treatment with afatinib, he experienced relapse and rebiopsy revealed SCLC with EGFR exon 19 deletion. Tumor marker tests at this point showed normal levels of serum neuron-specific enolase and pro-gastrin releasing peptide. Our case highlights the importance of rebiopsy for revealing SCLC transformation, a potential mechanism of acquired resistance to afatinib as with other EGFR-TKIs, and normal-range values of tumor markers for SCLC cannot exclude the possibility of SCLC transformation.

Impact of Pleural Effusion on Outcomes of Patients Receiving Osimertinib for NSCLC Harboring EGFR T790M.

BACKGROUND/AIM: Osimertinib has demonstrated promising efficacy in patients with epidermal growth factor receptor (EGFR) T790M-positive non-small cell lung cancer (NSCLC). We investigated the efficacy of osimertinib in such patients presenting with pleural effusion, which has been unclear to date. PATIENTS AND METHODS: The medical records of all patients treated with osimertinib for advanced NSCLC with EGFR T790M between April 2016 and July 2017 at our Institution were retrospectively reviewed. Time to treatment failure (TTF) and overall survival (OS) were determined as endpoints. RESULTS: Twenty-three patients (seven with pleural effusions) were treated with osimertinib. Patients with pleural effusion had significantly shorter median TTF than those without (3.7 vs. 12.8 months, respectively, p=0.021), as well as shorter median OS (7.8 months vs. not attained, respectively, p=0.002). Metastasis to the brain, bone, and liver did not significantly influence our endpoints. CONCLUSION: Osimertinib monotherapy is less effective in patients with NSCLC with pleural effusions.

Successful retreatment with osimertinib after osimertinib-induced acute pulmonary embolism in a patient with lung adenocarcinoma: A case report.

Pulmonary embolism (PE) can be life-threatening, and it is challenging to diagnose because of its nonspecific signs and symptoms. PE is also an important potential risk of osimertinib treatment, however, clinical courses regarding retreatment after osimertinib-induced acute pulmonary embolism remain unclear. We described a 77-year-old woman with postoperative recurrent lung adenocarcinoma who developed osimertinib-induced acute PE. She received apixaban and was later successfully retreated with osimertinib. This case suggests that retreatment with osimertinib after osimertinib-induced acute PE may be a treatment option when alternative therapeutic options are limited.

Determination of Both Fetus' and Mother's Blood Type from an Autopsy Case Immersed in Formalin for Over 50 Years.

A female fetus which had been immersed in formalin for more than 50 years was found in Japan. Because no liquid blood could be obtained, we tried to use immunohistochemistry (IHC) methods to tissue samples obtained at autopsy to identify both the fetal and mother's blood type. We detected B antigens on endothelial cells in paraffin sections of the fetal organs. Furthermore, we observed both anti-A- and anti-B-positive red blood cells in the intervillous space, which is indicative of the mother's blood type. To our knowledge, this is the first case report on determining the blood type of both the fetus and the mother from tissue immersed in formalin for such a long time. The results suggest that IHC is valuable for the determination of ABO blood type in circumstances of long postmortem duration and unfavorable storage conditions.

Comparison of the injury severity and medical history of disease-related versus trauma-related bicyclist fatalities.

The objective of this study was to clarify the relationship between injury severity and mechanism of death in bicycle fatalities resulting from trauma compared with those resulting from disease, to propose effective measures to prevent fatal bicyclist accidents. Autopsy and accident records were reviewed for bicyclist fatalities who had undergone forensic autopsy at the Dokkyo Medical University School of Medicine between September 1999 and March 2014. Victims' health histories, blood alcohol levels, causes of death, mechanisms of injury, Abbreviated Injury Scale (AIS) scores and Injury Severity Scores (ISSs) were determined. Fifty-five bicyclists (43 male and 12 female) with a mean age of 62.5±17.3 years were included in this study. Sixteen victims had driven under the influence of alcohol (mean blood concentration of 1.8±0.7 mg/ml). Mean ISS was 32.4 and the chest had the highest mean AIS score (2.6), followed by the head (2.1) and the neck (1.8). Thirty-nine victims (70.9%) had died of trauma and 16 had died of disease. The disease-death victims had significantly higher prevalence of having diabetes mellitus, hyperlipidemia, hypertension, heart disease or cerebrovascular diseases (50.0% vs. 22.2%, p=0.03) and a lower rate of drunk driving (6.3% vs. 41.0%, p=0.01) than the trauma-death group. All victims who were affected by disease, and 33.3% of trauma-death victims, had fallen on the road without a vehicle collision (p<0.001). The mean ISS of the trauma-death group was significantly higher than that of the disease-death group (44.0 vs. 4.2, p<0.001). Except for facial injuries, the AIS scores were significantly higher in trauma-death victims than in the disease-death group (p<0.005). To effectively reduce bicyclist fatalities, the authors strongly advocate efforts that will increase compliance with drunk driving prohibitions. For victims of fatal bicycle accidents with a medical history of diseases, a forensic autopsy should be performed to establish a disease-related death while bicycle riding. We must also put into effect preventative safety measures, which take into consideration the physical condition of bicyclists, to reduce the incidence of these types of accidents.

An autopsy case of fatal repellent air freshener poisoning.

We describe a first fatal case of repellent air freshener ingestion. A 79-year-old Japanese man with Alzheimer-type senile dementia orally ingested repellent air freshener containing three surfactants: polyoxyethylene 9-lauryl ether, polyoxyethylene (40) hydrogenated castor oil, and lauric acid amidopropyl amine oxide (weight ratio of 1.3%). About 1h after the collapse, he was in cardiopulmonary arrest and subsequently died 10h after his arrival. The forensic autopsy performed 5.5h after death revealed the 380ml of stomach contents with a strong mint perfume identical to that of the repellent air freshener and the findings of acute death. Toxicologically, 9.1µg/ml and 558.2µg/ml of polyoxyethylene 9-lauryl ether were detected from the serum and stomach contents taken at autopsy. Generally, ingestion of anionic or non-ionic surfactants have been considered as safe. However, because the patient suffered from cardiac insufficiency with a low dose of repellent air freshener ingestion, medical staff members must evaluate the elderly patient for cardiac and circulatory problems regardless of the ingested dose. Not only medical and nursing staff members, but also families who are obliged to care for elderly persons must be vigilant to prevent accidental ingestion of toxic substances generally used in the household.