Mannitol versus furosemide in patients with thoracic malignancies who received cisplatin-based chemotherapy using short hydration: A randomized phase II trial.

BACKGROUND: Mannitol is exclusively recommended in the National Comprehensive Cancer Network guidelines for diuresis in cisplatin (CDDP)-based chemotherapy. The utility of furosemide, a widely used and convenient diuretic, thus requires clarification. METHODS: This is a prospective, single-centered, open-label, noninferiority phase II study. Patients with thoracic malignancies who planned to receive CDDP-based chemotherapy were randomly assigned to receive either mannitol (arm A) or furosemide (arm B). The primary end point was set as the proportion of patients who experienced any grade of "creatinine (Cr) increased" based on the upper limit of the normal range (ULN) during the first cycle as assessed by Common Terminology Criteria for Adverse Events Version 4.0. Secondary end points were Cr increased based on the baseline value during the first cycle, Cr increased after the completion of CDDP, and the proportion of patients with phlebitis. RESULTS: Between April 2018 and March 2022, 115 patients were enrolled and 106 were analyzed. Any grade of Cr increased based on the ULN during the first cycle was 17.3% (arm A) and 24.1% (arm B), respectively (p = 0.34). Therefore, the primary end point was not met. After completion of chemotherapy, any grade of Cr increased was observed in 23.1% (arm A) and 31.5% (arm B), respectively. However, the actual serum Cr level and Cr clearance during the courses were not different between the arms. Phlebitis occurred more frequently in arm A (28.8%) than arm B (16.7%). CONCLUSIONS: Mannitol should remain the standard diuresis in CDDP-based chemotherapy assessed by conventional CTCAE grading, but furosemide can be room for consideration when assessed by actual serum Cr level and Cr clearance.

A Phase II Study of High-Flow Nasal Cannula for Relieving Dyspnea in Advanced Cancer Patients.

CONTEXT: The efficacy and tolerability of high-flow nasal cannula (HFNC) for relieving dyspnea in advanced cancer patients with limited prognosis requires elucidation. OBJECTIVES: The primary aim of this trial was to assess the efficacy and tolerability of HFNC regarding dyspnea including severe as well as moderate for longer durations in patients under palliative care. METHODS: In this prospective study, hospitalized patients with advanced cancer who had dyspnea at rest (numeric rating scale, NRS≥3) and hypoxemia were enrolled. They were treated with HFNC for five days in the respiratory unit. Primary endpoint was mean change of modified Borg scale at 24 hours. Key secondary endpoints consisted of mean changes in modified Borg scale during the study period and feasibility (Trial Identifier, UMIN000035738). RESULTS: Between February 2019 and February 2022, 25 patients were enrolled and 21 were analyzed. Twenty patients used inspired oxygen and the mean fraction of inspired oxygen (FiO2) was 0.34 (range, 0.21-1.0). At baseline, mean NRS (dyspnea) was 5.9 (range, 3-10). Median survival time was 19 days (range, 3-657). The mean change of modified Borg scale was 1.4 (80% confidence interval [CI]: 0.8-1.9) at 24 hours, 12 patients (57%) showed 1.0 points improvement of modified Borg scale. Within two hours, 15 patients showed 1.0 points improvement of modified Borg scale and such early responders were likely to maintain dyspnea improvement for 24 hours. Nineteen patients could continue HFNC for 24 hours and 11 patients completed five days of HFNC. CONCLUSION: To our knowledge, this trial is the first prospective study to assess the five-day efficacy and tolerability of HFNC for dyspnea in patients under palliative care. Although this did not reach the prespecified endpoint, about half of the patients showed 1.0 point improvement, a minimally clinically important difference (MCID) in the chronic lung disease. HFNC can be a palliative treatment option in advanced cancer patients with dyspnea.

Pre-treatment serum protein levels predict survival of non-small cell lung cancer patients without durable clinical benefit by PD-1/L1 inhibitors.

