A Phase I Dose Escalation Study of the Safety,Tolerability, and Pharmacokinetics of Ipilimumab in Chinese Patients with Select Advanced Solid Tumors

Lessons Learned

• The overall safety profiles of ipilimumab 3 mg/kg and 10 mg/kg administered every 3 weeks, were consistent between Chinese patients with solid tumors in the current study and patients from previous U.S. ipilimumab monotherapy studies. No new safety signals were identified.
• The mean systemic exposures to ipilimumab (assessed by first dose area under the curve during the dosing interval and maximum serum concentration) were numerically lower in the Chinese patient population than in U.S. patients for both 3 mg/kg and 10 mg/kg doses; however, the range of serum concentrations in the Chinese and U.S. populations overlapped (3 mg/kg and 10 mg/kg), suggesting that ipilimumab pharmacokinetics was ethnically insensitive in this study.

BackgroundThis phase I, open‐label study assessed ipilimumab safety, tolerability, pharmacokinetics (PK), immunogenicity, and antitumor activity in Chinese patients with unresectable, metastatic, recurrent malignant melanoma (MM) or nasopharyngeal carcinoma (NPC).MethodsOf 39 patients enrolled, 25 received ipilimumab (11 patients received 3 mg/kg, and 14 patients received 10 mg/kg). Reasons for not receiving treatment were withdrawal of consent (3 patients), no longer meeting the criteria (10 patients), and one recorded as “other.” During the induction phase, patients received ipilimumab (3 mg/kg, i.v.), on day 1 of a 3‐week cycle, to a maximum of four doses or progressive disease (PD). During the maintenance phase at week 24, patients received ipilimumab (3 mg/kg, i.v.) on day 1 of a 12‐week cycle, to a maximum of 3 years or PD. Considering the co‐primary safety and PK endpoints, the successive dosing required nine patients with two or fewer dose‐limiting toxicities during the 42‐day observation period to proceed with a new cohort of nine patients at 10 mg/kg.ResultsIpilimumab safety and PK profiles were similar in Chinese and predominantly White populations. Ipilimumab was well tolerated. Most adverse events (AEs) were grades 1–2 and experienced by 11 patients treated with 3 mg/kg and 14 patients treated with 10 mg/kg. There were no new safety concerns. Incidence of anti‐ipilimumab antibodies was low (1 of 10 in the 3 mg/kg patients and 2 of 13 in the 10 mg/kg patients) and without safety implications. In the 3 mg/kg group, 8 of 11 patients had PD. In the 10 mg/kg group (all NPC, 0 MM patients), 11 of 14 patients had PD. Three patients had stable disease (one at 3 mg/kg and two at 10 mg/kg).ConclusionIpilimumab was well tolerated in Chinese patients, showing similar safety and PK to previous studies in predominantly White populations.     

Left ventricular mass regression following aortic valve replacement with mechanical valves

Objective The degree of Left Ventricular Mass Index (LVMI) regression following aortic valve replacement correlates with long-term survival. This study aims to assess the extent of LVMI regression at 3 months following aortic valve replacement (AVR) with different types and sizes of mechanical valves in rheumatic aortic valve disease. Methods The LVMI regression was studied in 34 consecutive patients, undergoing elective AVR for rheumatic aortic stenosis and/or regurgitation. They were grouped in A and B, matched in age, body surface area and pre-operative LVMI, receiving respectively a tilting disc and a bileaflet mechanical valve. The LVMI was calculated by M-mode echocardiography using the Devereux' formula pre-operatively and three months post-operatively. The trend of LVMI reduction was compared between the two groups and amongst the patients with stenotic, regurgitant and mixed aortic valve, pathologies; and receiving different sizes of valves. Results The mean preoperative LVMI was 199g±79.5 g/m². At three months post aortic valve replacement, the mean LVMI was 130g±49.0 g/m². There was a significant reduction of LVMI post-operatively (p=0.001) at three months follow-up. The extent of LVMI regression following surgery amongst the groups A and B did not vary significantly (p=0.92). The extent of LVMI regression did not vary significantly in patients with different aortic valve pathology nor with different sizes of the valves implanted. Conclusions There is a significant early LVMI regression following aortic valve replacement in rheumatic aortic valve disease. The type and the size of the mechanical prosthesis or the rheumatic pathology do not appear to influence this regression.     

Endarterectomy as an adjunct to coronary artery bypass grafting

Between November 1988 and February 1992, 416 patients required coronary endarterectomy for diffuse coronary artery disease. This constitutes 16.19 per cent of all patients who underwent coronary artery bypass grafting during the same period. A total of 528 endarterectomies were performed. Four-hundred and twenty-two endarterectomies were performed on right coronary system and 106 endarterectomies were performed on left coronary system. One-hundred and twelve (26.92%) patients required more than one endarterectomies. The hospital mortality was 2.16 percent. 3.37 per cent of patients had perioperative infarction. Intraaortic balloon pump was required in 1.92 per cent of patients. 5.77 per cent of the patients had significant arrhythmias. The patients have been followed up for a mean period of 27 months. One-hundred and forty patients were evaluated by exercise multigated radionuclide angiogram. One-hundred and thirty-four (95.71%) patients showed increase in ejection fraction as compared to preoperative value. Six (4.29%) patients did not show any significant change while eight (5.71%) patients had fall in ejection fraction. Postoperative coronary angiogram was done in 44 patients at a mean of 10 months. 89.59 per cent of grafts to the endarterectomised vessels and 91.67% of grafts to nonendarterectomised vessel were patent. The difference between the two groups was not statistically significant.     