While PD-1/L1 inhibitors are characterized by durable tumor control, they also prolong survival without prolongation of progression-free survival (PFS) in part of patients. However, little is known about the factors and mechanisms involved in this. Between December 2015 and September 2018, 106 patients with advanced non-small cell lung cancer treated with ICI monotherapy were enrolled in a prospective-observational study. Sixty-nine of whom progressed or died within 6 months after ICI initiation were defined as patients without durable clinical benefit (NDBs). Clinical factors and 39 serum proteins before ICI initiation and at the time of progressive disease (PD) were explored for an association with overall survival (OS) and OS after PD (OS-PD). As a result, median PFS, OS, and OS-PD were 44 days [95% confidence interval (CI): 39-56), 211 days (95% CI: 158-425), and 193 days (95% CI: 118-349), respectively. By multivariate analysis for OS, CRP (> 1.44 mg/dl) [HR 2.59 (95% CI:1.33-5.04), P = 0.005] and follistatin (> 685 pg/ml) [HR 2.29 (95% CI:1.12-4.69), P = 0.023] before ICI initiation were significantly predictive. Notably, no serum protein at the time of PD was predictive for OS-PD. There were also no serum predictive factors of OS in the 33 patients with durable clinical benefit. In conclusion, serum levels of CRP and follistatin before ICI initiation, not at the time of PD, are predictive for OS in NDBs, suggesting long-term survivor in NDBs are predetermined by the immune status before ICI initiation.

Phase Ib Study of Osimertinib Plus Ramucirumab in Japanese Lung Cancer Patients With EGFR Mutation.

BACKGROUND/AIM: To explore the safety of osimertinib plus ramucirumab in patients with EGFR-mutated lung adenocarcinoma. PATIENTS AND METHODS: Six advanced lung adenocarcinoma patients with EGFR mutation were treated with osimertinib 80 mg/day plus ramucirumab 10 mg/kg, every two weeks. Defined dose-limiting toxicity (DLT) was assessed within the first two treatment cycles. RESULTS: Of those enrolled, five patients had both EGFR exon 20 T790M mutation and sensitizing mutation. DLT was observed in one patient (grade 3 appetite loss). During the entire period, no other severe adverse event was observed. Five patients showed partial response and one disease progression. Median progression-free survival for patients with EGFR T790M was 9.2 months. In an exploratory analysis, changes of cell-free DNA at 2 weeks predicted radiological tumor responses. CONCLUSION: The safety results of osimertinib plus ramucirumab in Japanese lung adenocarcinoma patients with EGFR mutation will lead to further efficacy investigation.

CD24, not CD47, negatively impacts upon response to PD-1/L1 inhibitors in non-small-cell lung cancer with PD-L1 tumor proportion score < 50.

CD24, a heavily glycosylated glycosylphosphatidylinositol-anchored surface protein, inhibits phagocytosis as potently as CD47. The relationship between such anti-phagocytic factors and the immune response with immune-checkpoint inhibitors (ICI) remains unexplored. We evaluated CD24 and CD47 tumor proportion scores (TPS) in 68 of the 106 patients with advanced non-small-cell lung cancer who participated in a prospective observational study of ICI treatment. We also explored the impact of CD24 TPS and CD47 TPS on ICI efficacy and serum cytokine changes. CD24 positivity (TPS ≥ 1) was negatively associated with progression-free survival (PFS) of ICI when PD-L1 TPS was < 50 (median PFS; 37 vs 127 d, P = .033), but there was no association when PD-L1 TPS was ≥ 50 (median PFS; 494 vs 144 d, P = .168). CD24 positivity was also related to significantly higher increase of CCL2 from baseline to 4-6 wk later, and such increase was notably observed only when PD-L1 TPS < 50 (P = .0004). CCL2 increase after ICI initiation was negatively predictive for survival after initiation of ICI (median survival time; not reached vs 233 d; P = .028). CD47 TPS high (≥60) significantly suppressed the increase in vascular endothelial growth factor (VEGF)-A, D and PDGF-AB/BB after ICI initiation. There was no association, however, between CD47 tumor expression and the efficacy of ICI. In conclusion, CD24, not CD47, is a candidate negative predictive marker of ICI in advanced, non-small-cell lung cancer with PD-L1 TPS < 50. Tumor expression of both CD24 and CD47 was associated with changes in factors related to monocytes and angiogenesis after ICI initiation (UMIN000024414).

Immune-Related Adverse Events by Immune Checkpoint Inhibitors Significantly Predict Durable Efficacy Even in Responders with Advanced Non-Small Cell Lung Cancer.

BACKGROUND: Although predictive value of immune-related adverse events (irAEs) induced by immune checkpoint inhibitors (ICIs) have been suggested by several studies, their assessments were insufficient because patients were categorized only by the occurrence of irAEs. It has not been elucidated whether irAEs also play a significant role even in responders. MATERIALS AND METHODS: Between December 2015 and September 2018, 106 patients with advanced non-small cell lung cancer treated with ICIs were enrolled in our prospective biomarker study. Twenty-three of these were responders, defined as those with complete or partial response. We investigated the proportion of irAEs among overall and responders. For responders, progression-free survival (PFS) and overall survival of ICIs were compared between those with and without irAEs. As an exploratory analysis, we measured 41 proteins from peripheral blood before and after ICI treatment. RESULTS: The proportion of irAEs was significantly higher in responders than nonresponders (65.2% vs. 19.3%, p < .01). Among responders, clinical characteristics did not differ regardless of the occurrence of irAEs. However, there was a significant difference in PFS among responders (irAE group 19.1 months vs. non-irAE group 5.6 months; hazard ratio: 0.30 [95% confidence interval: 0.10-0.85]; p = .02). Of 41 protein analyses, fibroblast growth factor-2 at baseline and monocyte chemoattractant protein fold change showed significant differences between them (p < .04). CONCLUSION: Although this is a small sample-sized study, irAE might be a predictive factor of durable efficacy, even in patients who responded to ICIs. Investigation into the significance of irAEs in responders will contribute to the establishment of optimal administration of ICI. IMPLICATIONS FOR PRACTICE: Although the predictive value of immune-related adverse events (irAEs) induced by immune checkpoint inhibitors (ICIs) has been suggested by several studies, it has not been elucidated whether irAEs also play a significant role even in responders. This study showed that more than 60% of responders had irAEs. It demonstrated the strong correlation between irAEs and efficacy even in responders. Investigation into the significance of irAEs in responders will contribute to the establishment of optimal administration of ICI.

Furosemide versus mannitol in Japanese patients with thoracic malignancy who received cisplatin-based chemotherapy using short hydration: study protocol for a randomised controlled trial.

INTRODUCTION: Cisplatin (CDDP) is a key drug for various thoracic malignancies. To avoid renal toxicity of CDDP, mannitol is routinely used, but it sometimes causes phlebitis which damages patients' quality of life. Furosemide is another widely used option for diuresis administered more quickly. To date, previous comparisons of these diuretics have lacked statistical significance owing to study design. We therefore undertake a randomised phase II comparative study of furosemide and mannitol in CDDP-based chemotherapy using short hydration. METHODS AND ANALYSIS: This is a two-arm, prospective, randomised, single-centre, open-label phase II study. The primary endpoint is set as the proportion of patients who experienced any grade of 'creatinine increase' using the Common Terminology Criteria for Adverse Events V.4.0, during the first cycle. Secondary endpoints are: the proportion of patients who experienced ≥grade 2 of creatinine increase during the first cycle, any grade and ≥grade 2 of creatinine increase after the completion of fourth cycle, and the proportion of patients with phlebitis. Enrolled in this trial will be 105 patients. ETHICS AND DISSEMINATION: This study was approved by the Wakayama Medical University Institutional Review Board on 30 March 2018 study (approval number: 2258). Patients have been enrolled since May 2018. As the study will complete accrual in March 2021, results will be published by 2021. This study will provide important information about the utility of furosemide compared with mannitol to protect against nephrotoxicity. TRIAL REGISTRATION NUMBER: UMIN000031910.

Feasibility of Trypsin Digestion as a Sample Preparation for Daptomycin Quantification in Murine Skeletal Muscles.

It is important to evaluate the amount of daptomycin (DAP) distributed to skeletal muscles to elucidate the mechanisms related to penetration and side effects, such as myopathies. However, no attempt has been made to measure DAP concentrations in skeletal muscles. The study's aim to investigate the feasibility of trypsin digestion, as a muscle sample preparation technique for the determination of DAP in murine skeletal muscle, was evaluated in conjunction with a conventional HPLC-UV analysis. Compared with trypsin digestion, DAP was less recovered from spiked skeletal muscle by the conventional extraction, including homogenization, centrifugation, and filtration, because of its incorporation into the muscle protein. On the other hand, a sample preparation technique involving enzymatic digestion employing trypsin fully recovered DAP from the spiked skeletal muscle. Based on the spike recovery assay results, we proposed an efficient muscle sample preparation method involving trypsin digestion. HPLC analysis in conjunction with the sample preparation method has successfully determined DAP concentrations of skeletal muscles collected from mice administrated subcutaneously with DAP. The proposed method is suitable for application to investigations that include animal experiments on drug migration into muscle and mechanism underlying skeletal muscle injury as a side reaction, such as myopathies, of DAP therapy.

Correlation between immune-related adverse events and efficacy in non-small cell lung cancer treated with nivolumab.