Normal colon of Sprague-Dawley rats

Summary The patterns of expression of the human-tumor-associated antigens, CO17-1A, GA73-3, BR55-2, GICA19-9, CA50 and carcino-embryonic antigen (CEA) were studied in the normal colonic mucosa (the last three also in the serum) of Sprague-Dawley rats. Four immunohistochemically different segments were identified: caecum, ascending colon, transverse colon and descending colon. The immunohistochemical reactions of the cells at the lower part of the crypt were essential for the distinction of the four segments. In the caecum, the MAbs 17-1A, 73-3 and 19-9 stained the glycocalyx of the cells of the lower part of the crypts and the Golgi apparatus of the intercalated cells (IC). MAb55-2 stained very weakly the goblet-like cells (GLC) of the lower part of the crypt of transverse colon, in addition to a nearly complete lack of reaction in the upper part of the crypts. In the ascending colon, the lower part of the crypts showed a characteristic diffuse staining of the intercalated cells with MAb55-2. The perinuclear and mucosal staining observed in the GLC of the transverse colon with MAbs 17-1A, 73-3 and 19-9 as against the supranuclear and Golgi zone staining observed in the GLC/goblet cells (GC)/columnar cells (CC) of the lower part of crypts of the descending colon with the same MAbs, distinguished the former segment from the latter. The IC demonstrated by immunohistochemistry in the lower parts of the crypts of caecum and ascending colon appear to correspond to the replicating cells of the colonic crypts.     

Hematological profile of HIV positive patients

A series of 500 HIV positive patients referred to our centre for CD4 and CD8 cell enumeration are included in this study. The following parameters were studied in each of these patients: Hb, RBC indicates, WBC count, platelet count, three part differential count, absolute CD4 and CD8 counts. Male:Female ratio of 4.9:1 was noted 30.8% patients has anemia (Hb<10 gm%), with an average Hb value of 8.1 gm%. The anemia was normochromic, normocytic in 61% of patients, microcytic in 33% and macrocytic in 6% patients. The absolute CD4 count was less than 200 ul in 50.2% patients with an average value of 92/ul. Thrombocytopenia was seen in 13% patients with average platelet count 0.92x10(3)/ul.     

Detection of medullary carcinoma of thyroid, with liver metastasis, using 99mTc DMSA(V) scintigraphy

A sixty year old female referred for thyroid and liver scintigraphy had a clinical history of progressive swelling in the neck with hepatomegaly. A large cold area was detected in the right thyroid lobe using 99mTc pertechnetate and in the right lobe of liver using 99mTc phytate. Subsequent whole body scan with 99mTC DMSA(V) showed avid tracer uptake in right lobe of thyroid and liver. Aspiration cytology of thyroid and liver showed medullary carcinoma of thyroid with its metastasis in liver. Histopathology following thyroidectomy confirmed the diagnosis. Thus 99mTc pentavalent DMSA contributes specificity to diagnose medullary carcinoma of thyroid and metastatic lesions.     

Shifting US Patterns of COVID-19 Mortality by Race and Ethnicity From June–December 2020

ObjectivesThe COVID-19 pandemic has disproportionately affected racial and ethnic minorities in the United States and has been devastating for residents of nursing homes (NHs). However, evidence on racial and ethnic disparities in COVID-19–related mortality rates within NHs and how that has changed over time has been limited. This study examines the impact of a high proportion of minority residents in NHs on COVID-19–related mortality rates over a 30-week period.DesignLongitudinal study.Setting and ParticipantsCenters for Medicare & Medicaid Services Nursing Home COVID-19 Public Use File data from 50 states from June 1, 2020, to December 27, 2020.MethodsWe linked data from 11,718 NHs to (1) Nursing Home Compare data, (2) the Long-Term Care: Facts on Care in the U.S., and (3) US county-level data on COVID cases and deaths. Our primary independent variable was proportion of minority residents (blacks and Hispanics) in NHs and its association with mortality rate over time.ResultsDuring the first 6 weeks from June 1, 2020, NHs with a higher proportion of black residents reported more COVID-19 deaths per 1000 followed by NHs with a higher proportion of Hispanic residents. Between 7 and 12 weeks, NHs with a higher proportion of Hispanic residents reported more deaths per 1000, followed by NHs with a higher proportion of black residents. However, after 23 weeks (mid-November 2020), NHs serving a higher proportion of white residents reported more deaths per 1000 than NHs serving a high proportion of black and Hispanic residents.Conclusions and ImplicationsThe disparities in COVID-19–related mortality for nursing homes serving minority residents is evident for the first 12 weeks of our study period. Policy interventions and the equitable distribution of vaccine are required to mitigate the impact of systemic racial injustice on health outcomes of people of color residing in NHs.