OBJECTIVES: Patients treated with nivolumab often experience its unique adverse events, called immune-related adverse events (irAEs). Regarding the mechanisms of immune-checkpoint inhibitors (ICIs), the occurrence of irAEs may also reflect antitumor responses. Here, we report the clinical correlation between irAEs and efficacy in NSCLC patients treated with nivolumab. MATERIALS AND METHODS: Between December 2015 and February 2017, 38 advanced NSCLC patients were treated in our institution. All the patients were enrolled in our single-institutional, prospective, observational cohort study (UMIN000024414). IrAEs were defined as having a potential immunological basis that required more frequent monitoring and potential intervention. We divided the patients into two groups (irAEs group or no-irAEs group) and evaluated the objective response rate (ORR) and progression-free survival (PFS). RESULTS: The median age of the patients was 68.5 years (range 49-86 years); male/female ratio was 28/10; squamous/non-squamous cell carcinoma cases were 10/28; performance status was 0-1/2/3, 7/26/5. Among the overall population, ORR was 23.7% and median PFS was 91days. At the data cutoff, 14 irAEs were observed. The most common irAE was interstitial pneumonia (n=5). Other irAEs were hypothyroidism (n=4), hyperthyroidism, hypopituitarism, liver dysfunction, rash, and elevated thyroid stimulating hormone levels (n=1, each). Patients with irAEs had significantly higher ORRs compared with no-irAE patients (63.6% versus 7.4%, p <0.01). Similarly, the PFS among irAE patients was longer (median: not reached [95% confidence interval {CI}: 91days to not applicable]) than no-irAE patients (median 49days [95% CI: 36-127days], hazard ratio [HR] 0.10 [95% CI: 0.02-0.37, p<0.001]). Landmark analysis of patients who achieved PFS ≥60days demonstrated similar tendencies, but this was not significant (HR 0.28 [95% CI: 0.04-1.46], p=0.13). CONCLUSION: There was a correlation between irAE and efficacy in NSCLC patients treated with nivolumab.

Considerations about the Use of a Loading Dose of Daptomycin in a Neutropenic Murine Thigh Infection Model with Methicillin-Resistant Staphylococcus aureus Infection.

Previous clinical studies have showed the clinical benefits of the initiation of treatment with a daptomycin (DAP) loading dose, but only a few studies have evaluated its antimicrobial benefits. We evaluated the efficacy of a DAP loading dose against methicillin-resistant Staphylococcus aureus (MRSA) infections in a neutropenic murine thigh infection model. Three MRSA isolates (DAP MIC: 0.5, 1, and 2 mg/L) were tested. Four DAP regimens simulating human concentration-time profiles, i.e., (i) day 1: 8 mg/kg and day 2: 6 mg/kg, (ii) days 1 and 2: 6 mg/kg/day, (iii) day 1: 8 mg/kg and day 2: 4 mg/kg, and (iv) days 1 and 2: 4 mg/kg/day, were administered to the mice. Efficacy was calculated as the change in bacterial density. DAP loading-dose regimen iii showed greater antimicrobial activity against MRSA with MIC 1 mg/L than nonloading regimen iv (-3.10 ± 0.63 vs. -0.71 ± 0.34 log10 CFU; p < 0.01). Loading-dose regimen iii achieved greater log10 CFU changes than nonloading regimen ii, while the total DAP dose for 2 days was the same (-3.10 ± 0.63 vs. -1.46 ± 0.48 log10 CFU; p < 0.05). DAP loading-dose regimen iii showed enhanced antimicrobial activity against MRSA with DAP MIC 0.5 mg/L when compared with nonloading regimen iv. However, loading-dose regimens i and iii did not reduce bacterial density for MRSA with DAP MIC 2 mg/L. Our data suggest that a DAP loading-dose regimen would be an advantageous procedure for patients infected with MRSA with DAP MIC ≤1 mg/L.

Roles of Ras Homolog A in Invasive Ductal Breast Carcinoma.

Breast cancer has a poor prognosis owing to tumor cell invasion and metastasis. Although Ras homolog (Rho) A is involved in tumor cell invasion, its role in breast carcinoma is unclear. Here, RhoA expression was examined in invasive ductal carcinoma (IDC), with a focus on its relationships with epidermal-mesenchymal transition (EMT) and collective cell invasion. Forty-four surgical IDC tissue samples and two normal breast tissue samples were obtained. RhoA, E-cadherin, vimentin, and F-actin protein expression were analyzed by immunohistochemistry. RhoA, ROCK, mTOR, AKT1, and PIK3CA mRNA expression were conducted using laser microdissection and semi-nested quantitative reverse transcription-polymerase chain reaction. RhoA expression was stronger on the tumor interface of IDCs than the tumor center (P<0.001). RhoA expression was correlated with ROCK expression only in HER2-subtype IDC (P<0.05). In IDCs co-expressing RhoA and ROCK, F-actin expression was stronger on the tumor interface, particularly at the edges of tumor cells, than it was in ROCK-negative IDCs (P<0.0001). In conclusion, RhoA expression was not correlated with EMT in IDC, but enhanced F-actin expression was localized on the edge of tumor cells that co-expressed ROCK. RhoA/ROCK signaling may be associated with collective cell invasion, particularly in HER2-subtype IDC.

Altered intracellular region of MUC1 and disrupted correlation of polarity-related molecules in breast cancer subtypes.

MUC1 glycoprotein is overexpressed and its intracellular localization altered during breast carcinoma tumorigenesis. The present study aimed to clarify the relationship of cytoplasmic localization of MUC1 with the breast cancer subtype and the correlation of 10 molecules associated with cell polarity in breast cancer subtypes. We immunostained 131 formalin-fixed and paraffin-embedded breast cancer specimens with an anti-MUC1 antibody (MUC1/CORE). For 48 of the 131 tumor specimens, laser-assisted microdissection and real-time quantitative RT-PCR were performed to analyze mRNA levels of MUC1 and 10 molecules, ß-catenin, E-cadherin, claudin 3, claudin 4, claudin 7, RhoA, cdc42, Rac1, Par3 and Par6. Localization of MUC1 protein varied among breast cancer subtypes, that is, both the apical domain and cytoplasm in luminal A-like tumors (P < 0.01) and both the cytoplasm and cell membrane in luminal B-like (growth factor receptor 2 [HER2]+) tumors (P < 0.05), and no expression was found in triple negative tumors (P < 0.001). Estrogen receptor (ER)+ breast cancers showed higher MUC1 mRNA levels than ER- breast cancers (P < 0.01). The incidence of mutual correlations of expression levels between two of the 10 molecules (55 combinations) was 54.5% in normal breast tissue and 38.2% in luminal A-like specimens, 16.4% in luminal B-like (HER2+), 3.6% in HER2 and 18.2% in triple negative specimens. In conclusion, each breast cancer subtype has characteristic cytoplasmic localization patterns of MUC1 and different degrees of disrupted correlation of the expression levels between the 10 examined molecules in comparison with normal breast tissue.

[A case of stromal sarcoma with multiple local recurrences].

A 53-year-old woman presented with a right breast lump identified approximately 6 months previously on palpation. Because the lump gradually increased in size, she initially visited a general practitioner who referred her to our hospital. Mammography and breast ultrasonography revealed a lesion in the right breast. Biopsy indicated a case of stromal sarcoma. Three months later, another lesion was detected, and simple mastectomy was performed. A recurrent lesion was detected after 1 month, and lumpectomy was performed. Another mass developed 1 month later, and extirpation was performed. After 1 month, another mass was detected, and extirpation was performed again. The stump was negative for lesions and recurrences. A thorough examination did not reveal metastasis to remote organs. There are no established therapies for stromal sarcoma. Surgical excision is undoubtedly indicated, as observed in this patient who showed multiple recurrent lesions despite the surgeries performed.

[A case of pityriasis rubra pilaris associated with rapidly progressive finger joint destruction].

A 40-year-old female noticed edema of the lower limbs in March 1995. Nephrotic syndrome due to membranous nephropathy was diagnosed and administration of high-dose corticosteroids resulted in incomplete remission. Progressively enlarging, red scaling skin lesions developed concomitantly from the scalp to the extremities. Pityriasis rubra pilaris (PRP) was diagnosed in 1996 in the Department of Dermatology at Sapporo Medical University hospital. Various treatments proved ineffective. Arthritis of the finger joints developed in July 1999, and proteinuria recurred in April 2000. She was admitted to our department in August 2000. Physical examination on admission revealed marked swelling of both distal interphalangeal (DIP) joints and the right fourth proximal interphalangeal (PIP) joint. Results of testing for antinuclear antibody, rheumatoid factor, and HLA-B27 were all negative. Radiography of the hands revealed destruction of the DIP and PIP joints where MRI indicated the presence of synovitis. Bone scintigraphy demonstrated accumulation in bilateral metatarso-phalangeal joints and the left sacroiliac joint. Arthritis associated with PRP was diagnosed, as both PRP and psoriasis represent keratinizing disorders of the skin and clinical features in the present case resembled those of psoriatic arthritis. Despite administration of high-dose corticosteroids, destruction of finger joints progressed rapidly. Administration of cyclosporine in April 2002 improved arthritic symptoms. Cases of PRP accompanied by arthritis need to be accumulated to allow analysis of the pathogenesis and clinical picture of this association.